Functional informed genome‐wide interaction analysis of body mass index, diabetes and colorectal cancer risk

Cancer Medicine

Peter T. Campbell¹  Graham G. Giles²  Graham Casey³  Mark A. Jenkins⁴  Edward L. Giovannucci⁵  Amit D. Joshi⁶  Daniel D. Buchanan⁷  Gad Rennert⁸  Shuji Ogino⁹  Hongmei Nan^1,10  Polly A. Newcomb^1,11  Emily White^1,11  Zhiyu Xia^1,11  Ulrike Peters^1,11  Li Li^1,12  Noralane M. Lindor^1,13  Martha L. Slattery^1,14  Rami Nassir^1,15  Andre E. Kim^1,16  Jane C. Figueiredo^1,16  David V. Conti^1,16  Juan P. Lewinger^1,16  Stephen B. Gruber^1,16  W. James Gauderman^1,16  Lihong Qi^1,17  Paul D. P. Pharoah^1,18  Jenny Chang‐Claude^1,19  Sonja I. Berndt^2,20  Demetrius Albanes^2,20  Michael Hoffmeister^2,21  Hermann Brenner^2,21  Mingyang Song^2,22  Andrew T. Chan^2,22  David A. Drew^2,22  Alicja Wolk^2,23  Steven J. Gallinger^2,24  Michael O. Woods^2,25  Victor Moreno^2,26  Yi Lin^2,27  Paneen Petersen^2,27  Stephanie Bien^2,27  Yu‐Ru Su^2,27  Li Hsu^2,27  Lori C. Sakoda^2,27  Xiaoliang Wang^2,27  Marc J. Gunter^2,28  Neil Murphy^2,28  Stéphane Bézieau^2,29  Loic Le Marchand^3,30 

[1] Behavioral and Epidemiology Research Group American Cancer Society Atlanta GA USA;Cancer Epidemiology Division Melbourne Victoria Australia;Center for Public Health Genomics University of Virginia Charlottesville VA USA;Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia;Channing Division of Network Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA;Clinical and Translational Epidemiology Unit Massachusetts General Hospital Harvard Medical School Boston MA USA;Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville Victoria Australia;Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel;Department of Epidemiology Harvard T.H. Chan School of Public Health Harvard University Boston MA USA;Department of Epidemiology Richard M. Fairbanks School of Public Health Indiana University Indianapolis IN USA;Department of Epidemiology University of Washington Seattle WA USA;Department of Family Medicine University of Virginia Charlottesville VA USA;Department of Health Science Research Mayo Clinic Scottsdale AZ USA;Department of Internal Medicine University of Utah Salt Lake City UT USA;Department of Pathology School of Medicine Umm Al‐Qura University Makkah Saudi Arabia;Department of Preventive Medicine & USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA USA;Department of Public Health Sciences University of California Davis Davis CA USA;Department of Public Health and Primary Care University of Cambridge Cambridge UK;Division of Cancer Epidemiology German Cancer Research Center (DKFZ) Heidelberg Germany;Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD USA;Division of Clinical Epidemiology and Aging Research German Cancer Research Center (DKFZ) Heidelberg Germany;Division of Gastroenterology Massachusetts General Hospital Harvard Medical School Boston MA USA;Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden;Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada;Memorial University of Newfoundland Discipline of Genetics St. John's Canada;Oncology Data Analytics Program Catalan Institute of Oncology‐IDIBELL, L'Hospitalet de Llobregat Barcelona Spain;Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA;Section of Nutrition and Metabolism International Agency for Research on Cancer Lyon France;Service de Génétique Médicale Centre Hospitalier Universitaire (CHU) Nantes Nantes France;University of Hawaii Cancer Center Honolulu HI USA;

关键词: BMI;    colorectal cancer;    diabetes;    gene expression;    gene‐environmental interaction;   

DOI  :  10.1002/cam4.2971

来源: DOAJ

【 摘 要 】

Abstract Background Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5). Conclusions Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

【 授权许可】

Unknown