High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.
High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.
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DOI：
10.1371/journal.pgen.1000696
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发表时间：
2009-10
期刊：
影响因子：
4.5
通讯作者：
Criswell LA
中科院分区：
文献类型：
--
作者：
Barcellos LF;May SL;Ramsay PP;Quach HL;Lane JA;Nititham J;Noble JA;Taylor KE;Quach DL;Chung SA;Kelly JA;Moser KL;Behrens TW;Seldin MF;Thomson G;Harley JB;Gaffney PM;Criswell LA
系统性红斑狼疮（SLE）风险的重大遗传贡献是由染色体6p21上的主要组织相容性复合体（MHC）基因赋予的。先前对SLE的研究缺乏统计能力和遗传分辨率来完全定义MHC的影响。我们对1610例白种人SLE病例和1470名父母进行了1974个MHC snp、高度多态性的HLA-DRB1位点和一组祖先信息标记的特征分析。单标记分析揭示了几个MHC区域内snp的强信号，以及HLA-DRB1（全局p = 9.99×10−16）。与DRB1相关最强烈的等位基因为：*0301（比值比，OR = 2.21, p = 2.53×10−12）、*1401（比值比，OR = 0.50, p = 0.0002）和*1501（比值比，OR = 1.39, p = 0.0032）。与SLE相关性最强的MHC区SNP为rs3117103， OR = 2.44, p = 2.80×10−13。条件单倍型和逐步逻辑回归分析发现了SLE与扩展的I类、I类、III类、II类和扩展的II类MHC区域之间存在关联的有力证据。顺序去除sle1相关的DRB1单倍型显示出OR2H2（扩展类I， rs362521, p = 0.006）、CREBL1（扩展类III， rs8283, p = 0.01）和DQB2（扩展类II， rs7769979, p = 0.003, rs10947345, p = 0.0004）内部变异的独立效应。此外，条件单倍型分析表明MICB （class I, rs3828903, p = 0.006）内的变异也与SLE风险无关，与HLA-DRB1*0301无关。我们的结果首次以高分辨率描绘了几个MHC区域与SLE风险的独立贡献。基于生物学和功能方面的考虑，我们提供了一个候选变异列表，这些变异可能与SLE风险有因果关系，值得进一步调查。系统性红斑狼疮（SLE）是一种以自身抗体产生和多器官系统参与为特征的自身免疫性疾病。虽然SLE的病因尚不清楚，但一些证据强调了遗传因素的重要性。与大多数自身免疫性疾病一样，6号染色体上的主要组织相容性复合体（MHC）基因是疾病风险的重要遗传因素。基因组的这个区域包含了大量参与免疫反应的基因。然而，该基因组区域对SLE风险的全部贡献尚未确定。在目前的研究中，我们对大量SLE患者和家庭成员进行了大约2000个MHC区域变异的表征，以确定影响疾病风险的特定基因。我们的研究结果首次揭示了4个不同的MHC区域与SLE风险的关系。基于生物学和功能方面的考虑，我们提供了一个候选变异列表，这些变异可能与SLE风险有因果关系，值得进一步调查。
A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10−16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10−12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10−13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and involvement of multiple organ systems. Although the cause of SLE remains unknown, several lines of evidence underscore the importance of genetic factors. As is true for most autoimmune diseases, a substantial genetic contribution to disease risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6. This region of the genome contains a large number of genes that participate in the immune response. However, the full contribution of this genomic region to SLE risk has not yet been defined. In the current study we characterize a large number of SLE patients and family members for approximately 2,000 MHC region variants to identify the specific genes that influence disease risk. Our results, for the first time, implicate four different MHC regions in SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.
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影响因子：
3.9
作者：
Kosoy, Roman;Nassir, Rami;Tian, Chao;White, Phoebe A.;Butler, Lesley M.;Silva, Gabriel;Kittles, Rick;Alarcon-Riquelme, Marta E.;Gregersen, Peter K.;Belmont, John W.;De La Vega, Francisco M.;Seldin, Michael F.
通讯作者：
Seldin, Michael F.
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D
DOI：
10.1006/bbrc.1998.9296
发表时间：
1998-09-18
影响因子：
3.1
作者：
Grifa, A;Totaro, A;Gasparini, P
通讯作者：
Gasparini, P
影响因子：
9.8
作者：
Graham, RR;Ortmann, WA;Behrens, TW
通讯作者：
Behrens, TW
6q23 上 TNFAIP3 附近的遗传变异与系统性红斑狼疮相关。
影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
通讯作者：
Gaffney, Patrick M.