Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants

Peter T Campbell; Yi Lin; Stephanie A Bien; Jane C Figueiredo; Tabitha A Harrison; Mark A Guinter; Sonja I Berndt; Hermann Brenner; Andrew T Chan; Jenny Chang-Claude; Steven J Gallinger; Susan M Gapstur; Graham G Giles; Edward Giovannucci; Stephen B Gruber; Marc Gunter; Michael Hoffmeister; Eric J Jacobs; Mark A Jenkins; Loic Le Marchand; Li Li; John R McLaughlin; Neil Murphy; Roger L Milne; Polly A Newcomb; Christina Newton; Shuji Ogino; John D Potter; Gad Rennert; Hedy S Rennert; Jennifer Robinson; Lori C Sakoda; Martha L Slattery; Yiqing Song; Emily White; Michael O Woods; Graham Casey; Li Hsu; Ulrike Peters

doi:10.1093/jnci/djaa058

Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants

J Natl Cancer Inst. 2021 Jan 4;113(1):38-47. doi: 10.1093/jnci/djaa058.

Authors

Peter T Campbell¹, Yi Lin², Stephanie A Bien², Jane C Figueiredo^{3

4}, Tabitha A Harrison², Mark A Guinter¹, Sonja I Berndt⁵, Hermann Brenner^{6

7

8}, Andrew T Chan^{9

10

11

12

13

14}, Jenny Chang-Claude^{15

16}, Steven J Gallinger¹⁷, Susan M Gapstur¹, Graham G Giles^{18

19

20}, Edward Giovannucci^{13

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 Milne^{18

19

20}, Polly A Newcomb², Christina Newton¹, Shuji Ogino^{12

13

27

28}, John D Potter², Gad Rennert^{29

30

31}, Hedy S Rennert^{29

30

31}, Jennifer Robinson³², Lori C Sakoda^{2

33}, Martha L Slattery³⁴, Yiqing Song³⁵, Emily White^{2

36}, Michael O Woods³⁷, Graham Casey³⁸, Li Hsu², Ulrike Peters^{2

36}

Affiliations

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.

MeSH terms

Aged
Body Mass Index*
Colorectal Neoplasms / epidemiology
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study
Genotype
Humans
Logistic Models
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics
Risk Assessment
Risk Factors
Smad7 Protein / genetics*

Substances

SMAD7 protein, human
Smad7 Protein

Abstract

MeSH terms

Substances

Grants and funding