Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis.
Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis.
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DOI：
10.1186/ar1164
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发表时间：
2004
影响因子：
4.9
通讯作者：
Keyszer G
中科院分区：
文献类型：
--
作者：
Dörr S;Lechtenböhmer N;Rau R;Herborn G;Wagner U;Müller-Myhsok B;Hansmann I;Keyszer G
类风湿性关节炎（RA）的遗传背景仅部分了解，似乎涉及几个基因。基质金属蛋白酶MMP 1（间质胶原酶）和MMP 3（基质溶素1）被认为是重要的破坏性关节变化中看到的RA。在本研究中，在308例患者和110例对照中，对MMP 1和MMP 3的功能相关启动子多态性进行了基因分型，以测试多态性是否有助于通过关节破坏的放射学进展来测量疾病的严重程度。为了比较，通过聚合酶链反应确定HLADR4和DR1的共享表位（SE）。MMP基因多态性与RA的易感性无关。而MMP 1的1G/2G和MMP 3的5A/6A两个位点之间存在明显的连锁不平衡（P <<10~（-6），连锁不平衡指数D '= 0.46）。在析因回归分析中，放射学关节破坏程度与1G-5A单倍型（P = 0.0001）和交互作用项"估计的1G-5A单倍型数量×疾病持续时间"（P = 0.0007）显著相关。这种关联是阶段性的，表明拥有1G-5A单倍型在约15年的RA期间具有保护作用，但可能与以后更明显的放射学进展有关。在MMP 1的1G等位基因中也发现了类似的结果（P = 0.015）和交互作用项"1G等位基因估计数×病程"（P = 0.014）。SE与拉廷根评分的相关性相当（0.044）。MMP单倍型的回归模型解释了放射学评分变异的35%，而SE解释了29%。跨紧密连锁的MMP 1和MMP 3基因位点的1G-5A单倍型是一种新描述的与RA关节损伤进展密切相关的遗传因子。我们的研究结果表明，有单倍型在MMP簇区域，修改关节破坏RA在一个阶段性的方式。
The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However, a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10-6; linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype (P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes × duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles × duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner.
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DOI：
10.1006/bbrc.1999.0153
发表时间：
1999-02-05
影响因子：
3.1
作者：
Rao, CN;Mohanam, S;Rao, JS
通讯作者：
Rao, JS
影响因子：
4.1
作者：
MURPHY, G;COCKETT, MI;DOCHERTY, AJP
通讯作者：
DOCHERTY, AJP
影响因子：
--
作者：
ARNETT, FC;EDWORTHY, SM;HUNDER, GG
通讯作者：
HUNDER, GG
影响因子：
--
作者：
GREGERSEN, PK;SILVER, J;WINCHESTER, RJ
通讯作者：
WINCHESTER, RJ
影响因子：
--
作者：
Cunnane, G;FitzGerald, O;Bresnihan, B
通讯作者：
Bresnihan, B