Genome-wide association scan identifies variants near Matrix Metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels.
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.
Cheng
Yu-Ching
YC
Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, MD, USA. ycheng@medicine.umaryland.edu
Kao
Wen-Hong L
WH
Mitchell
Braxton D
BD
O'Connell
Jeffrey R
JR
Shen
Haiqing
H
McArdle
Patrick F
PF
Gibson
Quince
Q
Ryan
Kathleen A
KA
Shuldiner
Alan R
AR
Pollin
Toni I
TI
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
D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1