| Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism. | |
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MedLine Citation:
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PMID: 17353515 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Fangwen Rao; Jennifer Wessel; Gen Wen; Lian Zhang; Brinda K Rana; Brian P Kennedy; Tiffany A Greenwood; Rany M Salem; Yuqing Chen; Srikrishna Khandrika; Bruce A Hamilton; Douglas W Smith; Niels-Henrik Holstein-Rathlou; Michael G Ziegler; Nicholas J Schork; Daniel T O'Connor |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Twin Study Date: 2007-03-12 |
Journal Detail:
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Title: Hypertension Volume: 49 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2007 May |
Date Detail:
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Created Date: 2007-04-19 Completed Date: 2007-05-07 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 1015-31 Citation Subset: IM |
Affiliation:
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Department of Medicine, Center for Human Genetics and Genomics, University of California at San Diego, La Jolla, CA 92093-0838, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult Aged Aged, 80 and over Albuminuria / genetics*, metabolism*, physiopathology Catecholamines / biosynthesis, metabolism Environment* Epistasis, Genetic Exocytosis Female Haplotypes Humans Kidney / metabolism* Male Middle Aged Polymorphism, Genetic* Receptors, Adrenergic / genetics Receptors, Dopamine D1 / genetics Signal Transduction / genetics Sympathetic Nervous System / physiopathology* |
| Grant Support | |
ID/Acronym/Agency:
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RR00827/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Catecholamines; 0/Receptors, Adrenergic; 0/Receptors, Dopamine D1 |
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