Genetic variants in the human leukocyte antigen region and survival of Chinese patients with non-small cell lung carcinoma

Abstract

Abstract Human leukocyte antigen (HLA) is highly polymorphic, driving antigen presentation, complement cascade and leukocyte maturation against cancer cells. Therefore, we extracted genotyping data in the HLA region from an ongoing Chinese genome-wide association study of non-small cell lung cancer (NSCLC). Using deep sequencing data of 10 689 healthy Han Chinese, we imputed for untyped genetic variants in the HLA region, followed by a two-stage survival analysis of 1531 NSCLC patients. In the discovery stage of 758 patients, we identified 301 out of 15 138 single-nucleotide polymorphisms to be independently associated with overall survival [P < 0.05 and Bayesian false-discovery probability < 0.8]. In further validation of another 773 patients, we confirmed chromosome 6p21, rs241424 (located at intron 3 of TAP2) and rs6457642 as two independent survival predictors. In the combined analysis of 1531 NSCLC patients, rs241424 G>A and rs6457642 C>T were associated with a hazards ratio of 1.26 [95% confidence interval (CI) = 1.14–1.40 and P = 4.04 × 10−6] and 0.76 (95% CI = 0.66–0.87 and P = 1.16 × 10−4), respectively. The analysis of publically available ChIP-sequencing and Hi-C data found that the rs241424 locus was involved in potential cis-regulatory element by a long-range interaction with the HLA-DQA1 promoter. Additional expression quantitative trait loci analysis showed that the rs241424 G>A change decreased HLA-DQA1 mRNA expression. Furthermore, expression levels of HLA-DQA1 were lower in lung cancer tissues than in adjacent normal tissues, and the lower expression was associated with a worse prognosis for patients with lung adenocarcinoma. Collectively, HLA genetic variants may modulate OS of NSCLC patients, possibly via a mechanism of long-range promoter interaction regulating HLA-DQA1 expression.