A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
Authors: Aglago Elom K. , Kim Andre , Lin Yi , Qu Conghui , Evangelou Marina , Ren Yu , Morrison John , Albanes Demetrius , Arndt Volker , Barry Elizabeth L. , Baurley James W. , Berndt Sonja I. , Bien Stephanie A. , Bishop D. Timothy , Bouras Emmanouil , Brenner Hermann , Buchanan Daniel D. , Budiarto Arif , Carreras-Torres Robert , Casey Graham , Cenggoro Tjeng Wawan , Chan Andrew T. , Chang-Claude Jenny , Chen Xuechen , Conti David V. , Devall Matthew , Diez-Obrero Virginia , Dimou Niki , Drew David , Figueiredo Jane C. , Gallinger Steven , Giles Graham G. , Gruber Stephen B. , Gsur Andrea , Gunter Marc J. , Hampel Heather , Harlid Sophia , Hidaka Akihisa , Harrison Tabitha A. , Hoffmeister Michael , Huyghe Jeroen R. , Jenkins Mark A. , Jordahl Kristina , Joshi Amit D. , Kawaguchi Eric S. , Keku Temitope O. , Kundaje Anshul , Larsson Susanna C. , Marchand Loic Le , Lewinger Juan Pablo , Li Li , Lynch Brigid M. , Mahesworo Bharuno , Mandic Marko , Obón-Santacana Mireia , Moreno Victor , Murphy Neil , Nan Hongmei , Nassir Rami , Newcomb Polly A. , Ogino Shuji , Ose Jennifer , Pai Rish K. , Palmer Julie R. , Papadimitriou Nikos , Pardamean Bens , Peoples Anita R. , Platz Elizabeth A. , Potter John D. , Prentice Ross L. , Rennert Gad , Ruiz-Narvaez Edward , Sakoda Lori C. , Scacheri Peter C. , Schmit Stephanie L. , Schoen Robert E. , Shcherbina Anna , Slattery Martha L. , Stern Mariana C. , Su Yu-Ru , Tangen Catherine M. , Thibodeau Stephen N. , Thomas Duncan C. , Tian Yu , Ulrich Cornelia M. , van Duijnhoven Franzel JB , Van Guelpen Bethany , Visvanathan Kala , Vodicka Pavel , Wang Jun , White Emily , Wolk Alicja , Woods Michael O. , Wu Anna H. , Zemlianskaia Natalia , Hsu Li , Gauderman W. James , Peters Ulrike , Tsilidis Konstantinos K. , Campbell Peter T. 
Published: May 2023

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.

Significance:

This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.