title: HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese.
abstract: 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.
authors.affiliation: Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan; Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, 50603, Malaysia.
authors.forename: Yoon-Ming
authors.initials: YM
authors.lastname: Chin
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Gopala
authors.initials: G
authors.lastname: Krishnan
authors.forename: Lee-Fah
authors.initials: LF
authors.lastname: Yap
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
authors.forename: Paul Vey-Hong
authors.initials: PV
authors.lastname: Lim
authors.forename: Yoke-Yeow
authors.initials: YY
authors.lastname: Yap
authors.forename: Kin-Choo
authors.initials: KC
authors.lastname: Pua
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Choon-Kook
authors.initials: CK
authors.lastname: Sam
authors.forename: Alan Soo-Beng
authors.initials: AS
authors.lastname: Khoo
authors.forename: Ching-Ching
authors.initials: CC
authors.lastname: Ng
mesh_terms: D000596:Amino Acids / Q000032:analysis; D044466:Asian People; D002277:Carcinoma; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D008296:Malaysia; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000596:Amino Acids; D015234:HLA-A Antigens
keywords: GWAS; HLA-A; Malaysian Chinese; imputation; nasopharyngeal carcinoma