Peter T Campbell1, Yi Lin2, Stephanie A Bien2, Jane C Figueiredo3,4, Tabitha A Harrison2, Mark A Guinter1, Sonja I Berndt5, Hermann Brenner6,7,8, Andrew T Chan9,10,11,12,13,14, Jenny Chang-Claude15,16, Steven J Gallinger17, Susan M Gapstur1, Graham G Giles18,19,20, Edward Giovannucci13,21, Stephen B Gruber22, Marc Gunter23, Michael Hoffmeister6, Eric J Jacobs1, Mark A Jenkins19, Loic Le Marchand24, Li Li25, John R McLaughlin26, Neil Murphy23, Roger L Milne18,19,20, Polly A Newcomb2, Christina Newton1, Shuji Ogino12,13,27,28, John D Potter2, Gad Rennert29,30,31, Hedy S Rennert29,30,31, Jennifer Robinson32, Lori C Sakoda2,33, Martha L Slattery34, Yiqing Song35, Emily White2,36, Michael O Woods37, Graham Casey38, Li Hsu2, Ulrike Peters2,36. 1. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA. 2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 3. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 4. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 6. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 7. Division of Preventive Oncology, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), Heidelberg, Germany. 8. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 9. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 10. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 11. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA. 12. Broad Institute of Harvard and MIT, Cambridge, MA, USA. 13. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. 14. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. 15. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 16. University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany. 17. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. 18. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. 19. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. 20. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. 21. Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. 22. Center for Precision Medicine and Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA. 23. Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France. 24. University of Hawaii Cancer Center, Honolulu, HI, USA. 25. Department of Family Medicine and Cancer Center, University of Virginia, Charlottesville, VA, USA. 26. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 27. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 28. Department of Pathology, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA, USA. 29. Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel. 30. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 31. Clalit National Cancer Control Center, Haifa, Israel. 32. Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA. 33. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA. 34. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. 35. Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA. 36. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA. 37. Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. 38. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Abstract
BACKGROUND: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS: We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS: Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. CONCLUSION: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.
BACKGROUND: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS: We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS: Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. CONCLUSION: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.
Authors: Ulrike Peters; Carolyn M Hutter; Li Hsu; Fredrick R Schumacher; David V Conti; Christopher S Carlson; Christopher K Edlund; Robert W Haile; Steven Gallinger; Brent W Zanke; Mathieu Lemire; Jagadish Rangrej; Raakhee Vijayaraghavan; Andrew T Chan; Aditi Hazra; David J Hunter; Jing Ma; Charles S Fuchs; Edward L Giovannucci; Peter Kraft; Yan Liu; Lin Chen; Shuo Jiao; Karen W Makar; Darin Taverna; Stephen B Gruber; Gad Rennert; Victor Moreno; Cornelia M Ulrich; Michael O Woods; Roger C Green; Patrick S Parfrey; Ross L Prentice; Charles Kooperberg; Rebecca D Jackson; Andrea Z Lacroix; Bette J Caan; Richard B Hayes; Sonja I Berndt; Stephen J Chanock; Robert E Schoen; Jenny Chang-Claude; Michael Hoffmeister; Hermann Brenner; Bernd Frank; Stéphane Bézieau; Sébastien Küry; Martha L Slattery; John L Hopper; Mark A Jenkins; Loic Le Marchand; Noralane M Lindor; Polly A Newcomb; Daniela Seminara; Thomas J Hudson; David J Duggan; John D Potter; Graham Casey Journal: Hum Genet Date: 2011-07-15 Impact factor: 4.132
Authors: Martha L Slattery; Maureen A Murtaugh; Carol Sweeney; Khe-Ni Ma; John D Potter; Bette J Caan; Wade Samowitz Journal: Nutr Cancer Date: 2005 Impact factor: 2.900
Authors: Jane C Figueiredo; Juan Pablo Lewinger; Chi Song; Peter T Campbell; David V Conti; Christopher K Edlund; Dave J Duggan; Jagadish Rangrej; Mathieu Lemire; Thomas Hudson; Brent Zanke; Michelle Cotterchio; Steven Gallinger; Mark Jenkins; John Hopper; Robert Haile; Polly Newcomb; John Potter; John A Baron; Loic Le Marchand; Graham Casey Journal: Cancer Epidemiol Biomarkers Prev Date: 2011-02-25 Impact factor: 4.254
Authors: Peter T Campbell; Michelle Cotterchio; Elizabeth Dicks; Patrick Parfrey; Steven Gallinger; John R McLaughlin Journal: Cancer Epidemiol Biomarkers Prev Date: 2007-09 Impact factor: 4.254
Authors: Neil Murphy; Howard D Strickler; Frank Z Stanczyk; Xiaonan Xue; Sylvia Wassertheil-Smoller; Thomas E Rohan; Gloria Y F Ho; Garnet L Anderson; John D Potter; Marc J Gunter Journal: J Natl Cancer Inst Date: 2015-08-01 Impact factor: 13.506
Authors: Amanda I Phipps; Polly A Newcomb; Xabier Garcia-Albeniz; Carolyn M Hutter; Emily White; Charles S Fuchs; Aditi Hazra; Shuji Ogino; Hongmei Nan; Jing Ma; Peter T Campbell; Jane C Figueiredo; Ulrike Peters; Andrew T Chan Journal: Gastroenterology Date: 2012-05-08 Impact factor: 22.682
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Authors: Song Yao; Peter T Campbell; Tomotaka Ugai; Gretchen Gierach; Montserrat Garcia-Closas; Timothy R Rebbeck; Christine B Ambrosone; Shuji Ogino; Mustapha Abubakar; Viktor Adalsteinsson; Jonas Almeida; Paul Brennan; Stephen Chanock; Todd Golub; Samir Hanash; Curtis Harris; Cassandra A Hathaway; Karl Kelsey; Maria Teresa Landi; Faisal Mahmood; Christina Newton; John Quackenbush; Scott Rodig; Nikolaus Schultz; Guillermo Tearney; Shelley S Tworoger; Molin Wang; Xuehong Zhang Journal: Cancer Causes Control Date: 2022-06-27 Impact factor: 2.532