Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus.
Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus.
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STAT4遗传关联的特异性是针对全身性红斑狼疮的严重疾病表现。
DOI：
10.1371/journal.pgen.1000084
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发表时间：
2008-05-30
期刊：
影响因子：
4.5
通讯作者：
Criswell, Lindsey A.
中科院分区：
文献类型：
--
作者：
Taylor, Kimberly E.;Remmers, Elaine F.;Lee, Annette T.;Ortmann, Ward A.;Plenge, Robert M.;Tian, Chao;Chung, Sharon A.;Nititham, Joanne;Hom, Geoffrey;Kao, Amy H.;Demirci, F. Yesim;Kamboh, M. Ilyas;Petri, Michelle;Manzi, Susan;Kastner, Daniel L.;Seldin, Michael F.;Gregersen, Peter K.;Behrens, Timothy W.;Criswell, Lindsey A.
系统性红斑狼疮（SLE）是一种遗传复杂的疾病，具有异质性的临床表现。STAT 4基因的多态性最近被确定为SLE的危险因素，但与特定SLE亚表型的关系尚未研究。我们研究了4个独立的SLE病例系列（总n = 1398）和2560名健康对照中STAT 4区域基因分型的137个SNP，沿着病例的临床数据。 使用条件检验，我们确认了SLE风险最显著的STAT 4单倍型。然后，我们研究了标记该单倍型的SNP与特定SLE亚表型的关联，包括自身抗体产生、肾炎、关节炎、皮肤粘膜表现和诊断时的年龄。为了防止可能的I型错误的人群分层，我们重新分析了数据使用的主题确定为最同质的基于全基因组数据的主成分分析的子集。我们证实，在非常高的LD（r2 = 0.94至0.99）的四个SNPs与SLE最密切相关，并没有令人信服的证据，在STAT 4区域的其他SLE风险位点。 标记该单倍型的SNP rs7574865在SLE病例中的次要等位基因频率（MAF）为31.1%，而对照组为22.5%（OR = 1.56，p = 10−16）。 该SNP与以双链DNA自身抗体为特征的SLE（MAF = 35.1%，OR = 1.86，p<10−19）、肾炎（MAF = 34.3%，OR = 1.80，p<10−11）和诊断时年龄<30岁（MAF = 33.8%，OR = 1.77，p<10−13）相关性更强。 与严重肾炎的相关性甚至更显著（MAF = 39.2%，OR = 2.35，在同质受试者亚组中p<10−4）。 相比之下，STAT 4与口腔溃疡的相关性较低，口腔溃疡是一种与轻度疾病相关的表现。我们的结论是，这种常见的多态性STAT 4有助于SLE的表型异质性，特别是更严重的疾病的易感性。系统性红斑狼疮是一种慢性致残性自身免疫性疾病，最常见于三四十岁的女性。它可以引起各种各样的临床表现，包括肾脏疾病，关节炎和皮肤病。根据这些临床特征，预后差异很大，肾脏疾病和相关特征导致更高的发病率和死亡率。它在遗传上也很复杂;虽然狼疮在家庭中运行，但基因会增加狼疮的风险，但并不完全决定结果。人们认为，多个基因的相互作用和/或基因与环境因素之间的相互作用可能导致狼疮，但这种非常异质性疾病的原因和疾病途径还没有很好地了解。通过检查狼疮亚型和特定基因之间的关系，我们希望更好地了解狼疮是如何被触发的，以及它是通过什么样的生物学途径发展的。我们在这项工作中表明，STAT 4基因，最近被确定为狼疮风险基因，特别容易导致狼疮的严重表现，包括肾脏疾病。
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10−16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10−19), nephritis (MAF = 34.3%, OR = 1.80, p<10−11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10−13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10−4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease. Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the STAT4 gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.
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影响因子：
158.5
作者：
Remmers, Elaine F.;Plenge, Robert M.;Gregersen, Peter K.
通讯作者：
Gregersen, Peter K.
影响因子：
4.4
作者：
Finnegan, A;Grusby, MJ;Zhang, J
通讯作者：
Zhang, J
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D
影响因子：
5
作者：
Thorburn, C. M.;Prokunina-Olsson, L.;Criswell, L. A.
通讯作者：
Criswell, L. A.
DOI：
10.1093/jurban/jth116
发表时间：
2004-06-01
影响因子：
6.6
作者：
Mitchell, MK;Gregersen, PK;Vlahov, D
通讯作者：
Vlahov, D