title: The principal genetic determinants for nasopharyngeal carcinoma in China involve the HLA class I antigen recognition groove.
abstract: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA -B, and HLA -C class I genes (P(HLA-A-aa-site-62) = 7.4 × 10(-29); P (HLA-B-aa-site-116) = 6.5 × 10(-19); P (HLA-C-aa-site-156) = 6.8 × 10(-8) respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.
authors.affiliation: College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China.
authors.forename: Minzhong
authors.initials: M
authors.lastname: Tang
authors.forename: James A
authors.initials: JA
authors.lastname: Lautenberger
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Gao
authors.forename: Efe
authors.initials: E
authors.lastname: Sezgin
authors.forename: Sher L
authors.initials: SL
authors.lastname: Hendrickson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Troyer
authors.forename: Victor A
authors.initials: VA
authors.lastname: David
authors.forename: Li
authors.initials: L
authors.lastname: Guan
authors.forename: Carl E
authors.initials: CE
authors.lastname: McIntosh
authors.forename: Xiuchan
authors.initials: X
authors.lastname: Guo
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jian
authors.initials: J
authors.lastname: Liao
authors.forename: Hong
authors.initials: H
authors.lastname: Deng
authors.forename: Michael
authors.initials: M
authors.lastname: Malasky
authors.forename: Bailey
authors.initials: B
authors.lastname: Kessing
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Guy
authors.initials: G
authors.lastname: Dé The
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People; D002277:Carcinoma; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology; D006239:Haplotypes; D004854:Herpesvirus 4, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens