on March 12, 2007
Published online before print March 12, 2007, doi: 10.1161/HYPERTENSIONAHA.106.081679
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Submitted on October 1, 2006
From the Departments of Medicine (F.R., G.W., L.Z., B.P.K., R.M.S., Y.C., S.K., B.A.H., M.G.Z., D.T.O.), Psychiatry (J.W., B.K.R., T.A.G., D.W.S., N.J.S.), Biology, and Pharmacology, Polymorphism Research Laboratory, and Center for Human Genetics and Genomics, University of California at San Diego; the VA San Diego Healthcare System, Calif; and the Department of Medical Physiology (N.-H.H.-R.), University of Copenhagen, Copenhagen, Denmark. * To whom correspondence should be addressed. E-mail: doconnor{at}ucsd.edu.
Abstract--Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning catecholamine biosynthesis, storage, catabolism, receptor action, and postreceptor signal transduction. We studied 134 single nucleotide polymorphisms at 46 loci for a total of >51 000 genotypes. Albumin excretion heritability was 45.2±7.4% (P=2x10-7), and the phenotype aggregated significantly with adrenergic, renal, metabolic, and hemodynamic traits. In the adrenergic system, excretions of both norepinephrine and epinephrine correlated with albumin. In the kidney, albumin excretion correlated with glomerular and tubular traits (Na+ and K+ excretion; fractional excretion of Na+ and Li+). Albumin excretion shared genetic determination (genetic covariance) with epinephrine excretion, and environmental determination with glomerular filtration rate and electrolyte intake/excretion. Albumin excretion associated with polymorphisms at multiple points in the adrenergic pathway: catecholamine biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention, diagnosis, and treatment.
Revised on October 25, 2006
Renal Albumin Excretion. Twin Studies Identify Influences of Heredity, Environment, and Adrenergic Pathway Polymorphism
Fangwen Rao;
Key words: hypertension • metabolic • inflammation • glomerulus • catecholamine • receptor • adrenergic
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