Genetically Determined Partial Complement C4 Deficiency States Are Not Independent Risk Factors for SLE in UK and Spanish Populations
Genetically Determined Partial Complement C4 Deficiency States Are Not Independent Risk Factors for SLE in UK and Spanish Populations
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DOI：
10.1016/j.ajhg.2012.01.012
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发表时间：
2012-03-09
影响因子：
9.8
通讯作者：
Fernando, Michelle M. A.
中科院分区：
文献类型：
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作者：
Boteva, Lora;Morris, David L.;Fernando, Michelle M. A.
系统性红斑狼疮（SLE）是一种慢性多系统自身免疫性疾病。补体成分C4的完全缺乏赋予SLE很强的遗传风险。部分C4缺乏状态也显示与SLE相关，但尽管在过去30年中进行了大量研究，但尚未确定这种关联是主要因果关系还是继发于远程连锁不平衡。补体C4位点位于主要组织相容性复合体（MHC） III类区域，具有拷贝数变异（CNV）， C4本身存在两个类似物C4A和C4B。为了确定部分C4缺乏是否是SLE的独立遗传危险因素，我们在迄今为止规模最大、最全面的补体C4研究中，在HLA-DRB1和MFIC区域SNP多态性的背景下研究了C4 CNV。具体来说，我们对2207名北欧和南欧血统的受试者（1028例SLE病例和1179例对照）进行了C4、C4A和C4B基因拷贝数的基因分型，以及C4外显子29号功能缺失的CT索引。我们使用多元逻辑回归来确定C4 CNV与已知SNP和HLA-DRB1关联的独立性。我们清楚地表明，基因决定的部分C4缺乏状态不是英国和西班牙人群SLE的独立危险因素。这些结果进一步证实了C4A外显子29 CT插入在两个队列中显示的缺乏相关性。因此，尽管补体C4的完全纯合缺乏症是SLE最强的遗传危险因素之一，但部分C4缺乏症并不独立地易患该疾病。
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease. Complete deficiency of complement component C4 confers strong genetic risk for SLE. Partial C4 deficiency states have also shown association with SLE, but despite much effort over the last 30 years, it has not been established whether this association is primarily causal or secondary to long-range linkage disequilibrium. The complement C4 locus, located in the major histocompatibility complex (MHC) class III region, exhibits copy-number variation (CNV) and C4 itself exists as two paralogs, C4A and C4B. In order to determine whether partial C4 deficiency is an independent genetic risk factor for SLE, we investigated C4 CNV in the context of HLA-DRB1 and MFIC region SNP polymorphism in the largest and most comprehensive complement C4 study to date. Specifically, we genotyped 2,207 subjects of northern and southern European ancestry (1,028 SLE cases and 1,179 controls) for total C4, C4A, and C4B gene copy numbers, and the loss-of-function C4 exon 29 CT indel. We used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. We clearly demonstrate that genetically determined partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. These results are further corroborated by the lack of association shown by the C4A exon 29 CT insertion in either cohort. Thus, although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.