Browsing by Author "Gauderman, W. James"

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    Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region
    (American Association for Cancer Research, 2022) Jordahl, Kristina M.; Shcherbina, Anna; Kim, Andre E.; Su, Yu-Ru; Lin, Yi; Wang, Jun; Qu, Conghui; Albanes, Demetrius; Arndt, Volker; Baurley, James W.; Berndt, Sonja I.; Bien, Stephanie A.; Bishop, D. Timothy; Bouras, Emmanouil; Brenner, Hermann; Buchanan, Daniel D.; Budiarto, Arif; Campbell, Peter T.; Carreras-Torres, Robert; Casey, Graham; Cenggoro, Tjeng Wawan; Chan, Andrew T.; Conti, David V.; Dampier, Christopher H.; Devall, Matthew A.; Díez-Obrero, Virginia; Dimou, Niki; Drew, David A.; Figueiredo, Jane C.; Gallinger, Steven; Giles, Graham G.; Gruber, Stephen B.; Gsur, Andrea; Gunter, Marc J.; Hampel, Heather; Harlid, Sophia; Harrison, Tabitha A.; Hidaka, Akihisa; Hoffmeister, Michael; Huyghe, Jeroen R.; Jenkins, Mark A.; Joshi, Amit D.; Keku, Temitope O.; Larsson, Susanna C.; Le Marchand, Loic; Lewinger, Juan Pablo; Li, Li; Mahesworo, Bharuno; Moreno, Victor; Morrison, John L.; Murphy, Neil; Nan, Hongmei; Nassir, Rami; Newcomb, Polly A.; Obón-Santacana, Mireia; Ogino, Shuji; Ose, Jennifer; Pai, Rish K.; Palmer, Julie R.; Papadimitriou, Nikos; Pardamean, Bens; Peoples, Anita R.; Pharoah, Paul D. P.; Platz, Elizabeth A.; Potter, John D.; Prentice, Ross L.; Rennert, Gad; Ruiz-Narvaez, Edward; Sakoda, Lori C.; Scacheri, Peter C.; Schmit, Stephanie L.; Schoen, Robert E.; Slattery, Martha L.; Stern, Mariana C.; Tangen, Catherine M.; Thibodeau, Stephen N.; Thomas, Duncan C.; Tian, Yu; Tsilidis, Konstantinos K.; Ulrich, Cornelia M.; van Duijnhoven, Franzel J. B.; Van Guelpen, Bethany; Visvanathan, Kala; Vodicka, Pavel; White, Emily; Wolk, Alicja; Woods, Michael O.; Wu, Anna H.; Zemlianskaia, Natalia; Chang-Claude, Jenny; Gauderman, W. James; Hsu, Li; Kundaje, Anshul; Peters, Ulrike; Epidemiology, Richard M. Fairbanks School of Public Health
    Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.
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    Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
    (Oxford, 2022) Tian, Yu; Kim, Andre E.; Bien, Stephanie A.; Lin, Yi; Qu, Conghui; Harrison, Tabitha A.; Carreras-Torres, Robert; Díez-Obrero, Virginia; Dimou, Niki; Drew , David A.; Hidaka, Akihisa; Huyghe, Jeroen R.; Jordahl, Kristina M.; Morrison , John; Murphy, Neil; Obón-Santacana, Mireia; Ulrich, Cornelia M.; Ose, Jennifer; Peoples, Anita R.; Ruiz-Narvaez, Edward A.; Shcherbina, Anna; Stern , Mariana C.; Su, Yu-Ru; van Duijnhoven, Franzel J. B.; Arndt, Volker; Baurley, James W.; Berndt, Sonja I.; Bishop, D. Timothy; Brenner, Hermann; Buchanan, Daniel D.; Chan, Andrew T.; Figueiredo, Jane C.; Gallinger, Steven; Gruber, Stephen B.; Harlid, Sophia; Hoffmeister, Michael; Jenkins, Mark A.; Joshi, Amit D.; Keku, Temitope O.; Larsson, Susanna C.; Marchand, Loic Le; Li, Li; Giles, Graham G.; Milne, Roger L.; Nan, Hongmei; Nassir, Rami; Ogino, Shuji; Budiarto, Arif; Platz, Elizabeth A.; Potter, John D.; Prentice, Ross L.; Rennert, Gad; Sakoda, Lori C.; Schoen, Robert E.; Slattery, Martha L.; Thibodeau, Stephen N.; Van Guelpen, Bethany; Visvanathan, Kala; White, Emily; Wolk, Alicja; Woods, Michael O.; Wu, Anna H.; Campbell, Peter T.; Casey, Graham; Conti, David V.; Gunter, Marc J.; Kundaje, Anshul; Lewinger, Juan Pablo; Moreno, Victor; Newcomb, Polly A.; Pardamean, Bens; Thomas, Duncan C.; Tsilidis, Konstantinos K.; Peters, Ulrike; Gauderman, W. James; Hsu, Li; Chang-Claude, Jenny; Community and Global Health, Richard M. Fairbanks School of Public Health
    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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    Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response
    (American Association for Cancer Research, 2023) Carreras-Torres, Robert; Kim, Andre E.; Lin, Yi; Díez-Obrero, Virginia; Bien, Stephanie A.; Qu, Conghui; Wang, Jun; Dimou, Niki; Aglago, Elom K.; Albanes, Demetrius; Arndt, Volker; Baurley, James W.; Berndt, Sonja I.; Bézieau, Stéphane; Bishop, D. Timothy; Bouras, Emmanouil; Brenner, Hermann; Budiarto, Arif; Campbell, Peter T.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chen, Xuechen; Conti, David V.; Dampier, Christopher H.; Devall, Matthew A. M.; Drew, David A.; Figueiredo, Jane C.; Gallinger, Steven; Giles, Graham G.; Gruber, Stephen B.; Gsur, Andrea; Gunter, Marc J.; Harrison, Tabitha A.; Hidaka, Akihisa; Hoffmeister, Michael; Huyghe, Jeroen R.; Jenkins, Mark A.; Jordahl, Kristina M.; Kawaguchi, Eric; Keku, Temitope O.; Kundaje, Anshul; Le Marchand, Loic; Lewinger, Juan Pablo; Li, Li; Mahesworo, Bharuno; Morrison, John L.; Murphy, Neil; Nan, Hongmei; Nassir, Rami; Newcomb, Polly A.; Obón-Santacana, Mireia; Ogino, Shuji; Ose, Jennifer; Pai, Rish K.; Palmer, Julie R.; Papadimitriou, Nikos; Pardamean, Bens; Peoples, Anita R.; Pharoah, Paul D. P.; Platz, Elizabeth A.; Rennert, Gad; Ruiz-Narvaez, Edward; Sakoda, Lori C.; Scacheri, Peter C.; Schmit, Stephanie L.; Schoen, Robert E.; Shcherbina, Anna; Slattery, Martha L.; Stern, Mariana C.; Su, Yu-Ru; Tangen, Catherine M.; Thomas, Duncan C.; Tian, Yu; Tsilidis, Konstantinos K.; Ulrich, Cornelia M.; van Duijnhoven, Fränzel J. B.; Van Guelpen, Bethany; Visvanathan, Kala; Vodicka, Pavel; Wawan Cenggoro, Tjeng; Weinstein, Stephanie J.; White, Emily; Wolk, Alicja; Woods, Michael O.; Hsu, Li; Peters, Ulrike; Moreno, Victor; Gauderman, W. James; Epidemiology, Richard M. Fairbanks School of Public Health
    Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.
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    Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk
    (Springer, 2022-11-07) Haas, Cameron B.; Su, Yu-Ru; Petersen, Paneen; Wang, Xiaoliang; Bien, Stephanie A.; Lin, Yi; Albanes, Demetrius; Weinstein, Stephanie J.; Jenkins, Mark A.; Figueiredo, Jane C.; Newcomb, Polly A.; Casey, Graham; Marchand, Loic Le; Campbell, Peter T.; Moreno, Victor; Potter, John D.; Sakoda, Lori C.; Slattery, Martha L.; Chan, Andrew T.; Li, Li; Giles, Graham G.; Milne, Roger L.; Gruber, Stephen B.; Rennert, Gad; Woods, Michael O.; Gallinger, Steven J.; Berndt, Sonja; Hayes, Richard B.; Huang, Wen-Yi; Wolk, Alicja; White, Emily; Nan, Hongmei; Nassir, Rami; Lindor, Noralane M.; Lewinger, Juan P.; Kim, Andre E.; Conti, David; Gauderman, W. James; Buchanan, Daniel D.; Peters, Ulrike; Hsu , Li; Epidemiology, Richard M. Fairbanks School of Public Health
    Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.