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  • Title: Fine-mapping the MHC region in Asian populations identified novel variants modifying susceptibility to lung cancer.
    Author: Qin N, Wang C, Zhu M, Lu Q, Ma Z, Huang M, Dai J, Ma H, Jin G, Hu Z, Shen H.
    Journal: Lung Cancer; 2017 Oct; 112():169-175. PubMed ID: 29191591.
    Abstract:
    OBJECTIVES: The 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 METHODS: In 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. RESULTS: We 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. CONCLUSION: We 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.
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