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Original Articles

Genome-Wide Association Scan Identifies Variants near Matrix Metalloproteinase (MMP) Genes on Chromosome 11q21–22 Strongly Associated With Serum MMP-1 Levels

Yu-Ching Cheng, PhD; Wen-Hong L. Kao, PhD; Braxton D. Mitchell, PhD; Jeffrey R. O'Connell, PhD; Haiqing Shen, PhD; Patrick F. McArdle, PhD; Quince Gibson, MBA; Kathleen A. Ryan, MPH; Alan R. Shuldiner, MD and Toni I. Pollin, PhD

From the Division of Endocrinology, Diabetes and Nutrition (Y.C.C., B.D.M., J.R.o.C., H.S., P.F.M.A., Q.G., K.A.R., A.R.S., T.I.P.), School of Medicine, University of Maryland, Baltimore, Md; Department of Epidemiology (W.H.L.K.), Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md; and Geriatric Research and Education Clinical Center (A.R.S.), Baltimore, Veterans Administration Medical Center, Baltimore, Md.

Correspondence to Yu-Ching Cheng, PhD, 660 W Redwood St, Room 478, Baltimore, MD 21201. E-mail ycheng{at}medicine.umaryland.edu

Received November 12, 2008; accepted April 30, 2009.

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=5.73x10^–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 (P10^–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.

Key Words: epidemiology • genetics • metalloproteinases • population

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