BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta Indonesia

BioRealm LLC Walnut CA USA

Biostatistics Division Kaiser Permanente Washington Health Research Institute Seattle WA USA

Broad Institute of Harvard and MIT Cambridge MA USA

Cancer Epidemiology Division Cancer Council Victoria Melbourne VIC Australia

Center for Cancer Research Medical University of Vienna Vienna Austria

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill NC USA

Center for Precision Medicine Department of Medical Oncology and Therapeutics Research City of Hope National Medical Center Duarte CA 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 and Harvard Medical School Boston MA USA

CIBER Epidemiología y Salud Pública Madrid Spain

Clalit National Cancer Control Center Haifa Israel

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA USA

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Barcelona 08908 Spain

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat 8908 Barcelona Spain

Computer Science Department School of Computer Science Bina Nusantara University Jakarta Indonesia

Consortium for Biomedical Research in Epidemiology and Public Health Barcelona 08908 Spain

Department of Biostatistics University of Washington Seattle WA USA

Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona 08908 Spain

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Computer Science Stanford University Stanford CA USA

Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx NY USA

Department of Epidemiology Geisel School of Medicine at Dartmouth Hanover NH USA

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston MA USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Epidemiology School of Public Health University of Washington Seattle WA USA

Department of Family Medicine University of Virginia Charlottesville VA USA

Department of General Surgery University of Virginia School of Medicine Charlottesville VA USA

Department of Genetics and Genome Sciences Case Western Reserve University Cleveland OH USA

Department of Genetics Stanford University Stanford CA USA

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston MA USA

Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale AZ USA

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA USA

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Nutritional Sciences University of Michigan School of Public Health Ann Arbor MI USA

Department of Population and Public Health Sciences and USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Population Health Sciences University of Utah Salt Lake City UH USA

Department of Population Science American Cancer Society Atlanta GA USA

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Public Health Sciences Center for Public Health Genomics Charlottesville VA USA

Division of Biostatistics Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles CA USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Division of Human Nutrition and Health Wageningen University and Research Wageningen The Netherlands

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

German Cancer Consortium Heidelberg Germany

Huntsman Cancer Institute University of Utah Salt Lake City UT USA

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto ON Canada

Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

Memorial University of Newfoundland Discipline of Genetics St John's NL Canada

Nantes Université CHU Nantes Service de Génétique médicale F 44000 Nantes France

Nutrition and Metabolism Branch International Agency for Research on Cancer Lyon France

ONCOBEL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Oncology Data Analytics Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VIC Australia

Public Health Sciences Division Fred Hutchinson Cancer Center Seattle WA USA

Research Centre for Hauora and Health Massey University Wellington New Zealand

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

School of Public Health Capital Medical University Beijing China

School of Public Health Imperial College London London United Kingdom

School of Public Health University of Washington Seattle WA USA

Slone Epidemiology Center at Boston University Boston MA USA

SWOG Statistical Center Fred Hutchinson Cancer Center Seattle WA USA

Unit of Biomarkers and Susceptibility Oncology Data Analytics Program Catalan Institute of Oncology Barcelona 08908 Spain

Unit of Nutrition Environment and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology Avda Gran Via Barcelona 199 203 08908L'Hospitalet de Llobregat Barcelona Spain

University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

University of Hawaii Cancer Center Honolulu HI USA

See more in PubMed

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. doi: 10.3322/caac.21660. PubMed DOI

Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 2019;51:76–87. doi: 10.1038/s41588-018-0286-6. PubMed DOI PMC

Schmit SL, Edlund CK, Schumacher FR, Gong J, Harrison TA, Huyghe JR, et al. Novel common genetic susceptibility loci for colorectal cancer. J Natl Cancer Inst. 2019;111:146–57.. doi: 10.1093/jnci/djy099. PubMed DOI PMC

Pearson-Stuttard J, Papadimitriou N, Markozannes G, Cividini S, Kakourou A, Gill D, et al. Type 2 diabetes and cancer: an umbrella review of observational and Mendelian randomisation studies. Cancer Epidemiol. Biomarkers Prev. 2021;30:1218–28. PubMed PMC

Chang CK, Ulrich CM. Hyperinsulinaemia and hyperglycaemia: possible risk factors of colorectal cancer among diabetic patients. Diabetologia. 2003;46:595–607. doi: 10.1007/s00125-003-1109-5. PubMed DOI

Yang T, Li X, Montazeri Z, Little J, Farrington SM, Ioannidis JPA, et al. Gene-environment interactions and colorectal cancer risk: an umbrella review of systematic reviews and meta-analyses of observational studies. Int J Cancer. 2019;145:2315–29.. doi: 10.1002/ijc.32057. PubMed DOI PMC

Sainz J, Rudolph A, Hoffmeister M, Frank B, Brenner H, Chang-Claude J, et al. Effect of type 2 diabetes predisposing genetic variants on colorectal cancer risk. J Clin Endocrinol Metab. 2012;97:E845–51. doi: 10.1210/jc.2011-2565. PubMed DOI

Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, et al. Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis. Gastroenterology. 2013;144:799–807.e24. doi: 10.1053/j.gastro.2012.12.020. PubMed DOI PMC

Schumacher FR, Schmit SL, Jiao S, Edlund CK, Wang H, Zhang B, et al. Genome-wide association study of colorectal cancer identifies six new susceptibility loci. Nat Commun. 2015;6:7138. doi: 10.1038/ncomms8138. PubMed DOI PMC

Hutter CM, Chang-Claude J, Slattery ML, Pflugeisen BM, Lin Y, Duggan D, et al. Characterization of gene-environment interactions for colorectal cancer susceptibility loci. Cancer Res. 2012;72:2036–44. doi: 10.1158/0008-5472.CAN-11-4067. PubMed DOI PMC

Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–7. doi: 10.1038/ng.3656. PubMed DOI PMC

Morrison J. Binarydosage: a package to create, merge, and read binary genotype files. Version 1.0. https://cran.rstudio.com/web/packages/BinaryDosage. 2020.

Hartung J, Knapp G. A refined method for the meta-analysis of controlled clinical trials with binary outcome. Stat Med. 2001;20:3875–89. doi: 10.1002/sim.1009. PubMed DOI

Cochran WG. The combination of estimates from different experiments. Int. Biometric Soc. 1954;10:101–29.

Morrison J, Gauderman J. GxEScanR: an R package to detect GxE interactions in a genomewide association study. Version 2.0 https://github.com/USCbiostats/GxEScanR. 2020.

Gauderman WJ, Zhang P, Morrison JL, Lewinger JP. Finding novel genes by testing G x E interactions in a genome-wide association study. Genet Epidemiol. 2013;37:603–13. doi: 10.1002/gepi.21748. PubMed DOI PMC

Gauderman WJ, Kim A, Conti DV, Morrison J, Thomas DC, Vora H, et al. A unified model for the analysis of gene-environment interaction. Am J Epidemiol. 2019;188:760–7. doi: 10.1093/aje/kwy278. PubMed DOI PMC

Kooperberg C, Leblanc M. Increasing the power of identifying gene x gene interactions in genome-wide association studies. Genet Epidemiol. 2008;32:255–63. doi: 10.1002/gepi.20300. PubMed DOI PMC

Murcray CE, Lewinger JP, Gauderman WJ. Gene-environment interaction in genome-wide association studies. Am J Epidemiol. 2009;169:219–26. doi: 10.1093/aje/kwn353. PubMed DOI PMC

Ionita-Laza I, McQueen MB, Laird NM, Lange C. Genomewide weighted hypothesis testing in family-based association studies, with an application to a 100K scan. Am J Hum Genet. 2007;81:607–14. doi: 10.1086/519748. PubMed DOI PMC

Kawaguchi E, Kim A, Lewinger JP, Gauderman WJ. A novel data-driven approach to two-stage hypothesis testing for discovery of gene-environment interactions. bioRxiv. https://www.biorxiv.org/content/10.1101/2022.06.14.496154v1.full 2022. DOI

Dai JY, Logsdon BA, Huang Y, Hsu L, Reiner AP, Prentice RL, et al. Simultaneously testing for marginal genetic association and gene-environment interaction. Am J Epidemiol. 2012;176:164–73. doi: 10.1093/aje/kwr521. PubMed DOI PMC

Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ. Exploiting gene-environment interaction to detect genetic associations. Hum Hered. 2007;63:111–9. doi: 10.1159/000099183. PubMed DOI

Zheng J, Li Y, Abecasis GR, Scheet P. A comparison of approaches to account for uncertainty in analysis of imputed genotypes. Genet Epidemiol. 2011;35:102–10. doi: 10.1002/gepi.20552. PubMed DOI PMC

Peeters PJ, Bazelier MT, Leufkens HG, de Vries F, De Bruin ML. The risk of colorectal cancer in patients with type 2 diabetes: associations with treatment stage and obesity. Diabetes Care. 2015;38:495–502. doi: 10.2337/dc14-1175. PubMed DOI

de Bakker PI, Ferreira MA, Jia X, Neale BM, Raychaudhuri S, Voight BF. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet. 2008;17:R122–8. doi: 10.1093/hmg/ddn288. PubMed DOI PMC

Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004. doi: 10.1111/j.0006-341X.1999.00997.x. PubMed DOI

Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7. doi: 10.1093/bioinformatics/btq419. PubMed DOI PMC

Diez-Obrero V, Dampier CH, Moratalla-Navarro F, Devall M, Plummer SJ, Diez-Villanueva A, et al. Genetic effects on transcriptome profiles in colon epithelium provide functional insights for genetic risk loci. Cell Mol Gastroenterol Hepatol. 2021;12:181–97.. doi: 10.1016/j.jcmgh.2021.02.003. PubMed DOI PMC

Cohen AJ, Saiakhova A, Corradin O, Luppino JM, Lovrenert K, Bartels CF, et al. Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome. Nat Commun. 2017;8:14400. doi: 10.1038/ncomms14400. PubMed DOI PMC

Lee J, Jolanki O, Kim D, Strattan JS, Kundaje A, Nordström K, et al. ENCODE-DCC/atac-seq-pipeline: v1.9.1. https://zenodo.org/record/4204092 2020.

Lee J, Strattan JS, Shcherbina A, Kagda M, Maurizio PL. ENCODE-DCC/chip-seq-pipeline2: v1.6.1. https://github.com/ENCODE-DCC/chip-seq-pipeline2 2020.

Li Q, Brown JB, Huang H, Bickel PJ. Measuring reproducibility of high-throughput experiments. Ann Appl Stat. 2011;5:1752–79.. doi: 10.1214/11-AOAS466. DOI

Lopez-Delisle L, Rabbani L, Wolff J, Bhardwaj V, Backofen R, Gruning B, et al. pyGenomeTracks: reproducible plots for multivariate genomic datasets. Bioinformatics. 2021;37:422–3. doi: 10.1093/bioinformatics/btaa692. PubMed DOI PMC

Quinlan AR. BEDTools: the Swiss-army tool for genome feature analysis. Curr Protoc Bioinforma. 2014;47:1–34. PubMed PMC

Lee D. LS-GKM: a new gkm-SVM for large-scale datasets. Bioinformatics. 2016;32:2196–8. doi: 10.1093/bioinformatics/btw142. PubMed DOI PMC

Su YR, Di CZ, Hsu L, Genetics, Epidemiology of Colorectal Cancer C. A unified powerful set-based test for sequencing data analysis of GxE interactions. Biostatistics. 2017;18:119–31.. doi: 10.1093/biostatistics/kxw034. PubMed DOI PMC

Gallagher EJ, LeRoith D. Hyperinsulinaemia in cancer. Nat Rev Cancer. 2020;20:629–44.. doi: 10.1038/s41568-020-0295-5. PubMed DOI

Murphy N, Song M, Papadimitriou N, Carreras-Torres R, Langenberg C, Martin RM, et al. Associations between glycemic traits and colorectal cancer: a Mendelian randomization analysis. J Natl Cancer Inst. 2022;114:740–52.. doi: 10.1093/jnci/djac011. PubMed DOI PMC

Lichten LA, Cousins RJ. Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr. 2009;29:153–76. doi: 10.1146/annurev-nutr-033009-083312. PubMed DOI

Jansen J, Karges W, Rink L. Zinc and diabetes-clinical links and molecular mechanisms. J Nutritional Biochem. 2009;20:399–417. doi: 10.1016/j.jnutbio.2009.01.009. PubMed DOI

Taylor CG. Zinc, the pancreas, and diabetes: insights from rodent studies and future directions. Biometals. 2005;18:305–12. doi: 10.1007/s10534-005-3686-x. PubMed DOI

Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14:1483–96.. doi: 10.7150/ijbs.27173. PubMed DOI PMC

Arcidiacono B, Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V, et al. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res. 2012;2012:789174. doi: 10.1155/2012/789174. PubMed DOI PMC

Argiles JM, Lopez-Soriano FJ. Insulin and cancer (Review) Int J Oncol. 2001;18:683–7. PubMed

Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445:881–5. doi: 10.1038/nature05616. PubMed DOI

Boesgaard TW, Zilinskaite J, Vanttinen M, Laakso M, Jansson PA, Hammarstedt A, et al. The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients-the EUGENE2 study. Diabetologia. 2008;51:816–20. doi: 10.1007/s00125-008-0955-6. PubMed DOI

Xu X, Han L, Zhao G, Xue S, Gao Y, Xiao J, et al. LRCH1 interferes with DOCK8-Cdc42-induced T cell migration and ameliorates experimental autoimmune encephalomyelitis. The. J Exp Med. 2017;214:209–26.. doi: 10.1084/jem.20160068. PubMed DOI PMC

Vega FM, Ridley AJ. Rho GTPases in cancer cell biology. FEBS Lett. 2008;582:2093–101. doi: 10.1016/j.febslet.2008.04.039. PubMed DOI

Gao L, Bai L, Nan Q. Activation of Rho GTPase Cdc42 promotes adhesion and invasion in colorectal cancer cells. Med Sci Monit Basic Res. 2013;19:201–7. doi: 10.12659/MSMBR.883983. PubMed DOI PMC

Gomez Del Pulgar T, Valdes-Mora F, Bandres E, Perez-Palacios R, Espina C, Cejas P, et al. Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism. Int J Oncol. 2008;33:185–93. PubMed

Wang Y, Zhang H, He H, Ai K, Yu W, Xiao X, et al. LRCH1 suppresses migration of CD4(+) T cells and refers to disease activity in ulcerative colitis. Int J Med Sci. 2020;17:599–608. doi: 10.7150/ijms.39106. PubMed DOI PMC

Orange JS, Ramesh N, Remold-O’Donnell E, Sasahara Y, Koopman L, Byrne M, et al. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci USA. 2002;99:11351–6. doi: 10.1073/pnas.162376099. PubMed DOI PMC

Dai K, Chen Z, She S, Shi J, Zhu J, Huang Y. Leucine rich repeats and calponin homology domain containing 1 inhibits NK-92 cell cytotoxicity through attenuating Src signaling. Immunobiology. 2020;225:151934. doi: 10.1016/j.imbio.2020.151934. PubMed DOI

Huang QY, Lai XN, Qian XL, Lv LC, Li J, Duan J, et al. Cdc42: a novel regulator of insulin secretion and diabetes-associated diseases. International journal of molecular sciences. 2019;20:179. PubMed PMC

Wang Z, Oh E, Clapp DW, Chernoff J, Thurmond DC. Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. J Biol Chem. 2011;286:41359–67.. doi: 10.1074/jbc.M111.291500. PubMed DOI PMC

Xia Z, Su YR, Petersen P, Qi L, Kim AE, Figueiredo JC, et al. Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk. Cancer Med. 2020;9:3563–73.. doi: 10.1002/cam4.2971. PubMed DOI PMC

Kamarudin MNA, Sarker MMR, Zhou JR, Parhar I. Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects. J Exp Clin Cancer Res. 2019;38:491. doi: 10.1186/s13046-019-1495-2. PubMed DOI PMC