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SHR Neuro Krebs Kardio Lipid

Salminen, A; Vlachopoulou, E; Havulinna, AS; Tervahartiala, T; Sattler, W; Lokki, ML; Nieminen, MS; Perola, M; Salomaa, V; Sinisalo, J; Meri, S; Sorsa, T; Pussinen, PJ.
Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases: A Genome-Wide Analysis
CIRC-CARDIOVASC GENE. 2017; 10(6): UNSP e001731
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Autor/innen der Med Uni Graz:
Sattler Wolfgang
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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 >20000 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=2.4x10(-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=5.3x10(-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.

Find related publications in this database (Keywords)
cardiovascular diseases
complement factor H
genome wide association study
immune system
matrix metalloproteinases
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