title: Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism.
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.
authors.affiliation: Department of Medicine, Center for Human Genetics and Genomics, University of California at San Diego, La Jolla, CA 92093-0838, USA.
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wessel
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.forename: Brinda K
authors.initials: BK
authors.lastname: Rana
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Srikrishna
authors.initials: S
authors.lastname: Khandrika
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Smith
authors.forename: Niels-Henrik
authors.initials: NH
authors.lastname: Holstein-Rathlou
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000419:Albuminuria / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D002395:Catecholamines / Q000096:biosynthesis / Q000378:metabolism; D004777:Environment; D004843:Epistasis, Genetic; D005089:Exocytosis; D005260:Female; D006239:Haplotypes; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011941:Receptors, Adrenergic / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013564:Sympathetic Nervous System / Q000503:physiopathology*
chemical_list: D002395:Catecholamines; D011941:Receptors, Adrenergic; D017447:Receptors, Dopamine D1