HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein-Barr virus type 1 (EBV-1) infection. We carried out a genome-wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA-A to NPC with the strongest signal detected in rs3869062 (p = 1.73 × 10(-9)). HLA-A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p(HLA-A-aa-site-99) = 3.79 × 10(-8), p(rs1136697) = 3.79 × 10(-8)) and T-cell receptor binding site (p(HLA-A-aa-site-145) = 1.41 × 10(-4), p(rs1059520) = 1.41 × 10(-4)) of the HLA-A. We also detected strong association signals in the 5'-UTR region with predicted active promoter states (p(rs41545520) = 7.91 × 10(-8)). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520-G correlated with reduced HLA-A expression. Multivariate logistic regression diminished the effects of HLA-A amino acid variants and SNPs, indicating a correlation with the effects of HLA-A*11:01, and to a lesser extent HLA-A*02:07. We report the strong genetic influence of HLA-A on NPC susceptibility in the Malaysian Chinese.