Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3

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 6p2l.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; P-combined = 3.9 X 10(-20) and 1.6 x 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; P-combined = 8.9 7 X 10(-17)) and HLA-F (rs3129055 and rs92S8122; P-combined = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 X 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) 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.