Genome-wide association scan identifies variants near Matrix Metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels.
Genome-wide association scan identifies variants near Matrix Metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels.
复制标题
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
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Pollin TI
中科院分区：
文献类型：
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作者：
Cheng YC;Kao WH;Mitchell BD;O'Connell JR;Shen H;McArdle PF;Gibson Q;Ryan KA;Shuldiner AR;Pollin TI
基质金属蛋白酶1 （MMP-1）可能通过其降解细胞外胶原的能力影响斑块破裂，从而在心血管疾病（CVD）易感性中发挥作用。我们使用500K snp对778名健康阿米什成年人的循环MMP-1水平进行了全基因组关联分析，以确定影响血清MMP-1水平变异的基因。对血清MMP-1水平进行对数转换，并根据年龄和性别进行调整，使用混合模型方差成分筛选与snp的关联，以解释家族相关性。中位MMP-1水平为3.05 ng/mL（四分位数范围：1.82 ~ 5.04 ng/mL），估计遗传率为81% （P < 0.0001）。血清MMP-1水平与染色体11q上延伸11.5兆碱基区域的179个snp群密切相关。与rs495366的关联最高（P = 5.73 × 10−34），位于MMP-1和MMP-3之间，等位基因频率较小，为0.36。11q区域内的另外两个snp rs12289128和rs11226373在占rs495366后与MMP-1水平密切相关（P≤10−7）。在调整年龄和性别后，这三个snp解释了31%的MMP-1水平差异。该研究提供了强有力的证据，证明血清MMP-1水平具有高度遗传性，11q染色体上靠近MMP-1的snp解释了MMP-1水平变异的重要部分。确定影响MMP-1水平的遗传变异可能为CVD的遗传机制提供见解。
Matrix metalloproteinase 1 (MMP-1) may play a role in cardiovascular disease (CVD) susceptibility by influencing plaque rupture via its ability to degrade extracellular collagens. We performed a genome-wide association analysis of circulating MMP-1 levels using 500K SNPs to identify genes influencing variation in serum MMP-1 levels in 778 healthy Amish adults. Serum MMP-1 levels, logarithm-transformed and adjusted for age and sex, were screened for association with SNPs using mixed model variance components to account for familial relatedness. Median MMP-1 level was 3.05 ng/mL (inter-quartile range: 1.82 to 5.04 ng/mL) with an estimated heritability of 81% (P < 0.0001). Serum MMP-1 levels were strongly associated with a cluster of 179 SNPs extending over an 11.5 megabase region on chromosome 11q. The peak association was with rs495366 (P = 5.73 × 10−34), located within the region between MMP-1 and MMP-3 and having a minor allele frequency of 0.36. Two other SNPs within the 11q region, rs12289128 and rs11226373, were strongly associated with MMP-1 levels after accounting for rs495366 (P ≤ 10−7). These three SNPs explained 31% of the variance in MMP-1 levels after adjusting for age and sex. The study provides strong evidence that serum MMP-1 level is highly heritable and that SNPs near MMPs on chromosome 11q explain a significant portion of the variation in MMP-1 levels. Identification of the genetic variants that influence MMP-1 levels may provide insights into genetic mechanisms of CVD.