Low MICA Gene Expression Confers an Increased Risk of Graves' Disease: A Mendelian Randomization Study
Low MICA Gene Expression Confers an Increased Risk of Graves' Disease: A Mendelian Randomization Study
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DOI：
10.1089/thy.2021.0417
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发表时间：
2022-02-01
期刊：
影响因子：
6.6
通讯作者：
Shimizu，Atsushi
中科院分区：
文献类型：
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作者：
Sutoh，Yoichi;Komaki，Shohei;Shimizu，Atsushi
背景：自然杀伤组2成员D （NKG2D）配体（NKG2DL）的表达作为应激细胞的“危险信号”，促进表达NKG2D的细胞毒性淋巴细胞对应激细胞的清除。外周免疫细胞（如巨噬细胞）中也发现了NKG2DL的表达；然而，这种表达的效果还有待确定。方法：通过对381名日本人外周血单个核细胞（PBMCs）的RNA-seq分析，确定工具变量（IVs，连锁不平衡R2<0.01），从nkg2dl的表达数量性状位点（eQTL）解释主要组织相容性复合体I类链相关蛋白A （MICA）和MICB （MICB）基因表达水平的主要差异。同时，PheWAS使用一项由44,739名日本居民组成的社区队列研究，从58种健康风险中过滤出目标结果。最后，我们使用孟德尔随机化方法估计基因表达水平对结果的因果影响。结果：我们确定了9个和4个IVs，分别解释了87.6%和33.0%的micamicbgene表达水平。在关联检验中，我们分别确定了10或13个与micormicbeqtl相关的显著结局，以及MICA表达对Graves病（GD）的因果效应（p= 4.2 × 10−3；使用加权中位数估计器，MICA表达每1 sd差异的比值比：0.983[置信区间：0.971-0.995]），没有显著的多效性（p> 0.05），敏感性分析的结果是一致的。结论：我们的研究提供了NKG2DL表达与GD（一种自身免疫性甲状腺炎）相关的新证据；结果表明MICA在PBMCs中的表达具有免疫调节作用，提示进一步的功能检测在炎症性疾病中的重要性。
Background:Expression of natural killer group 2 member D (NKG2D) ligand (NKG2DL) plays a major role as a “danger signal” on stressed cells to promote removal of the latter by NKG2D-expressing cytotoxic lymphocytes. NKG2DL expression has been found in peripheral immune cells as well, such as in macrophages; however, the effect of this expression is yet to be determined.Methods:We determined instrumental variables (IVs;R2<0.01 in linkage disequilibrium), explaining the major variance in major histocompatibility complex class I chain-related protein A (MICA) and B (MICB) gene expression levels from the expression-quantitative trait locus (eQTL) of NKG2DLs based on the RNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from 381 Japanese. Simultaneously, the target outcomes were filtered by PheWAS from 58 health risks, using a community-based cohort study composed of 44,739 Japanese residents. Finally, we estimated the causal effect of gene expression levels on the outcomes using the Mendelian randomization approach.Results:We determined nine and four IVs, explaining 87.6% and 33.0% ofMICAandMICBgene expression levels, respectively. In the association test, we identified 10 or 13 significant outcomes associated with theMICAorMICBeQTLs, respectively, as well as the causal effect of MICA expression on Graves' disease (GD) (p= 4.2 × 10−3; odds ratio per 1 S.D. difference in the expression: 0.983 [confidence interval: 0.971–0.995]), using the weighted median estimator, without significant pleiotropy (p> 0.05), and the results were consistent across the sensitivity analyses.Conclusions:Our study provide novel evidence associating NKG2DL expression with GD, an autoimmune thyroiditis; direction of the effect indicated the immunoregulatory role of MICA expression in PBMCs, suggesting the importance of further functional assays in inflammatory diseases.