X-chromosome association study reveals genetic susceptibility loci of nasopharyngeal carcinoma
X-chromosome association study reveals genetic susceptibility loci of nasopharyngeal carcinoma
复制标题
X染色体关联研究揭示鼻咽癌遗传易感位点
DOI：
10.1186/s13293-019-0227-9
复制
发表时间：
2019-03-25
影响因子：
7.9
通讯作者：
Bei, Jin-Xin
中科院分区：
文献类型：
--
作者：
Zuo, Xiao-Yu;Feng, Qi-Sheng;Bei, Jin-Xin
背景鼻咽癌（NPC）的发病以男性为主，提示X染色体与NPC的易感性有关。然而，迄今为止，还没有X连锁的易感位点被全基因组关联研究（GWASs）用于NPC的检测。方法为了了解X染色体在NPC易感性中的贡献，我们对1615名广东人NPC患者和1025名健康对照进行了X染色体全关联分析，结果首先估计发现样本中X连锁基因座的变异占表型变异的比例，结果显示，男性X染色体多态性解释的表型变异估计为12.63%（非剂量补偿模型），而女性为0.0001%。提示X染色体对鼻咽癌遗传变异的贡献不容忽视。关联分析显示，DMD基因rs 5927056在发现样本中具有X染色体范围的关联性（OR = 0.81，95%CI 0.73- 0.89，P = 1.49 × 10−5）。联合分析显示DMD基因rs 5927056具有提示意义（P= 9.44 × 10−5）。此外，ARHGAP 6基因中rs 5933886的女性特异性关联（OR = 0.62，95%CI：0.47- 0.81，P = 4.37 × 10−4）在中国台湾人中成功复制（P= 1.64 × 10−2）。rs 5933886在广东（P= 6.25 × 10−4）和台湾（P= 2.99 × 10−2）数据集中也表现出名义上显著的性别× SNP交互作用。
BackgroundThe 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.MethodsTo 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).ResultsFirstly, 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 inDMDgene 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 forDMDgene with suggestive significance (P= 9.44 × 10−5). Moreover, the female-specific association of rs5933886 inARHGAP6gene (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).ConclusionOur 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.