Multilocus analysis of hypertension: a hierarchical approach.
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.
Williams
Scott M
SM
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. smwilliams@chgr.mc.vanderbuilt.edu
Ritchie
Marylyn D
MD
Phillips
John A
JA
Dawson
Elliot
E
Prince
Melissa
M
Dzhura
Elvira
E
Willis
Alecia
A
Semenya
Amma
A
Summar
Marshall
M
White
Bill C
BC
Addy
Jonathan H
JH
Kpodonu
John
J
Wong
Lee-Jun
LJ
Felder
Robin A
RA
Jose
Pedro A
PA
Moore
Jason H
JH
D000483:Alleles; D001794:Blood Pressure; D004843:Epistasis, Genetic; D054771:G-Protein-Coupled Receptor Kinase 4; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005869:Ghana; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000208:ethnology* / Q000235:genetics*; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009569:Nitric Oxide / Q000378:metabolism; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012084:Renin-Angiotensin System; D014661:Vasoconstriction
D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human