No association between genetically predicted C-reactive protein levels and colorectal cancer survival in Korean: two-sample Mendelian randomization analysis

Abstract

Objectives: Elevated C-reactive protein (CRP) is associated with an increased risk for, and poor prognosis of, colorectal cancer (CRC), but it remains unclear whether these associations are causal. This study examined potential causality between CRP levels and CRC survival using two-sample Mendelian randomization (MR).Methods: From the Korean Genome and Epidemiology Study, a genome-wide association study (n = 59,605), 7 single nucleotide polymorphisms (SNPs) related to log2-transformed CRP levels were extracted as instrumental variables for CRP levels. The associations between the genetically predicted CRP and CRC-specific and overall mortality among CRC patients (n=6,460) were evaluated by Aalen’s additive hazard model. The sensitivity analysis excluded the SNP related to the blood lipid profile. Results: During a median of 8.5 years of follow-up, among 6,460 CRC patients, 2,676 (41.4%) CRC patients died, 1,622 (25.1%) from CRC. Genetically predicted CRP was not significantly associated with the overall or CRC-specific mortality in CRC patients. The hazard difference per 1,000 person-year (95% confidence interval) for overall and CRC-specific mortality per two-fold increase in CRP was -2.92 (-14.05–8.21) and -0.76 (-9.61–8.08), respectively. These associations were consistent in subgroup analysis according to metastasis and sensitivity analysis excluding the possible pleiotropic SNP. Conclusions: Our findings do not support causal roles for genetically predisposed CRP levels in CRC survival.