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首页> 外文期刊>Arthritis & Rheumatism >A 3′-untranslated region variant is associated with impaired expression of CD226 in T and natural killer T cells and is associated with susceptibility to systemic lupus erythematosus
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A 3′-untranslated region variant is associated with impaired expression of CD226 in T and natural killer T cells and is associated with susceptibility to systemic lupus erythematosus

机译：3'-非翻译区变体与T细胞和自然杀伤性T细胞中CD226的表达受损有关，并与系统性红斑狼疮易感性有关

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ObjectiveCostimulatory receptor CD226 plays an important role in T cell activation, differentiation, and cytotoxicity. This study was undertaken to investigate the genetic association of CD226 with susceptibility to systemic lupus erythematosus (SLE) and to assess the functional implications of this association.MethodsTwelve tag single-nucleotide polymorphisms (SNPs) in CD226 were typed in 1,163 SLE patients and 1,482 healthy control subjects from Europe or of European ancestry. Analyses of association were performed by single-marker Cochran-Mantel-Haenszel meta-analysis, followed by haplotype analysis. Gene expression was analyzed by quantitative real-time polymerase chain reaction analyses of RNA from peripheral blood mononuclear cells, and by fluorescence-activated cell sorter analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3′-untranslated region (3′-UTR) of the gene were prepared and used in transfection experiments.ResultsA 3-variant haplotype, rs763361;rs34794968;rs727088 (ATC), in the last exon of CD226 was associated with SLE (P = 1.3 × 10−4, odds ratio 1.24, 95% confidence interval 1.11–1.38). This risk haplotype correlated with low CD226 transcript expression and low CD226 protein levels on the surface of CD4+ and CD8+ T cells and natural killer T (NKT) cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only the presence of rs727088 could account for the differences in the levels of luciferase transcripts.ConclusionThis study identified an association of CD226 with SLE in individuals of European ancestry. These data support the importance of the 3′-UTR SNP rs727088 in the regulation of CD226 transcription both in T cells and in NKT cells.
机译：目的共刺激受体CD226在T细胞活化，分化和细胞毒性中起重要作用。这项研究旨在调查CD226与系统性红斑狼疮（SLE）易感性的遗传关联，并评估这种关联的功能含义。方法对1,163例SLE患者和1,482例健康的CD226中的12个标签单核苷酸多态性（SNP）进行分型控制来自欧洲或欧洲血统的对象。关联分析通过单标记Cochran-Mantel-Haenszel荟萃分析进行，然后进行单倍型分析。通过定量实时聚合酶链反应分析外周血单核细胞中的RNA，并通过荧光激活细胞分选仪分析基因表达。为了研究相关变体的功能影响，制备了包含基因的3'-非翻译区（3'-UTR）不同部分的荧光素酶报告基因构建体，并将其用于转染实验。结果3变异单倍型，rs763361; rs34794968； rs727088（ATC）在CD226的最后一个外显子与SLE相关（P = 1.3×10 -4 ，优势比1.24，95％置信区间1.11–1.38）。这种风险单倍型与CD4 +和CD8 + T细胞和自然杀伤性T（NKT）细胞表面上的低CD226转录表达和低CD226蛋白水平相关。 NK细胞表达高水平的CD226，但这种表达与单倍型无关。记者用缺失构建体进行的分析表明，只有rs727088的存在才能解释萤光素酶转录物水平的差异。结论本研究确定了欧洲血统的个体中CD226与SLE的关联。这些数据支持3'-UTR SNP rs727088在调节T细胞和NKT细胞中CD226转录中的重要性。

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