Original Paper

Multilocus Analysis of Hypertension: A Hierarchical Approach
Scott M. Williams^a,b,c,d, Marylyn D. Ritchie^a, John A. Phillips III^b,c,d, Elliot Dawson^e, Melissa Prince^d, Elvira Dzhura^d, Alecia Willis^b,d, Amma Semenya^c, Marshall Summar^b,d, Bill C. White^b, Jonathan H. Addyⁱ, John Kpodonuⁱ, Lee-Jun Wong^f, Robin A. Felder^g, Pedro A. Jose^h, Jason H. Moore<sup>b

a</sup>Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn.,
^bProgram in Human Genetics, Vanderbilt University Medical Center, Nashville, Tenn.,
^cDepartment of Microbiology, Meharry Medical College, Nashville, Tenn.,
^dDepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn.,
^eBioventures, Murfreesboro, Tenn.,
^fInstitute for Molecular and Human Genetics, Georgetown University Medical Center, Washington, D.C.,
^gDepartment of Pathology, Medical Automation Research Center, University of Virginia, Charlottesville, Va., and
^hDepartments of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, Washington, D.C., USA;
ⁱDepartment of Medicine and Therapeutics, University of Ghana, Accra, Ghana

Address of Corresponding Author

Hum Hered 2004;57:28-38 (DOI: 10.1159/000077387)

  Key Words

• Epistasis
• Hypertension
• Blacks
• Renin-angiotensin system

  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.

Copyright © 2004 S. Karger AG, Basel

  Author Contacts

Scott M. Williams, PhD
Division of Cardiovascular Medicine and Center for Human Genetics Research
519 Light Hall, Vanderbilt University Medical Center
Nashville, TN 37232 (USA)
Tel. +1 615 322 8036, Fax +1 615 343 8619, E-Mail smwilliams@chgr.mc.vanderbilt.edu

  Article Information

Received: August 28, 2003
Accepted after revision: December 8, 2003
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 7, Number of References : 49