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Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3 |
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| Authors: | Ka-Po Tse Wen-Hui Su Kai-Ping Chang Chia-Jung Yu Lee-Chu See Chuen Hsueh Min-Lee Yang Hong-Yi Li Ming-Hsi Wang Lih-Chyang Chen Timothy J Jorgensen Yu-Sun Chang Yin Yao Shugart |
| Institution: | 1 Genomic Medicine Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan 333 2 Molecular Epidemiology Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan 333 3 Bioinformatics Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan 333 4 Biostatistics Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan 333 5 Pathology Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan 333 6 Department of Otolaryngology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan 333 7 Department of Radiation Oncology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan 333 8 Department of Pathology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan 333 9 Department of Biochemistry and Molecular and Cellular Biology, Chang Gung University, Taoyuan, Taiwan 333 10 Department of Public Health, Chang Gung University, Taoyuan, Taiwan 333 11 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA 12 Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA 13 Director's Office, Health Bureau of Taoyuan County, Taoyuan, 33053 Taiwan 14 Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C. 20057, USA |
| Abstract: | Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; pcombined = 3.9 × 10−20 and 1.6 × 10−19, respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; pcombined = 8.97 × 10−17) and HLA-F (rs3129055 and rs9258122; pcombined = 7.36 × 10−11 and 3.33 × 10−10, respectively). Notably, the association of rs29232 remained significant (residual p < 5 × 10−4) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABAB receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development. |
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