An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma
An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma
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DOI：
10.1093/hmg/ddw200
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发表时间：
2016-08-15
影响因子：
3.5
通讯作者：
Bei, Jin-Xin
中科院分区：
文献类型：
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作者：
Cui, Qian;Feng, Qi-Sheng;Bei, Jin-Xin
为了进一步确定鼻咽癌(NPC)的新易感基因座，我们在此扩展了我们先前的全基因组关联研究(GWAS)，通过增加样本量来增强统计能力，并基于GWASP值在排名列表中验证更多的SNP。发现阶段包括1,583个病例和2,979个对照的463,250个SNP，发现了1,257个与鼻咽癌相关的顶级SNP，并在1,925个病例和1,947个对照中进行了验证。此外，在3,538例中国南方人和3,644名对照中选择了11个SNPs进行另一项独立验证。对7,046例病例和8,570名对照的联合分析发现两个关联超过全基因组意义(P<；5 x 10(-8))，包括位于染色体5p15的TERT-CLPTM1L(rs401681；P=2.65 x 10(-14)；优势比OR=0.82)和位于染色体16p13的CIITA(rs6498114；P=4.01 x 10(-9)；OR=0.87)。条件分析显示，rs401681解释了TERT-CLPTM1L基因座上所有被测试的关联，该基因与多种癌症的易感性有关。此外，生物信息学分析表明，这两个SNP都位于调控区域，并与邻近基因的表达相关(CLPTM1L和TERT为rs401681，CIITA为rs6498114)。CLPTM1L和TERT与癌症密切相关，而CIITA被认为是鼻咽癌相关MHC-II类基因表达的“主控因子”。这些表明，这两个SNP可能都是起作用的。总之，我们的发现扩大了我们对鼻咽癌风险的基因贡献的理解，并为鼻咽癌的发病机制提供了新的生物学见解。
To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 controls of southern Chinese. The joint analysis with 7,046 cases and 8,570 controls resulted in two associations surpassing genome-wide significance (P< 5 x 10(-8)), including TERT-CLPTM1L at chromosome 5p15 (rs401681; P = 2.65 x 10(-14); odds ratio, OR = 0.82) and CIITA at chromosome 16p13 (rs6498114; P = 4.01 x 10(-9); OR = 0.87). Conditional analysis revealed that rs401681 accounts for all the tested associations at TERT-CLPTM1L locus, which has been linked with multiple cancers' susceptibilities. Moreover, bioinformatics analyses showed that both SNPs are located in the regulatory regions and correlated with the expression of nearby genes (rs401681 for CLPTM1L and TERT, and rs6498114 for CIITA). CLPTM1L and TERT have been implicated in cancers, and CIITA is considered as the "master control factor" for the expression of NPC-associated MHC class II genes. These suggested that both SNPs might be functional. Altogether, our findings expand our understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis.