Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism.
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Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism. / Rao, Fangwen; Wessel, Jennifer; Wen, Gen; Zhang, Lian; Rana, Brinda K; Kennedy, Brian P; Greenwood, Tiffany A; Salem, Rany M; Chen, Yuqing; Khandrika, Srikrishna; Hamilton, Bruce A; Smith, Douglas W; Ziegler, Michael G; Schork, Nicholas J; O'Connor, Daniel T; Holstein-Rathlou, N.-H.
In: Hypertension, Vol. 49, No. 5, 2007, p. 1015-31.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism.
AU - Rao, Fangwen
AU - Wessel, Jennifer
AU - Wen, Gen
AU - Zhang, Lian
AU - Rana, Brinda K
AU - Kennedy, Brian P
AU - Greenwood, Tiffany A
AU - Salem, Rany M
AU - Chen, Yuqing
AU - Khandrika, Srikrishna
AU - Hamilton, Bruce A
AU - Smith, Douglas W
AU - Ziegler, Michael G
AU - Schork, Nicholas J
AU - O'Connor, Daniel T
AU - Holstein-Rathlou, N.-H.
N1 - Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Catecholamines; Environment; Epistasis, Genetic; Exocytosis; Female; Haplotypes; Humans; Kidney; Male; Middle Aged; Polymorphism, Genetic; Receptors, Adrenergic; Receptors, Dopamine D1; Signal Transduction; Sympathetic Nervous System
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
U2 - 10.1161/HYPERTENSIONAHA.106.081679
DO - 10.1161/HYPERTENSIONAHA.106.081679
M3 - Journal article
C2 - 17353515
VL - 49
SP - 1015
EP - 1031
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 5
ER -
ID: 8419863