Multilocus analysis of hypertension: A hierarchical approach

Scott M. Williams, Marylyn D. Ritchie, John A. Phillips, Elliot Dawson, Melissa Prince, Elvira Dzhura, Alecia Willis, Amma Semenya, Marshall Summar, Bill C. White, Jonathan H. Addy, John Kpodonu, Lee Jun Wong, Robin A. Felder, Pedro A. Jose, Jason H. Moore

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

While hypertension is a complex disease with a well-documented genetic component, genetic studies often fail to replicate findings. One possibility for such inconsistency is that the underlying genetics of hypertension is not based on single genes of major effect, but on interactions among genes. To test this hypothesis, we studied both single locus and multilocus effects, using a case-control design of subjects from Ghana. Thirteen polymorphisms in eight candidate genes were studied. Each candidate gene has been shown to play a physiological role in blood pressure regulation and affects one of four pathways that modulate blood pressure: vasoconstriction (angiotensinogen, angiotensin converting enzyme - ACE, angiotensin II receptor), nitric oxide (NO) dependent and NO independent vasodilation pathways and sodium balance (G protein-coupled receptor kinase, GRK4). We evaluated single site allelic and genotypic associations, multilocus genotype equilibrium and multilocus genotype associations, using multifactor dimensionality reduction (MDR). For MDR, we performed systematic reanalysis of the data to address the role of various physiological pathways. We found no significant single site associations, but the hypertensive class deviated significantly from genotype equilibrium in more than 25% of all multilocus comparisons (2,162 of 8,178), whereas the normotensive class rarely did (11 of 8,178). The MDR analysis identified a two-locus model including ACE and GRK4 that successfully predicted blood pressure phenotype 70.5% of the time. Thus, our data indicate epistatic interactions play a major role in hypertension susceptibility. Our data also support a model where multiple pathways need to be affected in order to predispose to hypertension.

Original languageEnglish (US)
Pages (from-to)28-38
Number of pages11
JournalHuman heredity
Volume57
Issue number1
DOIs
StatePublished - 2004

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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