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

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 =67.364.7% (p=3.0E-18), as were secretion of norepinephrine (h 2 =66.565.0%, p=3.2E-16) and dopamine (h 2 =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.