1. |
- Aglago, Elom K., et al.
(author)
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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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In: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
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Journal article (peer-reviewed)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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2. |
- Archambault, Alexi N., et al.
(author)
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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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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Journal article (peer-reviewed)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. |
- Aschard, Hugues, et al.
(author)
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Evidence for large-scale gene-by-smoking interaction effects on pulmonary function
- 2017
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 46:3, s. 894-904
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Journal article (peer-reviewed)abstract
- BACKGROUND: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.METHODS: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.RESULTS: We identified an interaction (βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV 1: /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.CONCLUSIONS: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.
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4. |
- Barrdahl, Myrto, et al.
(author)
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Association of breast cancer risk loci with breast cancer survival
- 2015
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In: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 137:12, s. 2837-2845
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Journal article (peer-reviewed)abstract
- The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS (HRper-allele=0.70; 95% CI: 0.58-0.85; ptrend=2.84 x 10-4; HRheterozygotes=0.71; 95% CI: 0.55-0.92; HRhomozygotes=0.48; 95% CI: 0.31-0.76; p2DF=1.45 x 10-3). In silico, the C allele of LSP1-rs3817198 was predicted to increase expression of the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C). In the meta-analysis, TNRC9-rs3803662 was significantly associated with increased death hazard (HRMETA =1.09; 95% CI: 1.04-1.15; ptrend=6.6 x 10-4; HRheterozygotes=0.96 95% CI: 0.90-1.03; HRhomozygotes=1.21; 95% CI: 1.09-1.35; p2DF=1.25 x 10-4). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1-rs3817198 and TNRC9-rs3803662.What's new? Genetic factors are known to influence the risk of breast cancer, but inherited genetic variation may also affect disease prognosis and response to treatment. In this study, the we investigated whether single nucleotide polymorphisms (SNPs) that are known to be associated with breast cancer risk might also influence the survival of breast-cancer patients. While two of the investigated SNPs may influence survival, there was otherwise no indication that SNP alleles related to breast cancer risk also play a role in the survival of breast cancer patients.
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5. |
- Barrdahl, Myrto, et al.
(author)
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Post-G WAS gene-environment interplay in breast cancer : results from the Breast and Prostate Cancer Cohort Consortium and a meta-analysis on 79 000 women
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:19, s. 5260-5270
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Journal article (peer-reviewed)abstract
- We studied the interplay between 39 breast cancer (BC) risk SNPs and established BC risk (body mass index, height, age at menarche, parity, age at menopause, smoking, alcohol and family history of BC) and prognostic factors (TNM stage, tumor grade, tumor size, age at diagnosis, estrogen receptor status and progesterone receptor status) as joint determinants of BC risk. We used a nested case-control design within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), with 16 285 BC cases and 19 376 controls. We performed stratified analyses for both the risk and prognostic factors, testing for heterogeneity for the risk factors, and case-case comparisons for differential associations of polymorphisms by subgroups of the prognostic factors. We analyzed multiplicative interactions between the SNPs and the risk factors. Finally, we also performed a meta-analysis of the interaction ORs from BPC3 and the Breast Cancer Association Consortium. After correction for multiple testing, no significant interaction between the SNPs and the established risk factors in the BPC3 study was found. The meta-analysis showed a suggestive interaction between smoking status and SLC4A7-rs4973768 (P-interaction = 8.84 x 10(-4)) which, although not significant after considering multiple comparison, has a plausible biological explanation. In conclusion, in this study of up to almost 79 000 women we can conclusively exclude any novel major interactions between genome-wide association studies hits and the epidemiologic risk factors taken into consideration, but we propose a suggestive interaction between smoking status and SLC4A7-rs4973768 that if further replicated could help our understanding in the etiology of BC.
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6. |
- Bouras, Emmanouil, et al.
(author)
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Genome-wide interaction analysis of folate for colorectal cancer risk
- 2023
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In: American Journal of Clinical Nutrition. - : Elsevier. - 0002-9165 .- 1938-3207. ; 118:5, s. 881-891
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Journal article (peer-reviewed)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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7. |
- Campa, Daniele, et al.
(author)
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Genetic risk variants associated with in situ breast cancer
- 2015
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 17
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Journal article (peer-reviewed)abstract
- Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.
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8. |
- Chen, Zhishan, et al.
(author)
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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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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)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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9. |
- Drew, David A., et al.
(author)
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Aspirin and NSAID use and the risk of COVID-19
- 2021
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Other publication (other academic/artistic)abstract
- Early reports raised concern that use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19). Users of the COVID Symptom Study smartphone application reported use of aspirin and other NSAIDs between March 24 and May 8, 2020. Users were queried daily about symptoms, COVID-19 testing, and healthcare seeking behavior. Cox proportional hazards regression was used to determine the risk of COVID-19 among according to aspirin or non-aspirin NSAID users. Among 2,736,091 individuals in the U.S., U.K., and Sweden, we documented 8,966 incident reports of a positive COVID-19 test over 60,817,043 person-days of follow-up. Compared to non-users and after stratifying by age, sex, country, day of study entry, and race/ethnicity, non-aspirin NSAID use was associated with a modest risk for testing COVID-19 positive (HR 1.23 [1.09, 1.32]), but no significant association was observed among aspirin users (HR 1.13 [0.92, 1.38]). After adjustment for lifestyle factors, comorbidities and baseline symptoms, any NSAID use was not associated with risk (HR 1.02 [0.94, 1.10]). Results were similar for those seeking healthcare for COVID-19 and were not substantially different according to lifestyle and sociodemographic factors or after accounting for propensity to receive testing. Our results do not support an association of NSAID use, including aspirin, with COVID-19 infection. Previous reports of a potential association may be due to higher rates of comorbidities or use of NSAIDs to treat symptoms associated with COVID-19.One Sentence Summary NSAID use is not associated with COVID-19 risk.Competing Interest StatementJW, RD, and JC are employees of Zoe Global Ltd. TDS is a consultant to Zoe Global Ltd. DAD and ATC previously served as investigators on a clinical trial of diet and lifestyle using a separate mobile application that was supported by Zoe Global Ltd. Other authors have no conflict of interest to declare.Clinical TrialNCT04331509Funding StatementZoe provided in kind support for all aspects of building running and supporting the app and service to all users worldwide. DAD is supported by the National Institute of Diabetes and Digestive and Kidney Diseases K01DK120742. CGG is supported by the Bau Tsu Zung Bau Kwan Yeu Hing Research and Clinical Fellowship. LHN is supported by the American Gastroenterological Association Research Scholars Award. ATC is the Stuart and Suzanne Steele MGH Research Scholar and Stand Up to Cancer scientist. The Massachusetts Consortium on Pathogen Readiness (MassCPR) and Mark and Lisa Schwartz supported MGH investigators (DAD CGG LHN ADJ WM RSM CHL SK ATC). CMA is supported by the NIDDK K23 DK120899 and the Boston Childrens Hospital Office of Faculty Development Career Development Award. Kings College of London investigators (KAL MNL TV MSG CHS SO CJS TDS) were supported by the Wellcome Trust and EPSRC (WT212904/Z/18/Z WT203148/Z/16/Z T213038/Z/18/Z) the NIHR GSTT/KCL Biomedical Research Centre MRC/BHF (MR/M016560/1) UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare and the Alzheimers Society (AS-JF-17-011). MNL is supported by an NIHR Doctoral Fellowship (NIHR300159). Work related to the Swedish elements of the study are supported by grants from the Swedish Research Council, Swedish Heart-Lung Foundation and the Swedish Foundation for Strategic Research (LUDC-IRC 15-0067). Sponsors had no role in study design analysis and interpretation of data report writing and the decision to submit for publication.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Participants provided informed consent to the use of app data for research purposes and agreed to privacy policies and terms of use. This research study was approved by the Partners Human Research Committee IRB 2020P000909 Kings College London Ethics Committee REMAS ID 18210 Review Reference LRS-19/20-18210 and the central ethics committee in Sweden DNR 2020-01803All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData collected in the app is being shared with other health researchers through the NHS-funded Health Data Research U.K. (HDRUK)/SAIL consortium, housed in the U.K. Secure Research Platform (UKSeRP) in Swansea. Anonymized data is available to be shared with bonafide researchers HDRUK according to their protocols (https://healthdatagateway.org/detail/9b604483-9cdc-41b2-b82c-14ee3dd705f6). U.S. investigators are encouraged to coordinate data requests through the COPE Consortium (www.monganinstitute.org/cope-consortium). Data updates can be found on https://covid.joinzoe.com.
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10. |
- Emilsson, Louise, 1982-, et al.
(author)
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Gall Bladder Disease and the Risk of Small Bowel Cancer : Results from a Nationwide Swedish Cohort Study
- 2022
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In: Cancers. - : MDPI. - 2072-6694. ; 14:3
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Small bowel cancer is a rare but rising malignancy. The etiology is poorly understood and there is a need for large-scale studies. Gallbladder disease (GBD), inducing localized inflammation, has been suggested to increase small bowel cancer risk.METHODS: We retrieved nationwide data from Sweden's 28 pathology departments on all adults (age 20-79) with pathology-confirmed GBD diagnosed in 1965-2017. In total 156,390 GBD patients were matched with up to 5 matched comparators from the general population and follow-up started one year after GBD diagnosis. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids.RESULTS: During a median follow-up of 12 years, we identified 92 small bowel adenocarcinomas, 132 adenomas, and 81 carcinoid tumors in the GBD cohort. Corresponding incidence rates were 4.8, 6.9, and 4.2 per 100,000 person-years (PY), compared to 3.2, 3.2, and 1.8 in matched comparators. The adjusted HR was 1.42 (95% CI = 1.08-1.87) for small bowel adenocarcinoma, 1.79 (95% CI = 1.41-2.27) for adenoma, and 2.07 (95% CI = 1.52-2.81) for carcinoid. The excess cancer risk was most pronounced during the first year of follow-up for adenocarcinomas and during the first six years for adenomas while for carcinoids the HR peaked 10-15 years after start of follow-up.CONCLUSIONS: In this nationwide cohort study, GBD was associated with an increased risk of small bowel cancer. The excess risk of small bowel adenocarcinoma was mainly seen during the first years of follow-up while small bowel carcinoid risk peaked 11-16 years after GBD diagnosis.
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11. |
- Fernandez-Rozadilla, Ceres, et al.
(author)
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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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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Journal article (peer-reviewed)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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12. |
- Gaudet, Mia M., et al.
(author)
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Interactions between breast cancer susceptibility loci and menopausal hormone therapy in relationship to breast cancer in the Breast and Prostate Cancer Cohort Consortium
- 2016
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 155:3, s. 531-540
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Journal article (peer-reviewed)abstract
- Current use of menopausal hormone therapy (MHT) has important implications for postmenopausal breast cancer risk, and observed associations might be modified by known breast cancer susceptibility loci. To provide the most comprehensive assessment of interactions of prospectively collected data on MHT and 17 confirmed susceptibility loci with invasive breast cancer risk, a nested case-control design among eight cohorts within the NCI Breast and Prostate Cancer Cohort Consortium was used. Based on data from 13,304 cases and 15,622 controls, multivariable-adjusted logistic regression analyses were used to estimate odds ratios (OR) and 95 % confidence intervals (CI). Effect modification of current and past use was evaluated on the multiplicative scale. P values < 1.5 x 10(-3) were considered statistically significant. The strongest evidence of effect modification was observed for current MHT by 9q31-rs865686. Compared to never users of MHT with the rs865686 GG genotype, the association between current MHT use and breast cancer risk for the TT genotype (OR 1.79, 95 % CI 1.43-2.24; P (interaction) = 1.2 x 10(-4)) was less than expected on the multiplicative scale. There are no biological implications of the sub-multiplicative interaction between MHT and rs865686. Menopausal hormone therapy is unlikely to have a strong interaction with the common genetic variants associated with invasive breast cancer.
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13. |
- Huyghe, Jeroen R., et al.
(author)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Journal article (peer-reviewed)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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14. |
- Huyghe, Jeroen R, et al.
(author)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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In: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Journal article (peer-reviewed)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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15. |
- Joshi, Amit D., et al.
(author)
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Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium
- 2014
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In: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 180:10, s. 1018-1027
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Journal article (peer-reviewed)abstract
- Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 x 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.
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16. |
- Joshi, Deepika, et al.
(author)
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Why IoT Enablement of Agrifood Transportation Disappoints Its Stakeholders: Unravelling Barriers for Enhanced Logistics
- 2024
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In: Journal of Food Quality. - 0146-9428. ; 2024:1
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Journal article (peer-reviewed)abstract
- The present research work investigates the barriers of weak IoT adoption in agrifood transportation, with special reference to India. It is built on a premise that few barriers upshots from the other more impactful ones. Thus, it is important to identify their linkages and classify them based on their strength of relationship. The data collected from 13 agricultural technology (AgriTech) firms of India were subjected to integrated techniques of M-TISM and Fuzzy MICMAC. As a result, a unique position of autonomous, dependent, linkage, and independent barriers was obtained which revealed that inadequate Internet connectivity, interoperability, and unclear roadmaps are precarious to the use of IoT in agrifood transportation. They are responsible for creating issues like data processing, vehicle tracking, and data privacy. This study offers a contextual phenomenon of barriers that may assist AgriTech stakeholders in developing appropriate strategies to embrace IoT transformation. It extends the theoretical literature by providing critical connections that aspiring researchers can examine through hypothesis testing or building a hierarchical framework. A sensitivity analysis is suggested to optimise decision-making and bring out a robust and reliable set of obstacles.
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17. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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18. |
- Khankari, Nikhil K, et al.
(author)
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Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.
- 2020
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In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 29:4, s. 860-870
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Journal article (peer-reviewed)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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19. |
- Khawaja, Tasveer, et al.
(author)
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Coronary artery calcium, hepatic steatosis, and atherosclerotic cardiovascular disease risk in patients with type 2 diabetes mellitus: Results from the Dallas heart study
- 2023
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In: Progress in cardiovascular diseases. - : W B SAUNDERS CO-ELSEVIER INC. - 0033-0620 .- 1873-1740. ; 78, s. 67-73
-
Research review (peer-reviewed)abstract
- Introduction: Cardiovascular disease (CVD) risk amongst those with type 2 diabetes (T2D) is heterogenous. The role of imaging-based cardiometabolic biomarkers (e.g., coronary artery calcium [CAC] score, and hepatic triglyceride content [HTC]) in CVD risk stratification in T2D is unclear. To better understand this, we sought to evaluate the individual and joint associations between CAC and hepatic steatosis (HS) with clinical atherosclerotic CVD (ASCVD) in Dallas Heart Study (DHS) participants with and without T2D. Methods: We examined participants in the DHS, a multi-ethnic cohort study, without self-reported ASCVD. CAC scoring was performed via computed tomography with the mean of two consecutive scores used. HTC was measured using magnetic resonance spectroscopy, and HS was defined as HTC >5.5% The primary outcome was incident ASCVD, defined as coronary heart disease (CHD; myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft surgery), ischemic stroke, transient ischemic attack, or CVD death. Cox regression analyses, and interaction testing was performed to evaluate the individual and joint associations between CAC and HS with ASCVD. The association between HS and coronary heart disease was validated in the UK Biobank (UKB).Results: A total of 1252 DHS participants were included with mean age 44.8 & PLUSMN; 9.3 years, mean body mass index 28.7 & PLUSMN; 5.9 kg/m2, 55% female, and 59% black with an overall prevalence of T2D of 9.7%. CAC scores were significantly higher (p < 0.01) and HS was significantly more prevalent in those with T2D (p < 0.01). Over a median of 12.3 years, 8.3% of participants experienced ASCVD events. The ASCVD event rate was significantly higher in participants with T2D (20.5% vs 7.0%, p < 0.01). Continuous CAC was associated with ASCVD events in the overall cohort regardless of T2D status with a significant interaction present between CAC and T2D status on ASCVD, Pinteraction = 0.02. HTC was not associated with ASCVD risk in participants without T2D but was inversely associated with risk in participants with T2D (HR 0.91, 95% CI 0.83-0.99 per 1% increase in HTC, p = 0.02), Pinteraction = 0.02. Amongst 37,266 UKB participants, 4.5% had T2D. CHD events occurred in 2.2% of participants, with 10.2% of events occurring amongst those with T2D. An inverse relationship between HTC and CHD was also found amongst those with T2D in UKB with a significant interaction between T2D status and HTC on CHD (HR per 1% increase in HTC 0.95, 95% CI 0.91-0.99, p = 0.01, Pinteraction = 0.02).Conclusions: In the DHS, we found that CAC was associated with ASCVD risk independent of T2D status. We did not observe an association between HTC and ASCVD in participants without T2D, but there was an inverse association between HTC and ASCVD in those with T2D that was replicated in the UKB cohort. Further investigation is warranted to understand the possible protective association of HS in participants with T2D.& COPY; 2023 Elsevier Inc. All rights reserved.
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20. |
- Lee, Karla A., et al.
(author)
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Cancer and Risk of COVID-19 Through a General Community Survey
- 2021
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In: The Oncologist. - : Oxford University Press (OUP). - 1083-7159 .- 1549-490X. ; 26:1
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Journal article (peer-reviewed)abstract
- Individuals with cancer may be at high risk for coronavirus disease 2019 (COVID-19) and adverse outcomes. However, evidence from large population-based studies examining whether cancer and cancer-related therapy exacerbates the risk of COVID-19 infection is still limited. Data were collected from the COVID Symptom Study smartphone application since March 29 through May 8, 2020. Among 23,266 participants with cancer and 1,784,293 without cancer, we documented 10,404 reports of a positive COVID-19 test. Compared with participants without cancer, those living with cancer had a 60% increased risk of a positive COVID-19 test. Among patients with cancer, current treatment with chemotherapy or immunotherapy was associated with a 2.2-fold increased risk of a positive test. The association between cancer and COVID-19 infection was stronger among participants >65 years and males. Future studies are needed to identify subgroups by tumor types and treatment regimens who are particularly at risk for COVID-19 infection and adverse outcomes.
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21. |
- Maret-Ouda, John, et al.
(author)
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Appendectomy and future risk of microscopic colitis : a population-based case-control study in Sweden
- 2023
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In: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 21:2, s. 467-475.e2
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Microscopic colitis (MC) is an inflammatory bowel disease and a common cause of chronic diarrhea. Appendectomy has been suggested to have immunomodulating effects in the colon, influencing the risk of gastrointestinal disease. The relationship between appendectomy and MC has only been sparsely studied.METHODS: This was a case-control study based on the nationwide ESPRESSO cohort, consisting of histopathological examinations in Sweden, linked to national registers. Patients with MC were matched to population controls by age, sex, calendar year of biopsy and county of residence. Data on antecedent appendectomy and comorbidities were retrieved from the Patient Register. Unconditional logistic regression models were conducted presenting odds ratios (ORs) and 95% confidence intervals (Cl) adjusted for country of birth and matching factors. Further sub-analyses were made based on MC subtypes (lymphocytic colitis [LC] and collagenous colitis [CC]), follow-up time post appendectomy and severity of appendicitis.RESULTS: The study included 14,520 cases of MC and 69,491 controls, among these 7.6% (n=1,103) and 5.1% (n=3,510), respectively, had a previous appendectomy ≥1 year prior to MC/matching date. Patients with a previous appendectomy had an increased risk of MC in total (OR 1.50, 95% CI 1.40-1.61); and per subtype CC (OR 1.67, 95% CI 1.48-1.88), LC (OR 1.42, 95% CI 1.30-1.55). The risk remained elevated throughout follow-up, and the highest risk was observed in non-complicated appendicitis.CONCLUSIONS: This nationwide case-control study found a modestly increased risk of developing MC following appendectomy.
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22. |
- McNabb, Sarah, et al.
(author)
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Meta-analysis of 16 studies of the association of alcohol with colorectal cancer
- 2020
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:3, s. 861-873
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Journal article (peer-reviewed)abstract
- Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (<= 1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
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23. |
- Merino, Jordi, et al.
(author)
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Diet quality and risk and severity of COVID-19 : a prospective cohort study
- 2021
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70:11, s. 2096-2104
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Poor metabolic health and unhealthy lifestyle factors have been associated with risk and severity of COVID-19, but data for diet are lacking. We aimed to investigate the association of diet quality with risk and severity of COVID-19 and its interaction with socioeconomic deprivation. DESIGN: We used data from 592 571 participants of the smartphone-based COVID-19 Symptom Study. Diet information was collected for the prepandemic period using a short food frequency questionnaire, and diet quality was assessed using a healthful Plant-Based Diet Score, which emphasises healthy plant foods such as fruits or vegetables. Multivariable Cox models were fitted to calculate HRs and 95% CIs for COVID-19 risk and severity defined using a validated symptom-based algorithm or hospitalisation with oxygen support, respectively. RESULTS: Over 3 886 274 person-months of follow-up, 31 815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR 0.91; 95% CI 0.88 to 0.94) and severe COVID-19 (HR 0.59; 95% CI 0.47 to 0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (Pinteraction=0.005). The corresponding absolute excess rate per 10 000 person/months for lowest vs highest quartile of diet score was 22.5 (95% CI 18.8 to 26.3) among persons living in areas with low deprivation and 40.8 (95% CI 31.7 to 49.8) among persons living in areas with high deprivation. CONCLUSIONS: A diet characterised by healthy plant-based foods was associated with lower risk and severity of COVID-19. This association may be particularly evident among individuals living in areas with higher socioeconomic deprivation.
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24. |
- Mondul, Alison M., et al.
(author)
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Vitamin D-Associated Genetic Variation and Risk of Breast Cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)
- 2015
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In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:3, s. 627-630
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Journal article (peer-reviewed)abstract
- Background: Two recent genome-wide association studies (GWAS) identified SNPs in or near four genes related to circulating 25-hydroxyvitamin D [25(OH) D] concentration. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25 (OH) D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. Results: We found no association between any of the four SNPs or their polygenic score and breast cancer risk. Conclusions: Our findings do not support an association between vitamin D status, as reflected by 25(OH) D-related genotypes, and breast cancer risk. Impact: These findings may contribute to future meta-analyses and scientific review articles, and provide new data about the association between vitamin D-related genes and breast cancer.
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25. |
- Nguyen, Long H., et al.
(author)
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Antibiotic use and the development of inflammatory bowel disease : a national case-control study in Sweden
- 2020
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In: The Lancet Gastroenterology & Hepatology. - : Elsevier. - 2468-1253. ; 5:11, s. 986-995
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Journal article (peer-reviewed)abstract
- Background: Use of antibiotics in early life has been linked with childhood inflammatory bowel disease (IBD), but data for adults are mixed, and based on smaller investigations that did not compare risk among siblings with shared genetic or environmental risk factors. We aimed to investigate the association between antibiotic therapy and IBD in a large, population-based study.Methods: In this prospective case-control study, we identified people living in Sweden aged 16 years or older, with a diagnosis of IBD based on histology and at least one diagnosis code for IBD or its subtypes (ulcerative colitis and Crohn's disease). We identified consecutive patients with incident IBD from the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, cross-referenced with the Swedish Patient Register and the Prescribed Drug Register. We accrued data for cumulative antibiotic dispensations until 1 year before time of matching for patients and up to five general population controls per patient (matched on the basis of age, sex, county, and calendar year). We also included unaffected full siblings as a secondary control group. Conditional logistic regression was used to estimate multivariable-adjusted odds ratios (aORs) and 95% CIs for diagnosis of incident IBD.Findings: We identified 23 982 new patients with IBD (15 951 ulcerative colitis, 7898 Crohn's disease, 133 unclassified IBD) diagnosed between Jan 1, 2007, and Dec 31, 2016. 117 827 matched controls and 28 732 siblings were also identified. After adjusting for several risk factors, aOR in patients who had used antibiotics versus those who had never used antibiotics was 1.88 (95% CI 1.79-1.98) for diagnosis of incident IBD, 1.74 (1.64-1.85) for ulcerative colitis, and 2.27 (2.06-2.49) for Crohn's disease. aOR was higher in patients who had received one antibiotic dispensation (1.11, 1.07-1.15), two antibiotic dispensations (1.38, 1.32-1.44), and three or more antibiotic dispensations (1.55, 1.49-1.61) than patients who had none. Increased risk was noted for ulcerative colitis (aOR with three or more antibiotic dispensations 1.47, 95% CI 1.40-1.54) and Crohn's disease (1.64, 1.53-1.76) with higher estimates corresponding to broad-spectrum antibiotics. Similar but attenuated results were observed when siblings were used as the reference group, with an aOR of 1.35 (95% CI 1.28-1.43) for patients who had received three or more dispensations, compared with general population controls.Interpretation: Higher cumulative exposure to systemic antibiotic therapy, particularly treatments with greater spectrum of microbial coverage, may be associated with a greater risk of new-onset IBD and its subtypes. The association between antimicrobial treatment and IBD did not appear to differ when predisposed siblings were used as the reference controls. Our findings, if substantiated by longer-term prospective studies in humans or mechanistic preclinical investigations, suggest the need to further emphasise antibiotic stewardship to prevent the rise in dysbiosis-related chronic diseases, including IBD.
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26. |
- Nguyen, Long H., et al.
(author)
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Self-reported COVID-19 vaccine hesitancy and uptake among participants from different racial and ethnic groups in the United States and United Kingdom
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Worldwide, racial and ethnic minorities have been disproportionately impacted by COVID-19 with increased risk of infection, its related complications, and death. In the initial phase of population-based vaccination in the United States (U.S.) and United Kingdom (U.K.), vaccine hesitancy may result in differences in uptake. We performed a cohort study among U.S. and U.K. participants who volunteered to take part in the smartphone-based COVID Symptom Study (March 2020-February 2021) and used logistic regression to estimate odds ratios of vaccine hesitancy and uptake. In the U.S. (n = 87,388), compared to white participants, vaccine hesitancy was greater for Black and Hispanic participants and those reporting more than one or other race. In the U.K. (n = 1,254,294), racial and ethnic minority participants showed similar levels of vaccine hesitancy to the U.S. However, associations between participant race and ethnicity and levels of vaccine uptake were observed to be different in the U.S. and the U.K. studies. Among U.S. participants, vaccine uptake was significantly lower among Black participants, which persisted among participants that self-reported being vaccine-willing. In contrast, statistically significant racial and ethnic disparities in vaccine uptake were not observed in the U.K sample. In this study of self-reported vaccine hesitancy and uptake, lower levels of vaccine uptake in Black participants in the U.S. during the initial vaccine rollout may be attributable to both hesitancy and disparities in access.
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27. |
- Nilsson, Magnus, et al.
(author)
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Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed : The Study Protocol for the Randomized Controlled NEEDS Trial
- 2022
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In: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 12
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Journal article (peer-reviewed)abstract
- Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC.Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up.
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28. |
- Playdon, Mary C., et al.
(author)
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Metabolomics Analytics Workflow for Epidemiological Research : Perspectives from the Consortium of Metabolomics Studies (COMETS)
- 2019
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In: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 9:7
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Journal article (peer-reviewed)abstract
- The application of metabolomics technology to epidemiological studies is emerging as a new approach to elucidate disease etiology and for biomarker discovery. However, analysis of metabolomics data is complex and there is an urgent need for the standardization of analysis workflow and reporting of study findings. To inform the development of such guidelines, we conducted a survey of 47 cohort representatives from the Consortium of Metabolomics Studies (COMETS) to gain insights into the current strategies and procedures used for analyzing metabolomics data in epidemiological studies worldwide. The results indicated a variety of applied analytical strategies, from biospecimen and data pre-processing and quality control to statistical analysis and reporting of study findings. These strategies included methods commonly used within the metabolomics community and applied in epidemiological research, as well as novel approaches to pre-processing pipelines and data analysis. To help with these discrepancies, we propose use of open-source initiatives such as the online web-based tool COMETS Analytics, which includes helpful tools to guide analytical workflow and the standardized reporting of findings from metabolomics analyses within epidemiological studies. Ultimately, this will improve the quality of statistical analyses, research findings, and study reproducibility.
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29. |
- Schmit, Stephanie L, et al.
(author)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Journal article (peer-reviewed)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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30. |
- Seyed Khoei, Nazlisadat, et al.
(author)
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Circulating bilirubin levels and risk of colorectal cancer : serological and Mendelian randomization analyses
- 2020
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In: BMC Medicine. - : Springer Nature. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)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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31. |
- Song, Mingyang, et al.
(author)
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Risk of colorectal cancer incidence and mortality after polypectomy : a Swedish record-linkage study
- 2020
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In: The Lancet Gastroenterology & Hepatology. - : Elsevier. - 2468-1253. ; 5:6, s. 537-547
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Journal article (peer-reviewed)abstract
- Background: Long-term colorectal cancer incidence and mortality after colorectal polyp removal remains unclear. We aimed to assess colorectal cancer incidence and mortality in individuals with removal of different histological subtypes of polyps relative to the general population.Methods: We did a matched cohort study through prospective record linkage in Sweden in patients aged at least 18 years with a first diagnosis of colorectal polyps in the nationwide gastrointestinal ESPRESSO histopathology cohort (1993-2016). For each polyp case, we identified up to five matched reference individuals from the Total Population Register on the basis of birth year, age, sex, calendar year of biopsy, and county of residence. We excluded patients and reference individuals with a diagnosis of colorectal cancer either before or within the first 6 months after diagnosis of the index polyp. Polyps were classified by morphology codes into hyperplastic polyps, sessile serrated polyps, tubular adenomas, tubulovillous adenomas, and villous adenomas. Colorectal cancer cases were identified from the Swedish Cancer Registry, and cause-of-death data were retrieved from the Cause of Death Register. We collected information about the use of endoscopic examination before and after the index biopsy from the Swedish National Patient Registry, and counted the number of endoscopies done before and after the index biopsies. We calculated cumulative risk of colorectal cancer incidence and mortality at 3, 5, 10, and 15 years, and computed hazard ratios (HRs) and 95% CIs for colorectal cancer incidence and mortality using a stratified Cox proportional hazards model within each of the matched pairs.Findings: 178 377 patients with colorectal polyps and 864 831 matched reference individuals from the general population were included in our study. The mean age of patients at polyp diagnosis was 58.6 (SD 13.9) years for hyperplastic polyps, 59.7 (14.2) years for sessile serrated polyps, 63.9 (12.9) years for tubular adenomas, 67.1 (12.1) years for tubulovillous adenomas, and 68.9 (11.8) years for villous adenomas. During a median of 6.6 years (IQR 3.0-11.6) of follow-up, we documented 4278 incident colorectal cancers and 1269 colorectal cancer-related deaths in patients with a polyp, and 14 350 incident colorectal cancers and 5242 colorectal cancer deaths in general reference individuals. The 10-year cumulative incidence of colorectal cancer was 1.6% (95% CI 1.5-1.7) for hyperplastic polyps, 2.5% (1.9-3.3) for sessile serrated polyps, 2.7% (2.5-2.9) for tubular adenomas, 5.1% (4.8-5.4) for tubulovillous adenomas, and 8.6% (7.4-10.1) for villous adenomas compared with 2.1% (2.0-2.1) in reference individuals. Compared with reference individuals, patients with any polyps had an increased risk of colorectal cancer, with multivariable HR of 1.11 (95% CI 1.02-1.22) for hyperplastic polyps, 1.77 (1.34-2.34) for sessile serrated polyps, 1.41 (1.30-1.52) for tubular adenomas, 2.56 (2.36-2.78) for tubulovillous adenomas, and 3.82 (3.07-4.76) for villous adenomas (p<0.05 for all polyp subtypes). There was a higher proportion of incident proximal colon cancer in patients with serrated (hyperplastic and sessile) polyps (52-57%) than in those with conventional (tubular, tubulovillous, and villous) adenomas (30-46%). For colorectal cancer mortality, a positive association was found for sessile serrated polyps (HR 1.74, 95% CI 1.08-2.79), tubulovillous adenomas (1.95, 1.69-2.24), and villous adenomas (3.45, 2.40-4.95), but not for hyperplastic polyps (0.90, 0.76-1.06) or tubular adenomas (0.97, 0.84-1.12).Interpretation: In a largely screening-naive population, compared with individuals from the general population, patients with any polyps had a higher colorectal cancer incidence, and those with sessile serrated polyps, tubulovillous adenomas, and villous adenomas had a higher colorectal cancer mortality.
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32. |
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33. |
- Sudre, Carole H., et al.
(author)
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Attributes and predictors of long COVID
- 2021
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In: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 27:4, s. 626-631
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Journal article (peer-reviewed)abstract
- Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called ‘long COVID’, are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We ana- lyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) partici- pants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76–4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavi- rus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.
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34. |
- Thomas, Minta, et al.
(author)
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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
- 2020
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In: American Journal of Human Genetics. - Cambridge : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:3, s. 432-444
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Journal article (peer-reviewed)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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35. |
- Thomas, Minta, et al.
(author)
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Response to Li and Hopper
- 2021
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 108:3, s. 527-529
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Journal article (peer-reviewed)
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36. |
- Tian, Yu, et al.
(author)
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Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
- 2024
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In: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130:10, s. 1687-1696
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Journal article (peer-reviewed)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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37. |
- Tian, Yu, et al.
(author)
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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
- 2022
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In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:8, s. 1135-1148
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Journal article (peer-reviewed)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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38. |
- Wang, Xiaoliang, et al.
(author)
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Mendelian randomization analysis of C-reactive protein on colorectal cancer risk
- 2019
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 48:3, s. 767-780
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Journal article (peer-reviewed)abstract
- Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach.Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk.Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors.Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.
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39. |
- Xia, Zhiyu, et al.
(author)
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Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.
- 2020
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In: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:10, s. 3563-3573
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Journal article (peer-reviewed)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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