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

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• 作者：Yoon-Ming Chin ; Taisei Mushiroda ; Atsushi Takahashi ; Michiaki Kubo ; Gopala Krishnan ; Lee-Fah Yap ; Soo-Hwang Teo ; Paul Vey-Hong Lim ; Yoke-Yeow Yap ; Kin-Choo Pua ; Naoyuki Kamatani ; Yusuke Nakamura ; Choon-Kook Sam ; Alan Soo-Beng Khoo ; The Malaysian NPC Study Group and Ching-Ching Ng
• 关键词：nasopharyngeal carcinoma ; HLA-A ; GWAS ; imputation ; Malaysian Chinese
• 刊名：International Journal of Cancer
• 出版年：2015
• 出版时间：1 February 2015
• 年：2015
• 卷：136
• 期：3
• 页码：678-687
• 全文大小：531K
• ISSN：1097-0215

文摘

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.