title: Heritable influence of DBH on adrenergic and renal function: twin and disease studies.
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 h(2) = 67.3±4.7% (p = 3.0E-18), as were secretion of norepinephrine (h(2) = 66.5±5.0%, p = 3.2E-16) and dopamine (h(2) = 56.5±5.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (ρG = -0.557±0.088, p = 1.11E-08) as well as dopamine (ρG = -0.223±0.101, p = 2.3E-02). Since dopamine β-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.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Dalal N
authors.initials: DN
authors.lastname: Pasha
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Davis
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Maple M
authors.initials: MM
authors.lastname: Fung
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Danuta
authors.initials: D
authors.lastname: Trzebinska
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Maja
authors.initials: M
authors.lastname: Mustapic
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: C Makena
authors.initials: CM
authors.lastname: Hightower
authors.affiliation: Department of Medicine, Georgetown University, Washington, District of Columbia, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lipkowitz
authors.affiliation: Graduate School of Public Health, Division of Epidemiology and Biostatistics, San Diego State University, San Diego, California, United States of America.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.affiliation: Department of Psychiatry, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, United States of America ; Department of Pharmacology, University of California at San Diego, La Jolla, California, United States of America ; Veterans Affairs San Diego Healthcare System, La Jolla, California, United States of America.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D015331:Cohort Studies; D004298:Dopamine / Q000502:physiology; D004299:Dopamine beta-Hydroxylase / Q000235:genetics* / Q000502:physiology; D005260:Female; D014644:Genetic Variation; D005919:Glomerular Filtration Rate / Q000235:genetics* / Q000502:physiology; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000502:physiology; D011401:Promoter Regions, Genetic; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000503:physiopathology
chemical_list: D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine