Genetically determined elevated C-reactive protein associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions.

Systemic inflammation-related etiologic pathways via inflammatory cytokines 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. 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. 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 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 ( 10 years) of E plus progestin. 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.