Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases: A Genome-Wide Analysis. (December 2017)

• Record Type: Journal Article
• Authors: Salminen, Aino; Vlachopoulou, Efthymia; Havulinna, Aki S.; Tervahartiala, Taina; Sattler, Wolfgang; Lokki, Marja-Liisa; Nieminen, Markku S.; Perola, Markus; Salomaa, Veikko; Sinisalo, Juha; Meri, Seppo; Sorsa, Timo; Pussinen, Pirkko J.
• Is Part Of: Circulation. Volume 10:Number 6(2017)
• Publication Date: 2017-12
• Subjects: cardiovascular diseases -- complement factor H -- genome wide association study -- immune system -- matrix metalloproteinases; Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.117.001731
• Languages: English
• ISSNs: 1942-325X

Abstract

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. Abstract : Supplemental Digital Content is available in the text.