Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury.
Susceptibility to ischemic damage to the subcortical white matter of the brain has a strong genetic basis. Dysregulation of matrix metalloproteinases (MMPs) contributes to loss of cerebrovascular integrity and white matter injury. We investigated whether sequence variation in the genes encoding MMP3 and MMP9 is associated with variation in leukoaraiosis volume, determined by magnetic resonance imaging, in non-Hispanic whites and African-Americans using family-based association tests. Seven hundred and fifty-six white and 671 African-American individuals from sibships ascertained through two or more siblings with hypertension were genotyped for 7 and 8 haplotype-tagging polymorphisms in the MMP3 and MMP9 genes, respectively. MMP3 sequence variation was significantly associated with variation in leukoaraiosis volume in Whites. Two common haplotypes with opposing relationships to leukoaraiosis volume were identified. MMP9 sequence variation was also significantly associated with variation in leukoaraiosis volume in both African-Americans and Whites. Different haplotypes contributed to these associations in the two racial groups. These findings add to the growing body of evidence from animal models and human clinical studies suggesting a role of MMPs in ischemic white matter injury. They provide the basis for further investigation of the role of these genes in susceptibility and/or progression to clinical disease.
Fornage
Myriam
M
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Pressler St., Room 530.G, Houston, TX 77030, USA. myriam.fornage@uth.tmc.edu
Mosley
Thomas H
TH
Jack
Clifford R
CR
de Andrade
Mariza
M
Kardia
Sharon L R
SL
Boerwinkle
Eric
E
Turner
Stephen T
ST
D001741:Black or African American / Q000235:genetics; D000368:Aged; D001483:Base Sequence; D002545:Brain Ischemia / Q000150:complications; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D049292:Leukoaraiosis / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D035781:Siblings; D044465:White People / Q000235:genetics
D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9