PMID- 30378292 OWN - NLM STAT- MEDLINE DCOM- 20191114 LR - 20221207 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 7 IP - 12 DP - 2018 Dec TI - Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility. PG - 6308-6316 LID - 10.1002/cam4.1838 [doi] AB - BACKGROUND: Several genome-wide association studies (GWASs) have identified strong associations between genetic variants in the human leukocyte antigen (HLA) region and nasopharyngeal carcinoma (NPC). However, given the complex LD pattern in this region, the causal variants and the underlying mechanism of how genetic variants in HLA contribute to NPC development is yet to be understood. METHODS: To systematically characterize the HLA variants and their relationship to NPC susceptibility, we fine-mapped the HLA genes based on the GWAS data of 1583 NPC cases and 972 healthy controls, using SNP2HLA with the Pan-Asian panel as references. Stepwise conditional regression was used to identify independent association loci. RESULTS: Interestingly, the most significant association was the presence of Gln in HLA-A amino acid position 62 (OR = 0.57, P = 1.41 x 10(-16) ). The G allele of rs2894207 located between HLA-B and HLA-C showed protective effect of NPC development (OR = 0.52, P = 2.23 x 10(-13) ). Additionally, amino acid Phe-67 located in the peptide-binding pocket of HLA-DRB1 was identified as a novel functional variant with OR = 0.64 and P = 9.64 x 10(-11) . Another novel variant, Glu-45 in HLA-B pocket B, conferred a protective effect on NPC susceptibility (OR = 0.64, P = 5.23 x 10(-8) ). These four variants explained 2.07% of the phenotypic variance for NPC risk. CONCLUSION: In summary, by fine-mapping the HLA region in south Chinese population, we reported additional loci missed in the GWAS studies and provided a better understanding of the relationship between HLA and NPC susceptibility. CI - (c) 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Wang, Tong-Min AU - Wang TM AUID- ORCID: 0000-0003-0271-2098 AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Zhou, Ting AU - Zhou T AD - School of Public Health, Sun Yat-Sen University, Guangzhou, China. FAU - He, Yong-Qiao AU - He YQ AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Xue, Wen-Qiong AU - Xue WQ AUID- ORCID: 0000-0002-3824-8445 AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Zhang, Jiang-Bo AU - Zhang JB AUID- ORCID: 0000-0002-5546-7949 AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Zheng, Xiao-Hui AU - Zheng XH AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Li, Xi-Zhao AU - Li XZ AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Zhang, Shao-Dan AU - Zhang SD AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Zeng, Yi-Xin AU - Zeng YX AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. FAU - Jia, Wei-Hua AU - Jia WH AD - State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. AD - School of Public Health, Sun Yat-Sen University, Guangzhou, China. AD - Cancer Center of Guangzhou Medical University, Guangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181030 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 SB - IM MH - Asian People/genetics MH - *Genes, MHC Class I MH - *Genes, MHC Class II MH - Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - Humans MH - Nasopharyngeal Carcinoma/*genetics MH - Nasopharyngeal Neoplasms/*genetics MH - Polymorphism, Single Nucleotide PMC - PMC6308056 OTO - NOTNLM OT - fine-mapping OT - human leukocyte antigen OT - nasopharyngeal carcinoma OT - susceptibility EDAT- 2018/11/01 06:00 MHDA- 2019/11/15 06:00 PMCR- 2018/10/30 CRDT- 2018/11/01 06:00 PHST- 2018/07/31 00:00 [received] PHST- 2018/09/19 00:00 [revised] PHST- 2018/09/25 00:00 [accepted] PHST- 2018/11/01 06:00 [pubmed] PHST- 2019/11/15 06:00 [medline] PHST- 2018/11/01 06:00 [entrez] PHST- 2018/10/30 00:00 [pmc-release] AID - CAM41838 [pii] AID - 10.1002/cam4.1838 [doi] PST - ppublish SO - Cancer Med. 2018 Dec;7(12):6308-6316. doi: 10.1002/cam4.1838. Epub 2018 Oct 30.