ITM2A Expands Evidence for Genetic and Environmental Interaction in Graves Disease Pathogenesis

Xiao-Ping Ye, Fei-Fei Yuan, Lele Zhang, Yu-Ru Ma, Manman Zhang, W. Liu, F. Sun, Jing Wu, Meng-Zhu Lu, Li-qiong Xue, Jing-yi Shi, Shuang-Xia Zhao, Huai-Dong Song, Jun Liang, Cuixia Zheng
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引用次数: 11

Abstract

Context: Graves disease (GD) is a common autoimmune disease triggered by genetic predisposition and environmental factors. However, the mechanisms of interaction between genetic and environmental factors contributing to the development of GD remain unknown. Objective: We aimed to identify GD susceptibility variants and genes on Xq21.1 locus and interpret the contribution of interaction between genetic predisposition on Xq21.1 and environmental factors to GD. Design: We performed refining study on Xq21.1 in a 2-stage study and carried out expression quantitative trait locus analysis of the best association signal with GD. Setting and Participants: A total of 4316 GD patients and 4374 sex-matched controls were collected from the Chinese Han population by cooperation with multiple hospitals. Results: We identified that rs3827440 or its linkage single nucleotide polymorphisms (SNPs) were probably the causal variant in the Xq21.1 locus, with the most substantial association with GD in our combined cohorts (P = 2.45 × 10−15). The genotypes of rs3827440 were correlated with the expression of ITM2A in monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Notably, the expression of ITM2A in monocytes after lipopolysaccharide (LPS) and interferon-&ggr; (INF-&ggr;) stimulation showed substantial difference among the volunteers that carried different genotypes of rs3827440 (P = 9.40 × 10−7 and P = 1.26 × 10−5 for 24 hours’ LPS and INF-&ggr; stimulation, respectively). Moreover, ITM2A expression was significantly decreased in PBMCs from untreated GD patients than that from controls. Conclusion: The results suggest that ITM2A might be a susceptibility gene for GD in the Xq21.1 locus, and environmental factors, such as viral and bacterial infections, probably contribute to GD pathogenesis by interacting with the risk SNP rs3827440 mediating the regulation of ITM2A expression.
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ITM2A扩大了遗传和环境相互作用在Graves病发病机制中的证据
背景:Graves病(GD)是一种常见的由遗传易感性和环境因素引发的自身免疫性疾病。然而,遗传和环境因素之间相互作用的机制对GD的发展仍不清楚。目的:鉴定GD易感变异和Xq21.1位点基因,解释Xq21.1遗传易感性与环境因素相互作用对GD的贡献。设计:我们对Xq21.1进行细化研究,分两期研究,对与GD最佳关联信号进行表达数量性状位点分析。背景和参与者:与多家医院合作,从中国汉族人群中共收集了4316例GD患者和4374例性别匹配的对照组。结果:我们发现rs3827440或其连锁单核苷酸多态性(snp)可能是Xq21.1位点的因果变异,在我们的联合队列中,与GD的关联最为显著(P = 2.45 × 10−15)。rs3827440基因型与ITM2A在健康志愿者单核细胞和外周血单核细胞(PBMCs)中的表达相关。值得注意的是,ITM2A在脂多糖(LPS)和干扰素- ggr后单核细胞中的表达;(INF-&ggr;)刺激在携带不同rs3827440基因型的志愿者中显示出显著差异(P = 9.40 × 10 - 7和P = 1.26 × 10 - 5)。刺激,分别)。此外,未经治疗的GD患者的pbmc中ITM2A的表达明显低于对照组。结论:ITM2A可能是Xq21.1位点的GD易感基因,病毒、细菌感染等环境因素可能与介导ITM2A表达调控的风险SNP rs3827440相互作用,参与了GD的发病。
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