Genome-wide analysis of expression quantitative trait loci identified potential lung cancer susceptibility variants among Asian populations

Abstract

Even though genome-wide association studies (GWASs) have identified dozens of single nucleotide polymorphisms (SNPs) affecting the susceptibility to lung cancer, only a tiny fraction of heritability can be explained. Regulating the expression of surrounding genes is one of the important mechanisms for SNPs to exert their effect. So it is necessary to systematically evaluate the associations between expression quantitative trait loci (eQTL) and lung cancer risk. In this study, a two-stage case-control design was used to evaluate the associations of eQTL SNPs (eSNPs) defined by GTEx in normal lung tissues with the risk of lung cancer based on two GWAS datasets, including 7127 cases and 6818 controls. Promising variants were replicated in an independent population with 1026 lung cancer cases and 1006 controls. Functional annotations of the identified eSNPs and related genes were performed based on multiple public databases. Finally, we identified two potential eSNPs associated with the risk of lung cancer in 3q28 [rs505974, OR = 0.90 (0.86 - 0.94), P = 6.51 × 10-6] and 21q22.3 [rs79589812, OR = 1.38 (1.21 - 1.58), P = 2.46 × 10-6]. Subgroup analysis showed rs505974 might interact with smoking behaviour. Gene-set enrichment and pathway analysis revealed that rs505974 may affect the susceptibility to lung cancer via regulating the expression of CLDN16, which may be involved in the chemical carcinogenesis pathway, whereas rs79589812 may regulate the expression of SPATC1L, which may be involved in the base excision repair pathway. These results provide an overview of the associations between eSNPs and lung cancer in Asian populations.