Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury
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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.
The authors thank the staff and participants of the GENOA study for their contributions. This research was supported by grants from the National Institutes of Health NS41558 and NS41466 and by funds from the Mayo Foundation.
- Carmelli D, DeCarli C, Swan GE, Jack LM, Reed T, Wolf PA, Miller BL (1998a) Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 29:1177–1181Google Scholar
- Carmelli D, Swan GE, Reed T, Miller B, Wolf PA, Jarvik GP, Schellenberg GD (1998b) Midlife cardiovascular risk factors, ApoE, and cognitive decline in elderly male twins. Neurology 50:1580–1585Google Scholar
- Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229PubMedCrossRefADSGoogle Scholar
- de Leeuw FE, de Groot JC, Achten E, Oudkerk M, Ramos LM, Heijboer R, Hofman A, Jolles J, van Gijn J, Breteler MM (2001) Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 70:9–14PubMedCrossRefGoogle Scholar
- Li J, Brick P, O’Hare MC, Skarzynski T, Lloyd LF, Curry VA, Clark IM, Bigg HF, Hazleman BL, Cawston TE et al (1995) Structure of full-length porcine synovial collagenase reveals a C-terminal domain containing a calcium-linked, four-bladed beta-propeller. Structure 3:541–549PubMedCrossRefGoogle Scholar
- Schmidt H, Fazekas F, Kostner GM, van Duijn CM, Schmidt R (2001a) Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study. Stroke 32:405–412Google Scholar
- Schmidt R, Schmidt H, Fazekas F, Launer LJ, Niederkorn K, Kapeller P, Lechner A, Kostner GM (2001b) Angiotensinogen polymorphism M235T, carotid atherosclerosis, and small-vessel disease-related cerebral abnormalities. Hypertension 38:110–115Google Scholar
- SeattleSNPs Variation Discovery Resource http://www.pga.mbt.washington.edu. Cited 1 June 2006
- The ARIC investigators (1989) The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am J Epidemiol 129:687–702Google Scholar