Heritable Influence of DBH on Adrenergic and Renal Function: Twin and Disease Studies

Autor: Maple M. Fung, Fangwen Rao, Maja Mustapic, Dalal N. Pasha, Ming Ji, Jason T. Davis, Daniel T. O'Connor, C. Makena Hightower, Gen Wen, Michael S. Lipkowitz, Yuqing Chen, Kuixing Zhang, Manjula Mahata, Michael G. Ziegler, Caroline M. Nievergelt, Danuta Trzebinska
Jazyk: chorvatština
Rok vydání: 2013
Předmět:
Male
Non-Clinical Medicine
Dopamine
lcsh:Medicine
Adrenergic
Dopamine beta-Hydroxylase
030204 cardiovascular system & hematology
Cardiovascular
Norepinephrine secretion
Biochemistry
Cohort Studies
Norepinephrine
Endocrinology
0302 clinical medicine
Chronic Kidney Disease
030212 general & internal medicine
lcsh:Science
Promoter Regions
Genetic
Multidisciplinary
Applied Mathematics
Middle Aged
Pathophysiology
Nephrology
Hypertension
Medicine
Female
Algorithms
Research Article
Glomerular Filtration Rate
medicine.drug
Adult
medicine.medical_specialty
Clinical Research Design
Renal function
Biology
03 medical and health sciences
Internal medicine
Genetic variation
Genetics
medicine
Humans
Renal Insufficiency
Chronic
Clinical Genetics
Health Care Policy
Endocrine Physiology
lcsh:R
Haplotype
Health Risk Analysis
Genetic Variation
Heritability
Black or African American
Haplotypes
Computer Science
Genetic Polymorphism
Glomerular filtration rate
GFR
dopamine beta-hydroxylase
DBH
chronic kidney disease
CKD
norepinephrine
twin pair
heritability
genetic covariance
lcsh:Q
Meta-Analyses
Population Genetics
Mathematics
Zdroj: PLoS One
PLoS ONE
PLoS ONE, Vol 8, Iss 12, p e82956 (2013)
Popis: Background: Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits. Methods: We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance- components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort. Results: Norepinephrine secretion rose across eGFR tertiles while eGFR fell (p, 0.0001). eGFR was heritable, at h2= 67.364.7% (p = 3.0E-18), as were secretion of norepinephrine (h2= 66.565.0%, p = 3.2E-16) and dopamine (h2= 56.565.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (rG=20.55760.088, p = 1.11E- 08) as well as dopamine (rG=20.22360.101, p = 2.3E-02). Since dopamine b-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH ; DBH promoter haplotypes predicted transcriptional activity (p, 0.001), plasma DBH (p, 0.0001) and norepinephrine (p = 0.0297) secretion ; transcriptional activity was inversely (p, 0.0001) associated with basal eGFR. Meta- analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p = 0.003). Conclusions: The heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.
Databáze: OpenAIRE
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