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Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury

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Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Pressler St., Room 530.G, Houston, TX, 77030, USA

    Myriam Fornage & Eric Boerwinkle

  2. Division of Geriatrics, Department of Internal Medicine, University of Mississippi, Jackson, MS, USA

    Thomas H. Mosley

  3. Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN, USA

    Clifford R. Jack

  4. Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA

    Mariza de Andrade

  5. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

    Sharon L. R. Kardia

  6. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA

    Eric Boerwinkle

  7. Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA

    Stephen T. Turner

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  1. Myriam Fornage
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  2. Thomas H. Mosley
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  3. Clifford R. Jack
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  4. Mariza de Andrade
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  5. Sharon L. R. Kardia
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  6. Eric Boerwinkle
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  7. Stephen T. Turner
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Correspondence to Myriam Fornage.

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Fornage, M., Mosley, T.H., Jack, C.R. et al. Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury. Hum Genet 120, 671–680 (2007). https://doi.org/10.1007/s00439-006-0236-8

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