Fine Mapping in Chromosome 3q28 Identified Two Variants Associated with Lung Cancer Risk in Asian Population

Genome-wide association studies (GWASs) have consistently identified chromosome 3q28 as a lung cancer susceptibility region. To further characterize the potential genetic mechanism of the variants in this region, we conducted a fine-mapping study on chromosome 3q28 region. We performed a target resequencing in 200 lung cancer cases and 300 controls in the screening and followed by validation in multi-ethnic lung cancer GWASs with 12,843 cases and 12,639 controls. For our identified novel variants, we conducted expression quantitative trait loci (eQTL) analysis to reveal the potential target genes. Two susceptibility variants were identified (rs4396880: G>A, OR = 0.35, 95%CI: 0.20-0.62, P = 3.01×10^-4; and rs3856776: C>T, OR = 2.05, 95%CI: 1.32-3.18, P = 1.49×10^-3) and further supported in Asian population (rs4396880: OR = 0.88, P = 7.43×10^-6; and rs3856776: OR =1.17, P = 1.64×10^-4). The eQTL analysis showed the A allele of rs4396880 was significantly associated with higher mRNA expression of TP63 (P = 1.70×10^-4) in lung tissues, while rs3856776 showed significant association with the expression of LEPREL1-AS1 (P = 6.90×10^-3), which was the antisense RNA of LEPREL1 and could suppress the translation of LEPREL1. Notably, LEPREL1 was aberrantly downregulated (P = 2.54×10^-18) in lung tumor tissues based on TCGA database. In conclusion, this is the first fine-mapping analysis of 3q28 region in Han Chinese, and we found two variants associated with lung cancer susceptibility in Asian population. What's more, rs3856776 was newly identified and might modulate lung cancer susceptibility by suppressing the function of LEPREL1.