Research paperFine-mapping the MHC region in Asian populations identified novel variants modifying susceptibility to lung cancer

•We conducted a fine-mapping study of the MHC region in 13,945 Asian individuals.•Three independent loci were found significantly associated with lung cancer risk.•We identified a multiplicative interaction effect between rs12333226 and age.•Rs12333226 is a eQTL of HLA-A and HLA-H in monocytes.•HLA-DRβ1 positions 10, 16 and 25 may drive the effect of a reported SNP rs2395185.

ObjectivesThe polymorphic major histocompatibility complex (MHC) plays a vital role in the immune system and drives predisposition to multiple cancers. A number of lung cancer-related genetic variants in the MHC have been identified in recent genome-wide association studies; however, the causal variants remain unclear.Materials and methodsIn the present study, we conducted a large-scale fine-mapping study of lung cancer in the MHC region of 13,945 unrelated Asian individuals to search for potential causal variants. We used the recently constructed Pan-Asian panel as the reference and imputed eight HLA genes (HLA-A, HLC-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) using SNP2HLA software.ResultsWe identified one single nucleotide polymorphism, rs12333226 (OR = 1.41, P = 3.97 × 10−7), five HLA amino acid polymorphisms in HLA-DRB1 (OR = 0.89, P = 7.51 × 10−6-8.57 × 10−6), and one two-digit classic HLA allele HLA-A*11 (OR = 0.87, P = 9.68 × 10−6) that were strongly associated with the risk of lung cancer. Rs12333226 was an expression quantitative trait locus of HLA-A and HLA-H in circulating monocytes, and exerted effect on lung cancer risk especially in the younger. HLA-DRβ1 positions 10, 16, and 25 drove the effect of one reported SNP rs2395185. The peptide position analysis identified additional lung cancer susceptibility amino acid positions, including HLA-DRβ1 position 30 and 11 (Pomnibus = 6.11 × 10−5 and 6.91 × 10−5), HLA-DQa1 47 and 76 (Pomnibus = 3.96 × 10−4 and 1.41 × 10−2) and HLA-A 152 (Pomnibus = 4.86 × 10−4). Most of the peptide positions were located in the peptide-binding grooves and seemed to affect antigen presentation. All the existing and novel variants explained approximately 2.37% of the phenotypic variances, while 21.10% was attributed to the variants identified in this study.ConclusionWe identified seven novel bi-allelic variants and five polymorphic amino acid positions in HLA-DRβ1, HLA-DQα1, and HLA-A that confer a risk of lung cancer. This finding provides evidence for the substantial contributions of HLA class I and II molecules to lung cancer susceptibility.