Human Genetics

, Volume 120, Issue 5, pp 671–680 | Cite as

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

  • Myriam Fornage
  • Thomas H. Mosley
  • Clifford R. Jack
  • Mariza de Andrade
  • Sharon L. R. Kardia
  • Eric Boerwinkle
  • Stephen T. Turner
Original Investigation

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.

Notes

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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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Myriam Fornage
    • 1
  • Thomas H. Mosley
    • 2
  • Clifford R. Jack
    • 3
  • Mariza de Andrade
    • 4
  • Sharon L. R. Kardia
    • 5
  • Eric Boerwinkle
    • 1
    • 6
  • Stephen T. Turner
    • 7
  1. 1.Institute of Molecular MedicineUniversity of Texas Health Science Center at HoustonHoustonUSA
  2. 2.Division of Geriatrics, Department of Internal MedicineUniversity of MississippiJacksonUSA
  3. 3.Department of Diagnostic RadiologyMayo Clinic and FoundationRochesterUSA
  4. 4.Division of Biostatistics, Department of Health Sciences ResearchMayo Clinic and FoundationRochesterUSA
  5. 5.Department of EpidemiologyUniversity of MichiganAnn ArborUSA
  6. 6.Human Genetics CenterUniversity of Texas Health Science Center at HoustonHoustonUSA
  7. 7.Division of Nephrology and Hypertension, Department of Internal MedicineMayo Clinic and FoundationRochesterUSA

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