1. Heritable Influence of DBH on Adrenergic and Renal Function: Twin and Disease Studies
- Author
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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, and Danuta Trzebinska
- Subjects
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 - Abstract
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.
- Published
- 2013