Compelling Evidence Linking CD40 Gene With Graves' Disease in the Chinese Han Population.
Compelling Evidence Linking CD40 Gene With Graves' Disease in the Chinese Han Population.
复制标题
CD40 基因与中国汉族人群 Graves 病相关的令人信服的证据
DOI：
10.3389/fendo.2021.759597
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发表时间：
2021
影响因子：
5.2
通讯作者：
China Consortium for the Genetics of Autoimmune Thyroid Disease
中科院分区：
文献类型：
--
作者：
Jiang H;Yuan FF;Wang HN;Liu W;Ye XP;Yang SY;Xie HJ;Yu SS;Ma YR;Zhang LL;Zhao SX;Song HD;China Consortium for the Genetics of Autoimmune Thyroid Disease
CD40基因突变被广泛报道为Graves病(GD)的危险因素。该基因与其同源配体CD40L一起，可能调节促炎和免疫反应。Rs1883832位于Kozak序列的-1位，是CD40研究最深入的单核苷酸多态(SNP)，已被证实与GD易感性无关，与种族无关。我们的全基因组关联研究表明，在中国汉族人群中，包括位于CD40附近的rs1883832在内的几个SNPs与GD相关。为了确定最重要的单核苷酸多态性及其致病机制，我们对8,171例GD患者和7,906名对照进行了两个阶段的精细研究，发现CD40基因区域的rs1883832是与GD最显著相关的SNP(P联合=9.17×10-11，OR = 1.18)。通过检索顺式表达的数量性状基因座数据库，利用定量RT-PCR技术，进一步发现rs1883832基因可以影响CD40基因的转录。此外，我们还证实rs1883832是pTRAb+GD患者的易感基因。总之，本研究提供了强有力的证据，表明rs1883832可以调节CD40基因的表达并影响血清TRAb水平，从而最终促进GD的发生发展。
Mutations in CD40 have been widely reported to be risk factors for Graves’ disease (GD). The gene, along with its cognate ligand CD40L, may regulate pro-inflammatory and immune responses. Rs1883832, located at the -1 position of the Kozak sequence, is the most well-studied single nucleotide polymorphism (SNP) of CD40, and has been confirmed to predispose those with the alteration to GD, regardless of ethnicity. Our genome-wide association study (GWAS) indicated that several SNPs, including rs1883832 located within the vicinity of CD40 were associated with GD in the Han Chinese population. Aiming at identifying the most consequential SNP and its underlying pathogenic mechanism, we performed a two-stage refined study on 8,171 patients with GD and 7,906 controls, and found rs1883832 was the most significantly GD-associated SNP in the CD40 gene region (P Combined = 9.17×10-11, OR = 1.18). Through searching the cis-expression quantitative trait locus database and using quantitative RT-PCR, we further discovered that the rs1883832 genotype can influence CD40 gene transcription. Furthermore, we demonstrated that rs1883832 is a susceptibility locus for pTRAb+ GD patients. In conclusion, the current study provides robust evidence that rs1883832 can regulate CD40 gene expression and affect serum TRAb levels, which ultimately contributes to the development of GD.