Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200 139 SNPs of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer GWAS. Discovery data included 18 082 cases and 13 780 controls of European ancestry. Replication data included 1914 cases and 3065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH (rs34577742 C > T, OR = 0.90, 95% CI = 0.89–0.93, P = 7.64x10−9) and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10–1.21, P = 1.27x10−9) associated with overall lung cancer in the discovery data and validated in an independent replication data—CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80–0.96, P = 5.76x10−3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01–1.28, P = 3.25x10−2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85–0.92, P = 1.94x10−7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14–1.27, P = 4.25x10−11) associated with overall lung cancer in the discovery data and validated in the replication data—CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79–0.97, P = 1.64x10−2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01–1.30, P = 3.81x10−2). Subsequent TWAS using expression weights from a lung eQTL study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44x10−4) and SFTA2 (PTWAS = 2.32x10−6).