Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied. Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied. Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case–control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that com bined results from the initial GWA and replication studies was performed. Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR ¼ 0.81; P value 6.3 10 13). Our results also provide support for associations reported from published NPC GWAS—rs6774494 (P ¼ 1.5 10 12; located in the MECOM gene region), rs9510787 (P ¼ 5.0 10 10; located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P ¼ 2.8 108, P ¼ 7.0 107, and P ¼ 8.4 107, respectively; located in the CDKN2A/B gene region). Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity. Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(1); 188–92. 2015 AACR

Background: The male predominance in the incidence of nasopharyngeal carcinoma (NPC) suggests the contribution of the X chromosome to the susceptibility of NPC. However, no X-linked susceptibility loci have been examined by genome-wide association studies (GWASs) for NPC by far. Methods: To understand the contribution of the X chromosome in NPC susceptibility, we conducted an X chromosome wide association analysis on 1615 NPC patients and 1025 healthy controls of Guangdong Chinese, followed by two validation analyses in Taiwan Chinese (n = 562) and Malaysian Chinese (n = 716). Results: Firstly, the proportion of variance of X-linked loci over phenotypic variance was estimated in the discovery samples, which revealed that the phenotypic variance explained by X chromosome polymorphisms was estimated to be 12.63% (non-dosage compensation model) in males, as compared with 0.0001% in females. This suggested that the contribution of X chromosome to the genetic variance of NPC should not be neglected. Secondly, association analysis revealed that rs5927056 in DMD gene achieved X chromosome-wide association significance in the discovery sample (OR = 0.81, 95% CI 0.73–0.89, P = 1.49 × 10−5 ). Combined analysis revealed rs5927056 for DMD gene with suggestive significance (P = 9.44 × 10−5 ). Moreover, the female-specific association of rs5933886 in ARHGAP6 gene (OR = 0.62, 95%CI: 0.47–0.81, P = 4.37 × 10−4 ) was successfully replicated in Taiwan Chinese (P = 1.64 × 10−2 ). rs5933886 also showed nominally significant gender × SNP interaction in both Guangdong (P = 6.25 × 10−4 ) and Taiwan datasets (P = 2.99 × 10−2 ). Conclusion: Our finding reveals new susceptibility loci at the X chromosome conferring risk of NPC and supports the value of including the X chromosome in large-scale association studies.