Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases: A Genome-Wide Analysis.

Aino Salminen, Efthymia Vlachopoulou, Aki S Havulinna, Taina Tervahartiala, Wolfgang Sattler, Marja-Liisa Lokki, Markku S Nieminen, Markus Perola, Veikko Salomaa, Juha Sinisalo, Seppo Meri, Timo Sorsa, Pirkko J Pussinen
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引用次数: 20

Abstract

Background: Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear.

Methods and results: We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8-associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292; P=2.4×10-35). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes S100A8, S100A9, and S100A12 (strongest association: rs1560833; P=5.3×10-15). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82-0.99]; P=0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84-0.99]; P=0.032) in men but not in women.

Conclusions: According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in S100A9-S100A12-S100A8 locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.

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影响循环基质金属蛋白酶8水平的遗传变异及其与心血管疾病的关系:全基因组分析
背景:基质金属蛋白酶8 (MMP-8)是一种主要由中性粒细胞表达的促炎酶。血清和血浆MMP-8浓度升高与心血管疾病(cvd)的风险和结局相关。循环MMP-8的起源尚不完全清楚。方法和结果:我们对2个人群共6049人的血清MMP-8水平进行了全基因组关联研究。此外,我们研究了mmp -8相关变异是否与心血管疾病风险增加和超过2万名受试者的总死亡率有关。与血清MMP-8相关性最强的位点为1q31.3,包含补体因子H基因(先导单核苷酸多态性:rs800292;P = 2.4×10 - 35)。在功能实验中,激活rs800292次要等位基因(Ile62 In factor H)的补体替代途径,与主要等位基因(Val62 In factor H)相比,中性粒细胞中MMP-8的释放减少。在1q21.3中检测到另一个关联,包含基因S100A8、S100A9和S100A12(最强关联:rs1560833;P = 5.3×10 - 15)。rs1560833的次要等位基因与CVD呈负相关(优势比[95%可信区间]:0.90 [0.82-0.99];P=0.032)和发生心血管事件的时间(风险比[95%可信区间]:0.91 [0.84-0.99];P=0.032)。结论:根据我们的研究结果,补体系统替代途径的激活对血清MMP-8浓度有很大的影响。S100A9-S100A12-S100A8位点的遗传多态性影响血清和血浆MMP-8,并提示与心血管疾病的风险相关。我们的研究结果表明,遗传变异决定了循环MMP-8浓度的很大一部分。
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来源期刊
Circulation: Cardiovascular Genetics
Circulation: Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY
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6-12 weeks
期刊介绍: Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.
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