Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses
Authors: Dimou Niki , Kim Andre E. , Flanagan Orlagh , Murphy Neil , Diez-Obrero Virginia , Shcherbina Anna , Aglago Elom K. , Bouras Emmanouil , Campbell Peter T. , Casey Graham , Gallinger Steven , Gruber Stephen B. , Jenkins Mark A. , Lin Yi , Moreno Victor , Ruiz-Narvaez Edward , Stern Mariana C. , Tian Yu , Tsilidis Kostas K. , Arndt Volker , Barry Elizabeth L. , Baurley James W. , Berndt Sonja I. , Bézieau Stéphane , Bien Stephanie A. , Bishop D. Timothy , Brenner Hermann , Budiarto Arif , Carreras-Torres Robert , Cenggoro Tjeng Wawan , Chan Andrew T. , Chang-Claude Jenny , Chanock Stephen J. , Chen Xuechen , Conti David V. , Dampier Christopher H. , Devall Matthew , Drew David A. , Figueiredo Jane C. , Giles Graham G. , Gsur Andrea , Harrison Tabitha A. , Hidaka Akihisa , Hoffmeister Michael , Huyghe Jeroen R. , Jordahl Kristina , Kawaguchi Eric , Keku Temitope O. , Larsson Susanna C. , Le Marchand Loic , Lewinger Juan Pablo , Li Li , Mahesworo Bharuno , Morrison John , Newcomb Polly A. , Newton Christina C. , Obon-Santacana Mireia , Ose Jennifer , Pai Rish K. , Palmer Julie R. , Papadimitriou Nikos , Pardamean Bens , Peoples Anita R. , Pharoah Paul D. P. , Platz Elizabeth A. , Potter John D. , Rennert Gad , Scacheri Peter C. , Schoen Robert E. , Su Yu-Ru , Tangen Catherine M. , Thibodeau Stephen N. , Thomas Duncan C. , Ulrich Cornelia M. , Um Caroline Y. , van Duijnhoven Franzel J. B. , Visvanathan Kala , Vodicka Pavel , Vodickova Ludmila , White Emily , Wolk Alicja , Woods Michael O. , Qu Conghui , Kundaje Anshul , Hsu Li , Gauderman W. James , Gunter Marc J. , Peters Ulrike 
Published: June 2023

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.