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An angiotensin converting enzyme haplotype predicts survival in patients with end stage renal disease

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Abstract

The renin-angiotensin system is implicated in the development of a variety of human diseases. Many studies have sought to characterize the clinical implications of polymorphisms in the angiotensin converting enzyme (ACE) gene. Given the high mortality rate of individuals on chronic hemodialysis (HD), we sought to investigate whether genetic diversity in the ACE gene correlates with mortality in this population. We assembled a racially diverse cohort of prevalent individuals on chronic outpatient HD, and followed it prospectively for a mean of 2.1 years. Subjects were genotyped for seven single nucleotide polymorphisms (SNPs) in the ACE gene. Haplotype probabilities were calculated using an expectation–maximization algorithm. Cox proportional hazards regression was used to determine associations between haplotype and time to mortality from initiation of HD. There was strong linkage disequilibrium (LD) across the ACE gene, with three tagging SNPs found to account for all seven-SNP haplotypes that had a frequency of greater than 4%. After adjustment for age, race, gender, and diabetes status, a three-locus haplotype was associated with a 72% risk reduction in mortality (P = 0.004). The majority of this association was captured by the TT genotype of A-239T promoter polymorphism. The TGG (non-wild-type) haplotype, consisting of three tagging SNPs in the ACE gene, is associated with significantly decreased risk of all-cause mortality in HD patients independent of age, race, gender, and diabetic status. This “protective” haplotype may encompass loci with functional significance in the ACE gene.

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Acknowledgements

This study was supported by NIH grants DK 39776 (DHL), DK 56182 (KLJ), DK 07219 (JBW), UCSF Foundation Greenberg Awards #80357 and #60519 (DHL, KLJ), Amgen Grant #20010180 (AMH, DHL, KLJ), and National Kidney Foundation Grants (AMH, JBW). We thank the UCSF Genomics Core Facility for their assistance in genotyping, and Satellite Dialysis for assistance in patient recruitment.

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  1. Adriana M. Hung

    Present address: Tampa VAMC, University of South Florida, Tampa, FL, USA

Authors and Affiliations

  1. The Department of Medicine, San Francisco VAMC/University of California, San Francisco, CA, USA

    James B. Wetmore, Kirsten L. Johansen, Adriana M. Hung & David H. Lovett

  2. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

    Saunak Sen

  3. Medical Service (111J), SFVAMC, 4150 Clement Street, San Francisco, CA, 94121, USA

    James B. Wetmore

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  1. James B. Wetmore
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  2. Kirsten L. Johansen
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Correspondence to James B. Wetmore.

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Wetmore, J.B., Johansen, K.L., Sen, S. et al. An angiotensin converting enzyme haplotype predicts survival in patients with end stage renal disease. Hum Genet 120, 201–210 (2006). https://doi.org/10.1007/s00439-006-0191-4

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  • DOI: https://doi.org/10.1007/s00439-006-0191-4

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