Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis.
Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis.
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DOI：
10.4049/jimmunol.1402956
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Harris CL
中科院分区：
文献类型：
--
作者：
Giles JL;Choy E;van den Berg C;Morgan BP;Harris CL
补体与类风湿性关节炎（RA）的发病机制有关;在患者的血浆、滑液和滑膜组织中测量到补体激活产物水平升高。在全基因组关联研究中，补体多态性与RA相关。编码区多态性可能直接影响蛋白质活性;事实上，我们已经证明，补体多态性影响单个氨基酸的变化，导致单个组分功能的微妙变化，这些变化结合起来对补体活性和疾病风险产生巨大影响。在这项研究中，我们探讨的功能后果的单核苷酸多态性（SNP）（rs 17611）编码的V802 I多态性C5，并提出了一种机制，其链接到RA病理。在健康和RA供体中测定C5、C5 a和末端补体复合物的血浆水平，并与rs 17611多态性状态相关。评估SNP对C5功能的影响。血浆C5 a水平显著升高，C5水平显著降低，rs 17611的RA风险等位基因拷贝数较高，表明C5 V802的周转增加。使用纯化的C5变体的功能测定显示裂解活性无显著差异，表明增加的C5 V802周转率不由补体转化酶介导。C5在体内也被蛋白酶切割; C5 V802变体对弹性蛋白酶的切割更敏感，并且产生的“C5 a”具有生物活性。我们假设C5中的这种SNP改变了弹性蛋白酶在类风湿关节中产生活性C5 a的速率，因此将中性粒细胞募集到该部位，从而维持关节炎关节的炎症状态。
Complement is implicated in the pathogenesis of rheumatoid arthritis (RA); elevated levels of complement activation products have been measured in plasma, synovial fluid, and synovial tissues of patients. Complement polymorphisms are associated with RA in genome-wide association studies. Coding-region polymorphisms may directly impact protein activity; indeed, we have shown that complement polymorphisms affecting a single amino acid change cause subtle changes in individual component function that in combination have dramatic effects on complement activity and disease risk. In this study, we explore the functional consequences of a single nucleotide polymorphism (SNP) (rs17611) encoding a V802I polymorphism in C5 and propose a mechanism for its link to RA pathology. Plasma levels of C5, C5a, and terminal complement complex were measured in healthy and RA donors and correlated to rs17611 polymorphic status. Impact of the SNP on C5 functionality was assessed. Plasma C5a levels were significantly increased and C5 levels significantly lower with higher copy number of the RA risk allele for rs17611, suggesting increased turnover of C5 V802. Functional assays using purified C5 variants revealed no significant differences in lytic activity, suggesting that increased C5 V802 turnover was not mediated by complement convertase enzymes. C5 is also cleaved in vivo by proteases; the C5 V802 variant was more sensitive to cleavage with elastase and the “C5a” generated was biologically active. We hypothesize that this SNP in C5 alters the rate at which elastase generates active C5a in rheumatoid joints, hence recruiting neutrophils to the site thus maintaining a state of inflammation in arthritic joints.
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DOI：
10.1073/pnas.0812584106
发表时间：
2009-03-17
影响因子：
11.1
作者：
Montes, Tamara;Tortajada, Agustin;Harris, Claire L.
通讯作者：
Harris, Claire L.
影响因子：
158.5
作者：
Plenge, Robert M.;Seielstad, Mark;Gregersen, Peter K.
通讯作者：
Gregersen, Peter K.
影响因子：
--
作者：
Macor，Paolo;Durigutto，Paolo;Tedesco，Francesco
通讯作者：
Tedesco，Francesco
影响因子：
27.4
作者：
Kurreeman, Fina A. S.;Goulielmos, George N.;Martin, Javier
通讯作者：
Martin, Javier
影响因子：
30.8
作者：
Barton A;Thomson W;Ke X;Eyre S;Hinks A;Bowes J;Plant D;Gibbons LJ;Wellcome Trust Case Control Consortium;YEAR Consortium;BIRAC Consortium;Wilson AG;Bax DE;Morgan AW;Emery P;Steer S;Hocking L;Reid DM;Wordsworth P;Harrison P;Worthington J
通讯作者：
Worthington J