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2. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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3. |
- Arndt, D. S., et al.
(författare)
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State of the Climate in 2016
- 2017
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 98:8, s. S1-S280
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Tidskriftsartikel (refereegranskat)abstract
- In 2016, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-continued to increase and reach new record highs. The 3.5 +/- 0.1 ppm rise in global annual mean carbon dioxide from 2015 to 2016 was the largest annual increase observed in the 58-year measurement record. The annual global average carbon dioxide concentration at Earth's surface surpassed 400 ppm (402.9 +/- 0.1 ppm) for the first time in the modern atmospheric measurement record and in ice core records dating back as far as 800000 years. One of the strongest El Nino events since at least 1950 dissipated in spring, and a weak La Nina evolved later in the year. Owing at least in part to the combination of El Nino conditions early in the year and a long-term upward trend, Earth's surface observed record warmth for a third consecutive year, albeit by a much slimmer margin than by which that record was set in 2015. Above Earth's surface, the annual lower troposphere temperature was record high according to all datasets analyzed, while the lower stratospheric temperature was record low according to most of the in situ and satellite datasets. Several countries, including Mexico and India, reported record high annual temperatures while many others observed near-record highs. A week-long heat wave at the end of April over the northern and eastern Indian peninsula, with temperatures surpassing 44 degrees C, contributed to a water crisis for 330 million people and to 300 fatalities. In the Arctic the 2016 land surface temperature was 2.0 degrees C above the 1981-2010 average, breaking the previous record of 2007, 2011, and 2015 by 0.8 degrees C, representing a 3.5 degrees C increase since the record began in 1900. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 24 March, the sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, tying with 2015 at 7.2% below the 1981-2010 average. The September 2016 Arctic sea ice minimum extent tied with 2007 for the second lowest value on record, 33% lower than the 1981-2010 average. Arctic sea ice cover remains relatively young and thin, making it vulnerable to continued extensive melt. The mass of the Greenland Ice Sheet, which has the capacity to contribute similar to 7 m to sea level rise, reached a record low value. The onset of its surface melt was the second earliest, after 2012, in the 37-year satellite record. Sea surface temperature was record high at the global scale, surpassing the previous record of 2015 by about 0.01 degrees C. The global sea surface temperature trend for the 21st century-to-date of +0.162 degrees C decade(-1) is much higher than the longer term 1950-2016 trend of +0.100 degrees C decade(-1). Global annual mean sea level also reached a new record high, marking the sixth consecutive year of increase. Global annual ocean heat content saw a slight drop compared to the record high in 2015. Alpine glacier retreat continued around the globe, and preliminary data indicate that 2016 is the 37th consecutive year of negative annual mass balance. Across the Northern Hemisphere, snow cover for each month from February to June was among its four least extensive in the 47-year satellite record. Continuing a pattern below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska and at the Canadian observatory on northernmost Ellesmere Island. In the Antarctic, record low monthly surface pressures were broken at many stations, with the southern annular mode setting record high index values in March and June. Monthly high surface pressure records for August and November were set at several stations. During this period, record low daily and monthly sea ice extents were observed, with the November mean sea ice extent more than 5 standard deviations below the 1981-2010 average. These record low sea ice values contrast sharply with the record high values observed during 2012-14. Over the region, springtime Antarctic stratospheric ozone depletion was less severe relative to the 1991-2006 average, but ozone levels were still low compared to pre-1990 levels. Closer to the equator, 93 named tropical storms were observed during 2016, above the 1981-2010 average of 82, but fewer than the 101 storms recorded in 2015. Three basins-the North Atlantic, and eastern and western North Pacific-experienced above-normal activity in 2016. The Australian basin recorded its least active season since the beginning of the satellite era in 1970. Overall, four tropical cyclones reached the Saffir-Simpson category 5 intensity level. The strong El Nino at the beginning of the year that transitioned to a weak La Nina contributed to enhanced precipitation variability around the world. Wet conditions were observed throughout the year across southern South America, causing repeated heavy flooding in Argentina, Paraguay, and Uruguay. Wetter-than-usual conditions were also observed for eastern Europe and central Asia, alleviating the drought conditions of 2014 and 2015 in southern Russia. In the United States, California had its first wetter-than-average year since 2012, after being plagued by drought for several years. Even so, the area covered by drought in 2016 at the global scale was among the largest in the post-1950 record. For each month, at least 12% of land surfaces experienced severe drought conditions or worse, the longest such stretch in the record. In northeastern Brazil, drought conditions were observed for the fifth consecutive year, making this the longest drought on record in the region. Dry conditions were also observed in western Bolivia and Peru; it was Bolivia's worst drought in the past 25 years. In May, with abnormally warm and dry conditions already prevailing over western Canada for about a year, the human-induced Fort McMurray wildfire burned nearly 590000 hectares and became the costliest disaster in Canadian history, with $3 billion (U.S. dollars) in insured losses.
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4. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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5. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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6. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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7. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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8. |
- Seyed Khoei, Nazlisadat, et al.
(författare)
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Circulating bilirubin levels and risk of colorectal cancer : serological and Mendelian randomization analyses
- 2020
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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9. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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10. |
- Aglago, Elom K., et al.
(författare)
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A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
- 2023
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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11. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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12. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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13. |
- Guo, Xingyi, et al.
(författare)
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Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects
- 2020
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Ingår i: Gastroenterology. - : Elsevier. - 0016-5085 .- 1528-0012. ; 160:4, s. 1164-1178
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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14. |
- Khankari, Nikhil K, et al.
(författare)
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Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.
- 2020
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 29:4, s. 860-870
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.METHODS: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.RESULTS: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.CONCLUSIONS: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.IMPACT: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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15. |
- Lindström, Sara, et al.
(författare)
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Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
- 2023
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:6, s. 712-732
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
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16. |
- Murphy, Neil, et al.
(författare)
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Body mass index and molecular subtypes of colorectal cancer
- 2023
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:2, s. 165-173
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease.Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables.Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m(2) = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control).Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
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17. |
- Papadimitriou, Nikos, et al.
(författare)
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Body size and risk of colorectal cancer molecular defined subtypes and pathways : mendelian randomization analyses
- 2024
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 101
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain.Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO).Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03).Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4).Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.
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18. |
- Papadimitriou, Nikos, et al.
(författare)
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Physical activity and risks of breast and colorectal cancer : a Mendelian randomisation analysis
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value=0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value=0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers. Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
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19. |
- Payer, Stefan E., et al.
(författare)
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Regioselective para-Carboxylation of Catechols with a Prenylated Flavin Dependent Decarboxylase
- 2017
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 56:44, s. 13893-13897
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Tidskriftsartikel (refereegranskat)abstract
- The utilization of CO2 as a carbon source for organic synthesis meets the urgent demand for more sustainability in the production of chemicals. Herein, we report on the enzyme-catalyzed para-carboxylation of catechols, employing 3,4-dihydroxybenzoic acid decarboxylases (AroY) that belong to the UbiD enzyme family. Crystal structures and accompanying solution data confirmed that AroY utilizes the recently discovered prenylated FMN (prFMN) cofactor, and requires oxidative maturation to form the catalytically competent prFMN(iminium) species. This study reports on the in vitro reconstitution and activation of a prFMN-dependent enzyme that is capable of directly carboxylating aromatic catechol substrates under ambient conditions. A reaction mechanism for the reversible decarboxylation involving an intermediate with a single covalent bond between a quinoid adduct and cofactor is proposed, which is distinct from the mechanism of prFMN-associated 1,3-dipolar cycloadditions in related enzymes.
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20. |
- Schijven, Dick, et al.
(författare)
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Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:14
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Tidskriftsartikel (refereegranskat)abstract
- Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
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21. |
- Thomas, Minta, et al.
(författare)
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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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22. |
- Thomas, Minta, et al.
(författare)
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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
- 2020
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Ingår i: American Journal of Human Genetics. - Cambridge : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:3, s. 432-444
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Tidskriftsartikel (refereegranskat)abstract
- Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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23. |
- Thomas, Minta, et al.
(författare)
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Response to Li and Hopper
- 2021
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 108:3, s. 527-529
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Tidskriftsartikel (refereegranskat)
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24. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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25. |
- Tian, Yu, et al.
(författare)
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Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
- 2024
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130:10, s. 1687-1696
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Tidskriftsartikel (refereegranskat)abstract
- Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
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26. |
- Tian, Yu, et al.
(författare)
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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:8, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
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27. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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28. |
- Tsilidis, Konstantinos K., et al.
(författare)
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Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent : a Mendelian randomization study
- 2021
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Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 113:6, s. 1490-1502
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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29. |
- Aglago, Elom K., et al.
(författare)
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Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing
- 2024
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier. - 0002-9165 .- 1938-3207.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing.Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors.Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways.Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.
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30. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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31. |
- Bouras, Emmanouil, et al.
(författare)
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Genome-wide interaction analysis of folate for colorectal cancer risk
- 2023
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier. - 0002-9165 .- 1938-3207. ; 118:5, s. 881-891
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
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32. |
- Bouras, Emmanouil, et al.
(författare)
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Identification of potential mediators of the relationship between body mass index and colorectal cancer : a Mendelian randomization analysis
- 2024
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 53:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC.Methods: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR–Egger, Contamination Mixture). We used multivariable MR for the mediation analyses.Results: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) ¼ 1.17, 95% CI: 1.08–1.24, P-value ¼ 1.4 × 10−5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2–13%) of the association], smoking (31%, 4–57%) and PA (7%, 2–11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA.Conclusions: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI–CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.
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33. |
- Bull, Caroline J., et al.
(författare)
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Adiposity, metabolites, and colorectal cancer risk : Mendelian randomization study
- 2020
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Ingår i: BMC Medicine. - : BMC. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m(2)) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m(2)) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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34. |
- Carreras-Torres, Robert, et al.
(författare)
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Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation, and immune response
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 315-328
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33).CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response.IMPACT: These findings can guide potential prevention treatments.
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35. |
- Curtis, Bruce A., et al.
(författare)
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Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7427, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.
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36. |
- de Zwarte, Sonja M. C., et al.
(författare)
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Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 414-430
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Tidskriftsartikel (refereegranskat)abstract
- First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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37. |
- de Zwarte, Sonja M. C., et al.
(författare)
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The association between familial risk and brain abnormalities is disease specific : an ENIGMA-relatives study of schizophrenia and bipolar disorder
- 2019
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 86:7, s. 545-556
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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38. |
- Dimou, Niki, et al.
(författare)
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Causal effects of lifetime smoking on breast and colorectal cancer risk: Mendelian randomization study
- 2021
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 30:5, s. 953-964
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Tidskriftsartikel (refereegranskat)abstract
- Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking (n ¼ 126 variants) and ever having smoked regularly (n ¼ 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/ 105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00–1.26; P ¼ 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor–positive and estrogen receptor–negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04–1.40; P ¼ 0.01), colon cancer (OR, 1.31; 95% CI, 1.11–1.55; P < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07–1.73; P ¼ 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90–1.14; P ¼ 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86–1.10; P ¼ 0.68).Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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39. |
- Drew, David A., et al.
(författare)
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Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
- 2024
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:22
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Tidskriftsartikel (refereegranskat)abstract
- Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
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40. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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41. |
- Jarvik, Gail P., et al.
(författare)
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Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis
- 2020
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Ingår i: Human Genetics and Genomics Advances. - : Cell press. - 2666-2477. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91–1.29; p = 0.4) and 1.01 (95% CI, 0.78–1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.
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42. |
- Maxwell, Christopher A., et al.
(författare)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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43. |
- Murphy, Neil, et al.
(författare)
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Associations between Glycemic Traits and Colorectal Cancer : A Mendelian Randomization Analysis
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 114:5, s. 740-752
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycemic traits - such as hyperinsulinemia, hyperglycemia, and type 2 diabetes - have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. Methods: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). Results: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. Conclusions: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
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44. |
- Murphy, Neil, et al.
(författare)
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Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1300-1312.e20
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls])Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; P = 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; P = 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
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45. |
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46. |
- Nounu, Aayah, et al.
(författare)
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A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer
- 2021
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : Elsevier. - 1055-9965 .- 1538-7755. ; 30:3, s. 564-575
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence for aspirin’s chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively).Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin’s reduction of metastasis.Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
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47. |
- Nounu, Aayah, et al.
(författare)
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Salicylic Acid and Risk of Colorectal Cancer : A Two-Sample Mendelian Randomization Study
- 2021
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
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48. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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49. |
- Shu, Xiang, et al.
(författare)
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Large-scale Integrated Analysis of Genetics and Metabolomic Data Reveals Potential Links Between Lipids and Colorectal Cancer Risk
- 2022
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 31:6, s. 1216-1226
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Tidskriftsartikel (refereegranskat)abstract
- Background: The etiology of colorectal cancer is not fully understood.Methods: Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis.Results: Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini-Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60−2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99−1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer.Conclusions: This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data.Impact: The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
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50. |
- Su, Yu-Ru, et al.
(författare)
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Validation of a genetic-enhanced risk prediction model for colorectal cancer in a large community-based cohort
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 353-362
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance.METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group).RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity.CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort.IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.
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