Campbell, Peter T.Lin, YiBien, Stephanie A.Figueiredo, Jane C.Harrison, Tabitha A.Guinter, Mark A.Berndt, Sonja I.Brenner, HermannChan, Andrew T.Chang-Claude, JennyGallinger, Steven J.Gapstur, Susan M.Giles, Graham G.Giovannucci, EdwardGruber, Stephen B.Gunter, MarcHoffmeister, MichaelJacobs, Eric J.Jenkins, Mark A.Marchand, Loic LeLi, LiMcLaughlin, John R.Murphy, NeilMilne, Roger L.Newcomb, Polly A.Newton, ChristinaOgino, ShujiPotter, John D.Rennert, GadRennert, Hedy S.Robinson, JenniferSakoda, Lori C.Slattery, Martha L.Song, YiqingWhite, EmilyWoods, Michael O.Casey, GrahamHsu, LiPeters, Ulrike2024-03-122024-03-122021Campbell PT, Lin Y, Bien SA, et al. Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants. J Natl Cancer Inst. 2021;113(1):38-47. doi:10.1093/jnci/djaa058https://hdl.handle.net/1805/39216Background: 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.en-USPublisher PolicyBody Mass IndexColorectal neoplasmsGenetic predisposition to diseaseRisk assessmentArticle