A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity.
A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity.
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DOI：
10.1186/ar2299
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发表时间：
2007
影响因子：
4.9
通讯作者：
Holmdahl R
中科院分区：
文献类型：
--
作者：
Olsson LM;Lindqvist AK;Källberg H;Padyukov L;Burkhardt H;Alfredsson L;Klareskog L;Holmdahl R
类风湿性关节炎（RA）是一种遗传率为60%的慢性炎症性疾病。RA的遗传作用由多个基因决定，但只有少数基因关联尚未得到证实。通过对动物模型的研究，nadph氧化酶（NOX）复合物的能力降低，是由其组分之一（NCF1基因）的单核苷酸多态性（SNP）引起的，已被发现会增加关节炎的严重程度。然而，据我们所知，尚未有研究调查活性氧产生减少在人类RA中所起的潜在作用。为了研究NOX复合物在RA中的作用，我们在瑞典的一个病例对照队列中研究了NOX复合物（CYBB， CYBA, NCF4， NCF2和RAC2）的五个基因中的51个snp的关联，该队列包括1842例RA病例和1038例对照个体。在NCF4 （rs729749, P = 0.001）、NCF2 （rs789181, P = 0.02）和RAC2 （rs1476002, P = 0.05）中发现了几个snp与男性轻度相关。在CYBA或CYBB中未检测到关联。通过对自身抗体状态进行分层，我们发现rs729749（在NCF4中）与自身抗体阴性疾病有很强的相关性，在类风湿因子阴性的男性中检测到最强的相关性（CT基因型与CC基因型：优势比0.34,95%可信区间0.2 ~ 0.6;P = 0.0001）。据我们所知，这是第一个在RA和NOX复合物之间发现的遗传关联，它支持了先前从动物模型中发现的活性氧产生能力对关节炎发展的重要性。
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.
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影响因子：
--
作者：
AHO, K;PALOSUO, T;SALONEN, JT
通讯作者：
SALONEN, JT
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D
DOI：
10.1073/pnas.0604571103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Gelderman, Kyra A.;Hultqvist, Malin;Holmdahl, Rikard
通讯作者：
Holmdahl, Rikard
影响因子：
20.3
作者：
Heyworth, PG;Noack, D;Cross, AR
通讯作者：
Cross, AR
影响因子：
--
作者：
Burkhardt, H;Hüffmeier, U;Reis, A
通讯作者：
Reis, A