X-chromosome association study reveals genetic susceptibility loci of nasopharyngeal carcinoma

Biol Sex Differ. 2019 Mar 25;10(1):13. doi: 10.1186/s13293-019-0227-9.

Abstract

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.

Keywords: Association study; Genetic susceptibility; Male predominance; Nasopharyngeal carcinoma; X chromosome.

MeSH terms

  • Adult
  • Asian People / genetics
  • China
  • Chromosomes, Human, X*
  • Female
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Humans
  • Malaysia
  • Male
  • Middle Aged
  • Nasopharyngeal Carcinoma / genetics*
  • Nasopharyngeal Neoplasms / genetics*
  • Polymorphism, Single Nucleotide
  • Sex Characteristics*
  • Taiwan