Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.
Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5'-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.
Fung
Maple M
MM
Department of Medicine, Veterans Affairs San Diego Healthcare System and University of California at San Diego, La Jolla, California 92093-0838, USA.
Rana
Brinda K
BK
Tang
Chih-Min
CM
Shiina
Tetsuo
T
Nievergelt
Caroline M
CM
Rao
Fangwen
F
Salem
Rany M
RM
Waalen
Jill
J
Ziegler
Michael G
MG
Insel
Paul A
PA
O'Connor
Daniel T
DT
D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D005260:Female; D005787:Gene Frequency; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D014527:Uric Acid / Q000378:metabolism
D017447:Receptors, Dopamine D1; D014527:Uric Acid; D003404:Creatinine
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