TY - JOUR
T1 - The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove
AU - Tang, Minzhong
AU - Lautenberger, James A.
AU - Gao, Xiaojiang
AU - Sezgin, Efe
AU - Hendrickson, Sher L.
AU - Troyer, Jennifer L.
AU - David, Victor A.
AU - Guan, Li
AU - Mcintosh, Carl E.
AU - Guo, Xiuchan
AU - Zheng, Yuming
AU - Liao, Jian
AU - Deng, Hong
AU - Malasky, Michael
AU - Kessing, Bailey
AU - Winkler, Cheryl A.
AU - Carrington, Mary
AU - dé The, Guy
AU - Zeng, Yi
AU - O'Brien, Stephen J.
PY - 2012/11
Y1 - 2012/11
N2 - 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 (PHLA-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.
AB - 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 (PHLA-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.
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U2 - 10.1371/journal.pgen.1003103
DO - 10.1371/journal.pgen.1003103
M3 - Article
C2 - 23209447
AN - SCOPUS:84870711835
SN - 1553-7390
VL - 8
JO - PLoS Genetics
JF - PLoS Genetics
IS - 11
M1 - e1003103
ER -