A refined study of FCRL genes from a genome-wide association study for Graves' disease.
A refined study of FCRL genes from a genome-wide association study for Graves' disease.
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DOI：
10.1371/journal.pone.0057758
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
China Consortium for the Genetics of Autoimmune Thyroid Disease
中科院分区：
文献类型：
--
作者：
Zhao SX;Liu W;Zhan M;Song ZY;Yang SY;Xue LQ;Pan CM;Gu ZH;Liu BL;Wang HN;Liang L;Liang J;Zhang XM;Yuan GY;Li CG;Chen MD;Chen JL;Gao GQ;Song HD;China Consortium for the Genetics of Autoimmune Thyroid Disease
为了精确定位携带FCRL 1 -5和CD 5L基因的1q21.1处的病因变异，我们通过插补分析、logistic回归和cis-eQTL分析，在1,536例Graves病（GD）患者和1,516例性别匹配的对照中对整个FCRL区域进行了精细关联研究。在初始GWAS扫描中P<0.05的516个SNP中，与GD相关并与FCRL 3表达相关的最强信号位于包括rs7528684和rs3761959的SNP簇。rs3761959和rs7528684对FCRL 3表达的等位基因特异性效应显示，rs3761959的A和rs7528684的C等位基因与FCRL 3在PBMC及其亚群中的表达水平升高相关，尤其是在CD 19 + B细胞和CD 8 + T细胞亚群中。接下来，对5，300例GD病例和4，916例对照个体的联合分析证实FCRL 3是中国汉族人群中GD的易感基因，rs3761959和rs7528684符合全基因组关联显著性水平（Pcombined = 2.27×10−12和7.11×10−13）。 rs3761959的危险等位基因A和rs7528684的危险等位基因C的单倍型与GD风险相关。最后，我们的表观遗传学分析表明rs7528684的疾病相关C等位基因增加了对NF-κ B转录因子的亲和力。提示FCRL 3基因及其代理SNP rs7528684可能通过过度抑制B细胞受体信号传导，损害TCR 4的抑制功能而参与GD的发病。
To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves’ disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19+ B cells and CD8+ T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (Pcombined = 2.27×10−12 and 7.11×10−13, respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.
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