Background: Elevated levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival and CRC prognostic factors, such as obesity, smoking, and alcohol consumption. However, the mechanisms underlying these associations are not well understood. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality.
Methods: This study included 16,142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium (ISACC). We identified 741 common single nucleotide polymorphisms (SNPs) associated with CRP (minor allele frequency >5% in European ancestry) from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for SNP-specific association with CRC-specific mortality adjusting for age, sex, genotyping platform/study, and the first three principal components of genetic ancestry. SNPs were examined using log-additive models. Likelihood ratio tests were used to investigate multiplicative gene-environment interactions between CRP-associated SNPs and sex, obesity, ever smoking, and alcohol consumption. We also conducted stratified analyses according to these factors. P values were adjusted using Bonferroni correction, with corrected P <0.05 considered statistically significant.
Results: After a median of 4.7 years (interquartile range = 2.3 to 7.7 years) of follow-up since diagnosis, 5,472 (33.9%) deaths accrued, 3,547 (64.8%) of which were due to CRC. No variants were statistically significantly associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC mortality (corrected Pinteraction = 0.0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04 to 1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82 to 0.94). There was no evidence of statistically significant interactions between CRP-associated SNPs and alcohol, obesity or smoking in association with CRC-specific mortality.
Conclusions: Our study observed a statistically significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.
Citation Format: Yuhan Huang, Xinwei Hua, Julia D. Labadie, Tabitha A. Harrison, James Dai, Sara Lindstrom, Yi Lin, Sonja I. Berndt, Daniel D. Buchanan, Peter T. Campbell, Graham Casey, Steven J. Gallinger, Marc J. Gunter, Michael Hoffmeister, Mark A. Jenkins, Lori C. Sakoda, Robert E. Schoen, Brenda Diergaarde, Martha L. Slattery, Emily White, Roger Milne, Graham Giles, Andrew T. Chan, Ulrike Peters, Polly A. Newcomb. Genetic variants associated with C-reactive protein and colorectal cancer survival: Sex- and lifestyle factors- specific associations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 816.