Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 2, Issue 4, Pages 329-U76Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.108.834986
Keywords
epidemiology; genetics; metalloproteinases; population
Funding
- NIH [U01 HL72515, U01 HL84756, R01 088119]
- University of Maryland General Clinical Research Center [M01 RR 16500]
- Clinical Nutrition Research Unit of Maryland
- Baltimore Veterans Administration Medical Center Geriatric Research and Education Clinical Center
- Merck Foundation
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Background-Matrix metalloproteinase (MMP)-1 may play a role in cardiovascular disease susceptibility by influencing plaque rupture via its ability to degrade extracellular collagens. Methods and Results-We performed a genome-wide association analysis of circulating MMP-1 levels using 500 K single-nucleotide polymorphisms (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 (interquartile 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 x 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 3 SNPs explained 31% of the variance in MMP-1 levels after adjusting for age and sex. Conclusions-This study provides strong evidence that the 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 cardiovascular disease. (Circ Cardiovasc Genet. 2009; 2: 329-337.)
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