Genetic polymorphisms of matrix metalloproteinase 3 in primary sclerosing cholangitis.
Genetic polymorphisms of matrix metalloproteinase 3 in primary sclerosing cholangitis.
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原发性硬化性胆管炎基质金属蛋白酶3的遗传多态性。
DOI：
10.1111/j.1478-3231.2010.02420.x
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Lazaridis KN
中科院分区：
文献类型：
--
作者：
Juran BD;Atkinson EJ;Schlicht EM;Larson JJ;Ellinghaus D;Franke A;Lazaridis KN
原发性硬化性胆管炎（PSC）固有的损害性胆汁淤积是由于进行性纤维化导致的胆管狭窄。基质金属蛋白酶3（MMP 3）降解广泛的基质成分，并由活化的肝星状细胞表达，因此是参与PSC的纤维化过程的候选者。此外，MMP 3基因具有与其活性变化相关的多态性，直接影响临床表型。我们的目的是研究MMP 3多态性对PSC风险和进展的影响。对266例PSC患者和407例对照者的9个MMP 3常见遗传变异的单核苷酸多态性（SNPs）进行了基因分型。单核苷酸多态性和推断的单倍型进行了评估PSC的关联逻辑回归和得分测试。使用考克斯回归分析SNP对肝移植存活或死亡的影响，并构建Kaplan-Meier曲线。未检测到PSC与单个SNP或MMP 3单倍型的关联。然而，死亡或肝移植的进展与rs 522616、rs650108和rs683878的次要等位基因的纯合性显著相关，特别是在并发溃疡性结肠炎（UC）的PSC患者中。（冗余SNP rs650108/rs683878中最强，风险比= 3.23，95%置信区间1.45-7.25，P = 0.004）。MMP 3的遗传变异影响PSC进展，可能与UC共存。虽然功能变体和具体机制仍然未知，但这一发现暗示细胞外基质的周转是PSC发病机制的重要和可变组分。努力了解这一过程可以为开发有效的治疗方法奠定基础，这是目前缺乏的PSC。
The damaging cholestasis inherent to primary sclerosing cholangitis (PSC) results from bile duct stricturing because of progressive fibrosis. The matrix metalloproteinase 3 (MMP3) degrades a wide range of matrix components and is expressed by activated liver stellate cells, and so is a candidate for involvement with the fibrotic processes underlying PSC. Moreover, the MMP3 gene harbours polymorphisms associated with variation in its activity directly impacting clinical phenotypes. We aimed to examine the influence of MMP3 polymorphisms on PSC risk and progression. Nine single nucleotide polymorphisms (SNPs) tagging the common genetic variation of MMP3 were genotyped in 266 PSC patients and 407 controls. SNPs and inferred haplotypes were assessed for PSC association by logistic regression and score tests. The effect of SNPs on survival to liver transplant or death was analysed using Cox regression, and Kaplan–Meier curves were constructed. No association of PSC with individual SNPs or haplotypes of MMP3 was detected. However, progression to death or liver transplant was significantly associated with homozygosity for minor alleles of rs522616, rs650108 and rs683878, particularly among PSC patients with concurrent ulcerative colitis (UC) (strongest in redundant SNPs rs650108/rs683878, hazard ratio = 3.23, 95% confidence interval 1.45–7.25, P = 0.004). Genetic variation in MMP3 influences PSC progression, possibly in the context of coexisting UC. While the functional variants and specific mechanisms remain unknown, this finding implicates the turnover of the extracellular matrix as an important and variable component of PSC pathogenesis. Efforts to understand this process could form the basis for developing effective treatments, which are currently lacking for PSC.
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全基因组关联扫描鉴定染色体11q21-22上基质金属蛋白酶（MMP）基因附近的变体与血清MMP-1水平密切相关。
DOI：
10.1161/circgenetics.108.834986
发表时间：
2009-08
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Cheng YC;Kao WH;Mitchell BD;O'Connell JR;Shen H;McArdle PF;Gibson Q;Ryan KA;Shuldiner AR;Pollin TI
通讯作者：
Pollin TI
影响因子：
4.8
作者：
Kirstein, M;Sanz, L;Saus, J
通讯作者：
Saus, J
影响因子：
4.6
作者：
Louis, E;Ribbens, C;Malaise, M
通讯作者：
Malaise, M
影响因子：
9
作者：
Aron, Jonathan H.;Bowlus, Christopher L.
通讯作者：
Bowlus, Christopher L.
影响因子：
3.8
作者：
Li, J;Ji, L
通讯作者：
Ji, L