Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.
Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.
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DOI：
10.1371/journal.pgen.1002079
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发表时间：
2011-05
期刊：
影响因子：
4.5
通讯作者：
Tsao BP
中科院分区：
文献类型：
--
作者：
Zhao J;Wu H;Khosravi M;Cui H;Qian X;Kelly JA;Kaufman KM;Langefeld CD;Williams AH;Comeau ME;Ziegler JT;Marion MC;Adler A;Glenn SB;Alarcón-Riquelme ME;BIOLUPUS Network;GENLES Network;Pons-Estel BA;Harley JB;Bae SC;Bang SY;Cho SK;Jacob CO;Vyse TJ;Niewold TB;Gaffney PM;Moser KL;Kimberly RP;Edberg JC;Brown EE;Alarcon GS;Petri MA;Ramsey-Goldman R;Vilá LM;Reveille JD;James JA;Gilkeson GS;Kamen DL;Freedman BI;Anaya JM;Merrill JT;Criswell LA;Scofield RH;Stevens AM;Guthridge JM;Chang DM;Song YW;Park JA;Lee EY;Boackle SA;Grossman JM;Hahn BH;Goodship TH;Cantor RM;Yu CY;Shen N;Tsao BP
系统性红斑狼疮（SLE）是一种复杂的多基因自身免疫性疾病，与补体激活增加有关。编码补体调节因子H（CFH）和5个CFH相关蛋白（CFHR 1-CFHR 5）的基因变体与SLE连锁的染色体1 q32位点内，已与多种人类疾病相关，并可能导致SLE的补体激活失调。我们在来自四个种族的15，864例病例对照受试者中评估了CFH-CFHRs区域的60个SNP与SLE的相关性。在欧洲裔美国人（EA）和非洲裔美国人（AA）中检测到与SLE显著相关的等位基因，这可能归因于内含子CFH SNP（rs6677604，在内含子11中，P Meta = 6.6×10−8，OR = 1.18）和CFHR 1和CFHR 4之间的基因间SNP（rs 16840639，P Meta = 2.9×10−7，OR = 1.17），而不是先前确定的疾病相关CFH外显子SNP，包括I62 V，Y 402 H，A474 A和D936 E。 此外，rs6677604与SLE的等位基因关联随后在亚洲人（AS）中得到证实。单倍型分析表明，潜在的致病变异，标签的rs6677604和rs 16840639，是本地化的一个146 kb的块从内含子9的CFH的下游CFHR 1延伸。在该区块内，CFHR 3和CFHR 1（CFHR 3 -1Δ）的缺失（使用多重连接依赖性探针扩增测量的可能的致病变体）分别由EA和AS中的rs6677604和AA中的rs 16840639标记。从EA、AA和AS中标签SNP的基因型关联推断，CFHR 3 -1Δ纯合缺失（P Meta = 3.2×10−7，OR = 1.47）比杂合缺失（P Meta = 3.5×10−4，OR = 1.14）赋予更高的SLE风险。 这些结果表明，SLE相关区块内的CFHR 3 -1Δ缺失，而不是先前描述的CFH外显子SNP，可能有助于SLE在EA、AA和AS中的发展，为补体调节剂在SLE发病机制中的作用提供了新的见解。系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，与补体激活增加有关。以往的研究已证实SLE易感基因存在于染色体1 q31 -32位点。在1 q32内，编码补体调节因子H（CFH）和五种CFH相关蛋白（CFHR 1-CFHR 5）的基因可能有助于SLE的发展，因为这些基因的遗传变异损害补体调节并易患各种人类疾病。在这项研究中，我们测试了包含CFH和CFHRs的区域中的遗传变异与SLE的关联。我们在欧洲裔美国人、非洲裔美国人和亚洲人群中发现了易患SLE的遗传变异，这可能归因于CFHR 3和CFHR 1基因的缺失，但与之前发现的CFH疾病相关的外显子变异无关。这项研究提供了CFH/CFHRs和SLE之间在多祖先SLE数据集之间一致关联的第一个证据，为补体调节因子在SLE发病机制中的作用提供了新的见解。
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P meta = 6.6×10−8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P meta = 2.9×10−7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P meta = 3.2×10−7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P meta = 3.5×10−4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE. Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing CFH and CFHRs with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of CFHR3 and CFHR1 genes but not previously identified disease-associated exonic variants of CFH. This study provides the first evidence for consistent association between CFH/CFHRs and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.
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DOI：
10.1038/nrrheum.2010.176
发表时间：
2010-12
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
20.3
作者：
Jozsi, Mihaly;Strobel, Stefanie;Zipfel, Peter F.
通讯作者：
Zipfel, Peter F.
影响因子：
30.8
作者：
Hughes, Anne E.;Orr, Nick;Chakravarthy, Usha
通讯作者：
Chakravarthy, Usha
影响因子：
9.8
作者：
Johanneson, B;Lima, G;Alarcón-Riquelme, ME
通讯作者：
Alarcón-Riquelme, ME