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The effects of polymorphisms in genes from the renin–angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context

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Abstract

Thrombosis is a key factor in the pathophysiology of cardiovascular disease. Important biochemical constituents of the fibrinolytic system, affecting thrombosis, include tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both t-PA and PAI-1 are determined by multiple genetic and environmental factors. We aimed to investigate whether the effects of polymorphism in genes from the renin–angiotensin, bradykinin, and fibrinolytic systems on t-PA or PAI-1 levels are dependent on environmental factors in a large population-based sample from the PREVEND study in Groningen, The Netherlands (n = 2,527). We found strong evidence (P ≤ 0.02) for interaction effects of polymorphisms from the bradykinin receptor (BDKRB2) gene and alcohol consumption on t-PA in females and males and on PAI-1 in males. Only suggestive evidence (P ≤ 0.10) was present for an interaction effect of the BDKRB2 gene and alcohol consumption on PAI-1 levels in females. Another consistent finding was evidence for an interaction between bradykinin receptor (BDKRB2) gene polymorphisms and body size as measured by body mass index and/or waist–hip-ratio. For each gender and for both t-PA and PAI-1 there was at least one BDKRB2–body size combination that exhibited suggestive (P ≤ 0.10), significant (P ≤ 0.04) and/or strong evidence (P ≤ 0.02) for interaction. In conclusion, the genetic architecture of t-PA and PAI-1 is dependent on the environmental context such as body size and alcohol use. The present study emphasizes the importance of including environmental factors in genetic analyses to fully comprehend the genetic architecture of a specific trait.

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Acknowledgments

This work was supported by NIH grant HL65234, HL67466, RR018787, and by grant E.013 of Netherlands Kidney Foundation. F.W. Asselbergs is a research fellow of the Netherlands Heart Foundation (2003T010) and the Dutch Inter University Cardiology Institute Netherlands (ICIN).

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Authors and Affiliations

  1. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Folkert W. Asselbergs, Hans L. Hillege & Wiek H. van Gilst

  2. Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical School, Nashville, TN, USA

    Scott M. Williams & Douglas E. Vaughan

  3. Section of Cardiovascular Medicine, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    Patricia R. Hebert

  4. Department of Biostatistics, School of Public Health, University of Alabama Birmingham, Birmingham, AL, USA

    Christopher S. Coffey

  5. Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Folkert W. Asselbergs & Harold Snieder

  6. Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Gerjan Navis

  7. Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Wiek H. van Gilst

  8. Computational Genetics Laboratory, Departments of Genetics and Community and Family Medicine, Dartmouth Medical School, Lebanon, NH, USA

    Jason H. Moore

  9. HB 7937, One Medical Center Dr, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA

    Jason H. Moore

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  1. Folkert W. Asselbergs
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  2. Scott M. Williams
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  3. Patricia R. Hebert
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  4. Christopher S. Coffey
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  5. Hans L. Hillege
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  7. Gerjan Navis
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  8. Douglas E. Vaughan
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  9. Wiek H. van Gilst
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  10. Jason H. Moore
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Corresponding author

Correspondence to Jason H. Moore.

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Asselbergs, F.W., Williams, S.M., Hebert, P.R. et al. The effects of polymorphisms in genes from the renin–angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context. Hum Genet 122, 275–281 (2007). https://doi.org/10.1007/s00439-007-0400-9

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  • DOI: https://doi.org/10.1007/s00439-007-0400-9

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