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1. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Zhishan Chen, Xingyi Guo, Ran Tao, Jeroen R. Huyghe, Philip J. Law, Ceres Fernandez-Rozadilla, Jie Ping, Guochong Jia, Jirong Long, Chao Li, Quanhu Shen, Yuhan Xie, Maria N. Timofeeva, Minta Thomas, Stephanie L. Schmit, Virginia Díez-Obrero, Matthew Devall, Ferran Moratalla-Navarro, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah E. W. Briggs, Victoria Svinti, Kevin Donnelly, Susan M. Farrington, James Blackmur, Peter G. Vaughan-Shaw, Xiao-Ou Shu, Yingchang Lu, Peter Broderick, James Studd, Tabitha A. Harrison, David V. Conti, Fredrick R. Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Rish K. Pai, Jane C. Figueiredo, Robert W. Haile, Steven Gallinger, Michael O. Woods, Polly A. Newcomb, David Duggan, Jeremy P. Cheadle, Richard Kaplan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Jukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A. Aaltonen, Harri Rissanen, Eero Pukkala, Johan G. Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Satu Männistö, Demetrius Albanes, Stephanie J. Weinstein, Edward Ruiz-Narvaez, Julie R. Palmer, Daniel D. Buchanan, Elizabeth A. Platz, Kala Visvanathan, Cornelia M. Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter T. Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha L. Slattery, John D. Potter, Kostas K. Tsilidis, Matthias B. Schulze, Marc J. Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, D. Timothy Bishop, Graham G. Giles, Melissa C. Southey, Gregory E. Idos, Kevin J. McDonnell, Zomoroda Abu-Ful, Joel K. Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope O. Keku, Bethany van Guelpen, Thomas J. Hudson, Heather Hampel, Rachel Pearlman, Sonja I. Berndt, Richard B. Hayes, Marie Elena Martinez, Sushma S. Thomas, Paul D. P. Pharoah, Susanna C. Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly F. Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T. Chan, Marcia Cruz-Correa, Annika Lindblom, David J. Hunter, Amit D. Joshi, Clemens Schafmayer, Peter C. Scacheri, Anshul Kundaje, Robert E. Schoen, Jochen Hampe, Zsofia K. Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Christopher K. Edlund, W. James Gauderman, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen J. Chanock, Franzel van Duijnhoven, Edith J. M. Feskens, Lori C. Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Barbara Pardini, Liesel M. FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A. Bien, Charles Kooperberg, Christopher I. Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Loic Le Marchand, Anna H. Wu, Chenxu Qu, Caroline E. McNeil, Gerhard Coetzee, Caroline Hayward, Ian J. Deary, Sarah E. Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Ken S. Lau, Hongyu Zhao, Li Hsu, Qiuyin Cai, Malcolm G. Dunlop, Stephen B. Gruber, Richard S. Houlston, Victor Moreno, Graham Casey, Ulrike Peters, Ian Tomlinson, and Wei Zheng

Subjects
Science
Abstract

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.

Published
2024
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2. Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancerResearch in context

Author

Nikos Papadimitriou, Andre Kim, Eric S. Kawaguchi, John Morrison, Virginia Diez-Obrero, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, Stephanie A. Bien, D Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Robert Carreras-Torres, Andrew T. Chan, Jenny Chang-Claude, David V. Conti, Matthew A. Devall, Niki Dimou, David A. Drew, Stephen B. Gruber, Tabitha A. Harrison, Michael Hoffmeister, Jeroen R. Huyghe, Amit D. Joshi, Temitope O. Keku, Anshul Kundaje, Sébastien Küry, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M. Lynch, Victor Moreno, Christina C. Newton, Mireia Obón-Santacana, Jennifer Ose, Andrew J. Pellatt, Anita R. Peoples, Elizabeth A. Platz, Conghui Qu, Gad Rennert, Edward Ruiz-Narvaez, Anna Shcherbina, Mariana C. Stern, Yu-Ru Su, Duncan C. Thomas, Claire E. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Caroline Y. Um, Kala Visvanathan, Jun Wang, Emily White, Michael O. Woods, Stephanie L. Schmit, Finlay Macrae, John D. Potter, John L. Hopper, Ulrike Peters, Neil Murphy, Li Hsu, Marc J. Gunter, and W. James Gauderman

Subjects
Diet, Fibre, Gene-environment interaction, Colorectal cancer, GWAS, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

Published
2024
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3. Genetic variants of the lipoprotein lipase gene and myocardial infarction in the Central Valley of Costa Rica

Author

Yadong Yang, Edward Ruiz-Narvaez, Tianhua Niu, Xiping Xu, and Hannia Campos

Subjects
epidemiology, risk factor, single-nucleotide polymorphism, cardiovascular disease, Hispanic, Biochemistry, QD415-436
Abstract

To assess common variants of the LPL gene that could influence susceptibility to myocardial infarction (MI), we assessed three functional single-nucleotide polymorphisms (SNPs), D9N, N291S, and S447X, in 1,321 survivors of a first acute MI and 1,321 population-based controls, matched for age, gender, and area of residence, all living in the Central Valley of Costa Rica. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI). The frequency of the X447 mutant allele was significantly lower in cases than in controls (6.2% vs. 7.6%; P < 0.01), whereas no association with MI was found for D9N or N291S. The OR (95% CI) for carriers vs. noncarriers of the X447 allele was 0.80 (0.63–1.01); when considering the haplotype that contained X447 and normal alleles of D9N and N291S, the OR (95% CI) was 0.66 (0.48–0.91). Twelve other SNPs were assessed in a subgroup of the population, of which the four functional SNPs were found to be monomorphic, and no correlation with MI was observed for the other eight neutral SNPs.The X447 mutant allele of the LPL gene may protect from MI risk, although this effect is small.

Published
2004
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4. Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

Author

Kristina M. Jordahl, Anna Shcherbina, Andre E. Kim, Yu-Ru Su, Yi Lin, Jun Wang, Conghui Qu, Demetrius Albanes, Volker Arndt, James W. Baurley, Sonja I. Berndt, Stephanie A. Bien, D. Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Arif Budiarto, Peter T. Campbell, Robert Carreras-Torres, Graham Casey, Tjeng Wawan Cenggoro, Andrew T. Chan, David V. Conti, Christopher H. Dampier, Matthew A. Devall, Virginia Díez-Obrero, Niki Dimou, David A. Drew, Jane C. Figueiredo, Steven Gallinger, Graham G. Giles, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Heather Hampel, Sophia Harlid, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Amit D. Joshi, Temitope O. Keku, Susanna C. Larsson, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Bharuno Mahesworo, Victor Moreno, John L. Morrison, Neil Murphy, Hongmei Nan, Rami Nassir, Polly A. Newcomb, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Paul D.P. Pharoah, Elizabeth A. Platz, John D. Potter, Ross L. Prentice, Gad Rennert, Edward Ruiz-Narvaez, Lori C. Sakoda, Peter C. Scacheri, Stephanie L. Schmit, Robert E. Schoen, Martha L. Slattery, Mariana C. Stern, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Natalia Zemlianskaia, Jenny Chang-Claude, W. James Gauderman, Li Hsu, Anshul Kundaje, and Ulrike Peters

Subjects
Electron Transport Complex IV, Oncology, Alcohol Drinking, Nutrition and Disease, Epidemiology, Risk Factors, Voeding en Ziekte, Life Science, Humans, Colorectal Neoplasms, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

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.

Published
2022
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5. Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Author

Robert Carreras-Torres, Andre E. Kim, Yi Lin, Virginia Díez-Obrero, Stephanie A. Bien, Conghui Qu, Jun Wang, Niki Dimou, Elom K. Aglago, Demetrius Albanes, Volker Arndt, James W. Baurley, Sonja I. Berndt, Stéphane Bézieau, D. Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Arif Budiarto, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Xuechen Chen, David V. Conti, Christopher H. Dampier, Matthew A.M. Devall, David A. Drew, Jane C. Figueiredo, Steven Gallinger, Graham G. Giles, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Kristina M. Jordahl, Eric Kawaguchi, Temitope O. Keku, Anshul Kundaje, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Bharuno Mahesworo, John L. Morrison, Neil Murphy, Hongmei Nan, Rami Nassir, Polly A. Newcomb, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Paul D.P. Pharoah, Elizabeth A. Platz, Gad Rennert, Edward Ruiz-Narvaez, Lori C. Sakoda, Peter C. Scacheri, Stephanie L. Schmit, Robert E. Schoen, Anna Shcherbina, Martha L. Slattery, Mariana C. Stern, Yu-Ru Su, Catherine M. Tangen, Duncan C. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Fränzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Tjeng Wawan Cenggoro, Stephanie J. Weinstein, Emily White, Alicja Wolk, Michael O. Woods, Li Hsu, Ulrike Peters, Victor Moreno, and W. James Gauderman

Subjects
Oncology, Nutrition and Disease, Epidemiology, Voeding en Ziekte, Life Science
Abstract

Background:Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.Methods:A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.Results:Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR 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.

Published
2023

6. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Xingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran Moratalla-Navarro, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John Hopper, Mark Jenkins, Aung Ko Win, Rish Pai, Jane Figueiredo, Robert Haile, Steven Gallinger, Michael Woods, Polly Newcomb, David Duggan, Jeremy Cheadle, Richard Kaplan, Timothy Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri Aaltonen, Harri Rissanen, Eero Pukkala, Johan Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Brent Zanke, Satu Männistö, Demetrius Albanes, Stephanie Weinstein, Edward Ruiz-Narvaez, Julie Palmer, Daniel Buchanan, Elizabeth Platz, Kala Visvanathan, Cornelia Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha Slattery, John Potter, Konstantinos Tsilidis, Matthias Schulze, Marc Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana Stern, Bens Pardamean, Timothy Bishop, Graham Giles, Melissa Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu-Ful, Joel Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope Keku, Bethany van Guelpen, Thomas Hudson, Heather Hampel, Rachel Pearlman, Sonja Berndt, Richard Hayes, Marie Elena Martinez, Sushma Thomas, Douglas Corley, Paul Pharoah, Susanna Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly Doheny, Elizabeth Pugh, Tameka Shelford, Andrew Chan, Marcia Cruz-Correa, Annika Lindblom, David Hunter, Amit Joshi, Clemens Schafmayer, Peter Scacheri, Anshul Kundaje, Deborah Nickerson, Robert Schoen, Jochen Hampe, Zsofia Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Nickolas Papadopoulos, Chistopher Edlund, William Gauderman, Duncan Thomas, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen Chanock, Franzel van Duijnhoven, Edith Feskens, Lori Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Catherine Tangen, Elaine Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher Haiman, Loic Le Marchand, Anna Wu, Chenxu Qu, Caroline McNeil, Gerhard Coetzee, Caroline Hayward, Ian Deary, Sarah Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Victor Moreno, Graham Casey, Stephen Gruber, Ian Tomlinson, Wei Zheng, Malcolm Dunlop, Richard Houlston, and Ulrike Peters

Subjects
Global Nutrition, Wereldvoeding, Nutrition and Disease, Voeding en Ziekte, Genetics, Life Science, Article, VLAG
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. Cross-tissue analyses indicated that over a third of effector genes most likely 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.

Published
2023
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7. Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

Author

Niki Dimou, Andre E. Kim, Orlagh Flanagan, Neil Murphy, Virginia Diez-Obrero, Anna Shcherbina, Elom K Aglago, Emmanouil Bouras, Peter T Campbell, Graham Casey, Steven Gallinger, Stephen B Gruber, Mark A Jenkins, Yi Lin, Victor Moreno, Edward Ruiz-Narvaez, Mariana C Stern, Yu Tian, Kostas K Tsilidis, Volker Arndt, Elizabeth L Barry, James W Baurley, Sonja I Berndt, Stéphane Bézieau, Stephanie A Bien, D Timothy Bishop, Hermann Brenner, Arif Budiarto, Robert Carreras-Torres, Tjeng Wawan Cenggoro, Andrew T Chan, Jenny Chang-Claude, Stephen J Chanock, Xuechen Chen, David V Conti, Christopher H Dampier, Matthew Devall, David Drew, Jane C Figueiredo, Graham G Giles, Andrea Gsur, Tabitha A Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R Huyghe, Kristina Jordahl, Eric Kawaguchi, Temitope O Keku, Susanna C Larsson, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Bharuno Mahesworo, John Morrison, Polly A Newcomb, Christina C Newton, Mireia Obon-Santacana, Jennifer Ose, Rish K Pai, Julie R Palmer, Nick Papadimitrou, Bens Pardamean, Anita R Peoples, Paul D P Pharoah, Elizabeth A Platz, John D Potter, Gad Rennert, Peter C Scacheri, Robert E Schoen, Yu-Ru Su, Catherine M Tangen, Stephen N Thibodeau, Duncan C Thomas, Cornelia Ulrich, Caroline Y Um, Franzel JB van Duijnhoven, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Emily White, Alicja Wolk, Michael O Woods, Conghui Qu, Anshul Kundaje, Li Hsu, W. James Gauderman, Marc J Gunter, and Ulrike Peters

Abstract

Diabetes is an established risk factor for colorectal cancer; however, the mechanisms underlying this relationship are not fully understood and the role of genetic variation is unclear. We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes and joint testing of Gxdiabetes, G-colorectal cancer association and/or G-diabetes correlation (2,3-degrees of freedom joint tests; d.f.). Based on the joint tests, variant rs3802177 inSLC30A8(p-value3-d.f.:5.46×10−11; regulates phosphorylation of the insulin receptor and phosphatidylinositol-3 kinase activity) and rs9526201 inLRCH1(p-value2-d.f.:7.84×10−09; regulates T cell migration and Natural Killer Cell cytotoxicity) were associated with colorectal cancer. These results suggest that variation in genes related to insulin signalling and immune function may modify the association of diabetes with colorectal cancer and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

Published
2022
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8. Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Xingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran Moratalla-Navarro, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John Hopper, Mark Jenkins, Aung Ko Win, Rish Pai, Jane Figueiredo, Robert Haile, Steven Gallinger, Michael Woods, Polly Newcomb, David Duggan, Jeremy Cheadle, Richard Kaplan, Timothy Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri Aaltonen, Harri Rissanen, Eero Pukkala, Johan Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Brent Zanke, Satu Männistö, Demetrius Albanes, Stephanie Weinstein, Edward Ruiz-Narvaez, Julie Palmer, Daniel Buchanan, Elizabeth Platz, Kala Visvanathan, Cornelia Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha Slattery, John Potter, Konstantinos Tsilidis, Matthias Schulze, Marc Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana Stern, Bens Pardamean, Timothy Bishop, Graham Giles, Melissa Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu-Ful, Joel Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope Keku, Bethany van Guelpen, Thomas Hudson, Heather Hampel, Rachel Pearlman, Sonja Berndt, Richard Hayes, Marie Elena Martinez, Sushma Thomas, Douglas Corley, Paul Pharoah, Susanna Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly Doheny, Elizabeth Pugh, Tameka Shelford, Andrew Chan, Marcia Cruz-Correa, Annika Lindblom, David Hunter, Amit Joshi, Clemens Schafmayer, Peter Scacheri, Anshul Kundaje, Deborah Nickerson, Robert Schoen, Jochen Hampe, Zsofia Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Nickolas Papadopoulos, Chistopher Edlund, William Gauderman, Duncan Thomas, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen Chanock, Franzel van Duijnhoven, Edith Feskens, Lori Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Catherine Tangen, Elaine Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher Haiman, Loic Le Marchand, Anna Wu, Chenxu Qu, Caroline McNeil, Gerhard Coetzee, Caroline Hayward, Ian Deary, Sarah Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Victor Moreno, Graham Casey, Stephen Gruber, Ian Tomlinson, Wei Zheng, Malcolm Dunlop, Richard Houlston, and Ulrike Peters

Subjects
Global Nutrition, Wereldvoeding, Nutrition and Disease, Voeding en Ziekte, Genetics, Life Science, VLAG
Abstract

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article.

Published
2023
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9. Abstract 3562: The Ala12 Variant of the PPARG Gene is Associated with Higher Polyunsaturated Fatty Acids in Adipose Tissue and Attenuates the Protective Effect of Polyunsaturated Fat Intake on the Risk of MI

Author

Edward Ruiz-Narvaez, Peter Kraft, and Hannia Campos

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Background: Intake of polyunsaturated fat is protective against development of coronary heart disease (CHD). Less is known about genetic variation modulating this association. The Ala12 allele of the PPARG gene decreases lipolysis of triacylglycerols in adipose tissue, resulting in accumulation of fatty acids in adipocytes. Objective: Determine whether the Pro12Ala polymorphism interacts with polyunsaturated fat intake to affect the risk of myocardial infarction (MI). Design: Cases (n=1805) with a first nonfatal acute MI and age, sex and area of residence matched population-based controls (n=1805) living in Costa Rica, were genotyped for the PPARG Pro12Ala genetic polymorphism. Polyunsaturated fat intake was determined by a validated food frequency questionnaire and by GC analysis in adipose tissue. Odds ratios (ORs) and 95% confidence intervals (95% CI) for MI were estimated using logistic regression. Results: The relative allele frequencies of the Ala12 allele were 10% in controls and 11% in cases. ORs (95% CI) for MI per each 5% increase of energy from polyunsaturated fat were 0.66 (0.53, 0.82) in Pro12/Pro12 subjects, and 0.93 (0.61, 1.42) in carriers of the Ala12 allele (p for interaction = 0.03). Increments (95% CI) of polyunsaturated fat in adipose tissue per 5% increment in dietary intake were 5.4% (4.9%, 5.9%) in Pro12/Pro12 homozygous, and 7.0% (6.0%, 8.0%) in carriers of the Ala12 variant (p for homogeneity of slopes = 0.02). Conclusions: The protective effect of polyunsaturated fat intake on MI is attenuated in carriers of the Ala12 allele of the PPARG gene.

Published
2007
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