title: Genome-wide association scan identifies variants near Matrix Metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels.
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.
  
  
  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.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, MD, USA. ycheng@medicine.umaryland.edu
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Cheng
authors.forename: Wen-Hong L
authors.initials: WH
authors.lastname: Kao
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Haiqing
authors.initials: H
authors.lastname: Shen
authors.forename: Patrick F
authors.initials: PF
authors.lastname: McArdle
authors.forename: Quince
authors.initials: Q
authors.lastname: Gibson
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ryan
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
mesh_terms: D000328:Adult; D000367:Age Factors; D002318:Cardiovascular Diseases / Q000235:genetics; D002880:Chromosomes, Human, Pair 11; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood*; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1