| 231. |
- 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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| 232. |
- Xia, Zhiyu, et al.
(författare)
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Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.
- 2020
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:10, s. 3563-3573
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ).CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
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| 233. |
- 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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| 234. |
- Chen, Dorothy M, et al.
(författare)
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Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer
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Ingår i: Human Genetics and Genomics Advances. - 2666-2477.
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Tidskriftsartikel (refereegranskat)abstract
- Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10 -6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10 -6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10 -6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability > 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.
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| 235. |
- Chen, Dorothy M, et al.
(författare)
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Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5): EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6 , and RP11-327J17.2 . Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.
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| 236. |
- Chou, Alisha, et al.
(författare)
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Association of Prostate-Specific Antigen Levels with Prostate Cancer Risk in a Multiethnic Population : Stability over Time and Comparison with Polygenic Risk Score
- 2022
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 31:12, s. 2199-2207
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer (PCa) development that may help to risk-stratify men earlier in life.METHODS: We examined PSA levels in men measured up to 10+ years before a PCa diagnosis in association with PCa risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for PCa.RESULTS: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a PCa OR (95% CIs) of 9.12 (7.66-10.92) and 3.52 (2.50-5.03), respectively, compared to men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason ≤7 vs. 8+ disease. At 10+ years, the association of PCa with PSA was comparable to that with the PRS (OR per SD increase: 1.88 (1.45-2.46) and 2.12 (1.55-2.93), respectively).CONCLUSIONS: We found PSA to be an informative marker of PCa risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable to a PRS when measured 10+ years before diagnosis.IMPACT: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in PCa screening practices.
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| 237. |
- Darst, Burcu F., et al.
(författare)
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The Four-Kallikrein Panel Is Effective in Identifying Aggressive Prostate Cancer in a Multiethnic Population
- 2020
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 29:7, s. 1381-1388
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups. METHODS: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA ≥2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups. RESULTS: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel. CONCLUSIONS: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel. IMPACT: Our multiethnic investigation suggests potential for the 4K panel to improve current prostate cancer screening practices.
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| 238. |
- 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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| 239. |
- Hawthorn, F., et al.
(författare)
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TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf
- 2023
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 520:3, s. 3649-3668
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Tidskriftsartikel (refereegranskat)abstract
- We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (T = 8.5 mag), high proper motion (∼200 mas yr−1), low metallicity ([Fe/H]≈−0.28) K-dwarf with a mass of 0.68 ± 0.05 M and a radius of 0.67 ± 0.01 R. We obtain photometric follow-up observations with a variety of facilities, and we use these data sets to determine that the inner planet, TOI-836 b, is a 1.70 ± 0.07 R super-Earth in a 3.82-d orbit, placing it directly within the so-called ‘radius valley’. The outer planet, TOI-836 c, is a 2.59 ± 0.09 R mini-Neptune in an 8.60-d orbit. Radial velocity measurements reveal that TOI-836 b has a mass of 4.5 ± 0.9 M, while TOI-836 c has a mass of 9.6 ± 2.6 M. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 min for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet.
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| 240. |
- Hoffmann, Thomas J, et al.
(författare)
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Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.
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