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. 2009 Aug;2(4):329-37.
doi: 10.1161/CIRCGENETICS.108.834986. Epub 2009 May 14.

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  1 , Wen-Hong L Kao, Braxton D Mitchell, Jeffrey R O'Connell, Haiqing Shen, Patrick F McArdle, Quince Gibson, Kathleen A Ryan, Alan R Shuldiner, Toni I Pollin
Affiliations

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 et al. Circ Cardiovasc Genet. 2009 Aug.

Abstract

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 < or = 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.

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Figures

Figure 1
Figure 1
Genome-wide association results. (A) Negative log of p-values and a quantile-quantile (Q-Q) plot showing the association of single nucleotide polymorphisms (SNPs) with MMP-1 serum levels across the entire genome using mixed model variance components analysis, and (B) Association signals and genes present in the region of significance on chromosome 11.
Figure 1
Figure 1
Genome-wide association results. (A) Negative log of p-values and a quantile-quantile (Q-Q) plot showing the association of single nucleotide polymorphisms (SNPs) with MMP-1 serum levels across the entire genome using mixed model variance components analysis, and (B) Association signals and genes present in the region of significance on chromosome 11.
Figure 2
Figure 2
Linkage disequilibrium structure (r2) of SNPs in MMP-1, MMP-3 and their intergenic region in the Amish.
Figure 3
Figure 3
Geometric mean of MMP-1 serum levels by the diplotypes of rs12289128-rs495366.
See this image and copyright information in PMC

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