Abstract 825: Genetically determined elevated C-reactive protein levels and chronic inflammation status associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions

Abstract Purpose: Immune-related etiologic pathways in the development of colorectal cancer (CRC) have not been convincingly determined and may be confounded by lifestyle factors or reverse causality. We investigated the genetically predicted C-reactive protein (CRP) phenotype in the potential causal pathway of primary CRC risk in postmenopausal women in a Mendelian randomization (MR) framework. Methods: We employed individual-level data of the Women's Health Initiative Database for Genotypes and Phenotypes Study, which consists of 5 genome-wide association (GWA) studies, including 10,142 women, 737 of whom developed primary CRC. We examined 61 GWA single-nucleotide polymorphisms (SNPs) associated with CRP by using weighted/penalized MR weighted-medians and MR gene-environment interactions that allow some relaxation of the strict variable requirements and attenuate the heterogeneous estimates of outlying SNPs. Results: In lifestyle-stratification analyses, genetically determined CRP exhibited its effects on the decreased CRC risk in non-viscerally obese and high-fat diet subgroups. In contrast, genetically driven CRP was associated with an increased risk for CRC in women who smoked 15 or more cigarettes/day, with significant interaction of the gene-smoking relationship. Further, a substantially increased risk of CRC induced by CRP was observed in relatively short-term users (less than 5 years) of estrogen (E)-only and also longer-term users (longer than 5 years) of E plus progestin. Conclusions: Our findings may provide novel evidence on immune-related etiologic pathways connected to CRC risk and suggest the possible use of CRP as a CRC-predictive biomarker in women with particular behaviors and CRP marker-informed interventions to reduce CRC risk. Citation Format: Su Yon Jung, Herbert Yu, Matteo Pellegrini, Jeanette C. Papp, Eric M. Sobel, Zuo-Feng Zhang. Genetically determined elevated C-reactive protein levels and chronic inflammation status associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions [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 825.