Identification of multiple genetic variants related to nasopharyngeal carcinoma predisposition through genome-wide scan

Abstract

Nasopharyngeal carcinoma (NPC) is a multi-factorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. Recently, we have 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) using Illumina HumanHap 550 BeadChip. Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3 in the major histocompatibility complex region. These association signals were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042) were located in the previously identified NPC-susceptible HLA-A gene. Moreover, we detected novel significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232) and HLA-F (rs3129055 and rs9258122). Notably, the association of rs29232 remained significant after adjustment for age, gender, and HLA-related SNPs. 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. Following the GWAS study, we made an effort to search systematically for copy number variations (CNVs) that confer increased risk to NPC using the same dataset. We generated CNV calls using five different algorithms and used 12 internal duplicated samples to look for best filtering criteria. We identified eight regions with CNV that were significantly overrepresented in NPC patients compared to healthy controls. Association testing and follow-up replication analyses in an independent case-control sample using a self-established deletion-specific polymerase chain reaction (PCR) strategy confirmed the CNVs were associated with NPC. ? ? 中 央 研 究 院 統計科學研究所