Abstract 3445: C-reactive protein and lung cancer risk: a Mendelian randomization analysis

Abstract

Abstract Background: Elevated levels of C-reactive protein (CRP) are associated with increased risk of lung cancer in observational studies. We investigated the causal relation between CRP and lung cancer using previously discovered single-nucleotide polymorphisms (SNPs) associated with CRP levels as genetic instruments. Methods: We analyzed four lung cancer case-control studies (EAGE, PLCO, ATBC, CPSII) with available GWAS data (total 5,713 cases and 5,736 controls). We identified 21 SNPs associated with CRP levels at P<10-7 in genome-wide association studies (GWAS) and constructed a weighted polygenic score (PGS) multiplying the number of CRP-increasing alleles in each locus by the GWAS-reported effect of the respective allele on CRP levels; this is the largest number of CRP SNPs used in a Mendelian randomization for lung cancer to date. We first examined whether the PGS is associated with smoking phenotypes (smoking status, cigarettes per day, pack-years, smoking duration). Subsequently, we used this PGS as an instrumental variable and estimated the odds ratio (OR) and 95% confidence interval (CI) of lung cancer per standard deviation change in the PGS using logistic regression and adjusting for age, gender, and smoking. We conducted subgroup analyses for different types of lung cancer histologies. Analyses were performed separately for each study and study-specific results were combined through random-effect meta-analysis. Results: The PGS was not significantly associated with the number of cigarettes smoked per day (P = 0.621), pack-years (P = 0.829), smoking status (0.739), or smoking duration (P = 0.743). Overall, there was no association between PGS and lung cancer risk in EAGLE (OR = 1.02, 95% CI 0.77-1.36; P = 0.876), PLCO (OR = 0.94, 95% CI 0.68-1.31; P = 0.722), ATBC (OR = 0.80, 95% CI 0.59-1.07; P = 0.132), or CPSII (OR = 0.61, 95% CI 0.37-1.02; P = 0.059) as well as after meta-analysis (OR = 0.88, 95% CI 0.73-1.05; P = 0.149; I2 = 17.3%]. Meta-analysis results were similar for adenocarcinoma (OR = 0.94, 95% CI 0.74-1.20; P = 0.630; I2 = 9.3%), squamous cell carcinoma (OR = 1.03, 95% CI 0.79-1.34; P = .844; I2 = 0%), small-cell lung cancer (OR = 0.97, 95% CI 0.62-1.50; P = 0.882; I2 = 34.9%), and other non-small cell lung cancer (OR = 0.93 (0.53-1.65), P = 0.815, I2 = 59.2%). Conclusions: Genetically elevated CRP levels are not associated with the risk lung cancer. Hence, our results provide no evidence of causality between CRP and lung cancer. Citation Format: Orestis A. Panagiotou, Neil E. Caporaso, Maria T. Landi, Nilanjan Chatterjee, NCI Lung Cancer GWAS Group. C-reactive protein and lung cancer risk: a Mendelian randomization analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3445.