A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Area of Science:

• Genetics
• Epidemiology
• Oncology

Background:

• Colorectal cancer (CRC) risk is influenced by genetic, environmental, and lifestyle factors, including obesity.
• Gene-environment interactions (GxE) offer insights into obesity's impact on CRC.
• Understanding these interactions is crucial for developing targeted prevention strategies.

Purpose of the Study:

• To investigate genome-wide GxE interactions between body mass index (BMI) and single nucleotide polymorphisms (SNPs) for CRC risk.
• To identify specific genetic loci that modify the association between BMI and CRC.
• To explore the role of FMN1/GREM1 gene region in obesity-related CRC risk.

Main Methods:

• Utilized data from 36,415 CRC cases and 48,451 controls across three international consortia (CCFR, CORECT, GECCO).
• Employed logistic regression with multiplicative terms (1DF test), the two-step EDGE method, and the joint 3DF test for GxE interaction analysis.
• Assessed genome-wide interactions between common SNPs and BMI.

Main Results:

• A statistically significant GxE interaction between BMI and a SNP (rs58349661) in the FMN1/GREM1 gene region was identified using the two-step approach.
• This SNP was also suggested by the 3DF test and showed suggestive significance in the 1DF test.
• Individuals with the CC genotype of rs58349661 showed increased CRC risk with overweight and obesity, while TT genotype carriers had no significant association across BMI categories.

Conclusions:

• Discovered a novel locus in the FMN1/GREM1 gene region that interacts with BMI, affecting CRC risk.
• This finding underscores the importance of GxE interactions in the etiology of obesity-related CRC.
• Further research is warranted to elucidate the mechanisms underlying this interaction for potential precision prevention.