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

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.

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Forest plot for BMI (per 5 kg/m2) and colorectal cancer risk in women. Study-specific betas, odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression case-control models. The summary OR was calculated using fixed-effects meta-analysis. CCFR = Colon Cancer Family Registry; CCFR-CORECT = Colon Cancer Family Registry participants from the ColoRectal Transdisciplinary Study (CORECT); CPS-II = American Cancer Society Cancer Prevention Study-II Nutrition cohort; DACHS = Darmkrebs: Chancen der Verhütung durch Screening; DALS = Diet, Activity, and Lifestyle Study; Kentucky = Kentucky Case-Control study; MEC = Multiethnic Cohort Study; MECC = Molecular Epidemiology of Colorectal Cancer study; MCCS = Melbourne Collaborative Cohort Study; NFCCR = Newfoundland Familial Colorectal Cancer Registry; NHS = Nurses’ Health Study; OFCCR = Ontario Familial Colorectal Cancer Registry; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; SCCFR = Seattle Colon Cancer Family Registry; VITAL = VITamins And Lifestyle; WHI = Women’s Health Initiative.

Figure 2.

Forest plot for BMI (per 5 kg/m2) and colorectal cancer risk in men. Study-specific betas, odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression case-control models. The summary OR was calculated using fixed-effects meta-analysis. CCFR = Colon Cancer Family Registry; CCFR-CORECT = Colon Cancer Family Registry participants from the ColoRectal Transdisciplinary Study (CORECT); CPS-II = American Cancer Society Cancer Prevention Study-II Nutrition cohort; DACHS = Darmkrebs: Chancen der Verhütung durch Screening; DALS = Diet, Activity, and Lifestyle Study; Kentucky = Kentucky Case-Control study; MEC = Multiethnic Cohort Study; MECC = Molecular Epidemiology of Colorectal Cancer study; MCCS = Melbourne Collaborative Cohort Study; NFCCR = Newfoundland Familial Colorectal Cancer Registry; NHS = Nurses’ Health Study; OFCCR = Ontario Familial Colorectal Cancer Registry; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; SCCFR = Seattle Colon Cancer Family Registry; VITAL = VITamins And Lifestyle; WHI = Women’s Health Initiative.