Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility.

ABSTRACT: BACKGROUND:Several genome-wide association studies (GWASs) have identified strong associations between genetic variants in the human leukocyte antigen (HLA) region and nasopharyngeal carcinoma (NPC). However, given the complex LD pattern in this region, the causal variants and the underlying mechanism of how genetic variants in HLA contribute to NPC development is yet to be understood. METHODS:To systematically characterize the HLA variants and their relationship to NPC susceptibility, we fine-mapped the HLA genes based on the GWAS data of 1583 NPC cases and 972 healthy controls, using SNP2HLA with the Pan-Asian panel as references. Stepwise conditional regression was used to identify independent association loci. RESULTS:Interestingly, the most significant association was the presence of Gln in HLA-A amino acid position 62 (OR = 0.57, P = 1.41 × 10-16 ). The G allele of rs2894207 located between HLA-B and HLA-C showed protective effect of NPC development (OR = 0.52, P = 2.23 × 10-13 ). Additionally, amino acid Phe-67 located in the peptide-binding pocket of HLA-DRB1 was identified as a novel functional variant with OR = 0.64 and P = 9.64 × 10-11 . Another novel variant, Glu-45 in HLA-B pocket B, conferred a protective effect on NPC susceptibility (OR = 0.64, P = 5.23 × 10-8 ). These four variants explained 2.07% of the phenotypic variance for NPC risk. CONCLUSION:In summary, by fine-mapping the HLA region in south Chinese population, we reported additional loci missed in the GWAS studies and provided a better understanding of the relationship between HLA and NPC susceptibility.

SUBMITTER: Wang TM 

PROVIDER: S-EPMC6308056 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature