title: Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.
abstract: 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.
authors.affiliation: Department of Medicine, Veterans Affairs San Diego Healthcare System and University of California at San Diego, La Jolla, California 92093-0838, USA.
authors.forename: Maple M
authors.initials: MM
authors.lastname: Fung
authors.forename: Brinda K
authors.initials: BK
authors.lastname: Rana
authors.forename: Chih-Min
authors.initials: CM
authors.lastname: Tang
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shiina
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Jill
authors.initials: J
authors.lastname: Waalen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: 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
chemical_list: D017447:Receptors, Dopamine D1; D014527:Uric Acid; D003404:Creatinine
references.citation: Am J Physiol. 1989 Sep;257(3 Pt 2):F469-77
references.pmid: 2528916
references.citation: Pharmacogenomics. 2008 Sep;9(9):1211-5
references.pmid: 18781849
references.citation: Am J Nephrol. 2008;28(3):391-6
references.pmid: 18063857
references.citation: Twin Res. 2003 Oct;6(5):432-41
references.pmid: 14624727
references.citation: Nat Clin Pract Cardiovasc Med. 2008 Jul;5 Suppl 1:S36-43
references.pmid: 18580865
references.citation: Hypertension. 1990 Jun;15(6 Pt 1):560-9
references.pmid: 1971811
references.citation: Am J Physiol. 1990 Apr;258(4 Pt 2):F790-8
references.pmid: 2330978
references.citation: J Pharmacol Exp Ther. 1993 Mar;264(3):1154-9
references.pmid: 8095547
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: Clin Biochem Rev. 2006 Nov;27(4):173-84
references.pmid: 17581641
references.citation: Hypertension. 2009 Mar;53(3):564-70
references.pmid: 19139376
references.citation: Hypertension. 2008 Jun;51(6):1643-50
references.pmid: 18413491
references.citation: Kidney Int. 2005 Oct;68(4):1884-7
references.pmid: 16164667
references.citation: Am J Physiol. 1992 Jun;262(6 Pt 2):F1055-60
references.pmid: 1352429
references.citation: Kidney Int. 2004 Oct;66(4):1465-70
references.pmid: 15458439
references.citation: Hypertension. 2007 Jan;49(1):96-106
references.pmid: 17159089
references.citation: J Clin Invest. 1996 May 15;97(10):2283-8
references.pmid: 8636408
references.citation: Ann Rheum Dis. 1992 Mar;51(3):375-7
references.pmid: 1575585
references.citation: Physiol Genomics. 2004 Nov 17;19(3):277-91
references.pmid: 15367723
references.citation: J Biol Chem. 1994 Feb 11;269(6):4497-505
references.pmid: 8308019
references.citation: Stat Med. 2000 May 15;19(9):1217-35
references.pmid: 10797518
references.citation: Am J Hum Genet. 1998 May;62(5):1198-211
references.pmid: 9545414
references.citation: J Cardiovasc Pharmacol. 1991 Aug;18(2):243-53
references.pmid: 1717786
references.citation: Kidney Int. 1989 Sep;36(3):378-84
references.pmid: 2687564
references.citation: Hypertension. 1996 Oct;28(4):599-603
references.pmid: 8843884
references.citation: Am J Physiol. 1983 Feb;244(2):F95-104
references.pmid: 6297313
references.citation: Nihon Naibunpi Gakkai Zasshi. 1991 Nov 20;67(11):1271-81
references.pmid: 1761141
references.citation: Eur J Pharmacol. 1986 Jul 15;126(1-2):167-70
references.pmid: 2875883
references.citation: Am J Physiol. 1990 Mar;258(3 Pt 2):F627-35
references.pmid: 1969238
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1998 Oct;358(4):445-51
references.pmid: 9826067
references.citation: Ann Intern Med. 1999 Mar 16;130(6):461-70
references.pmid: 10075613
references.citation: Hypertension. 1997 Apr;29(4):962-8
references.pmid: 9095084
references.citation: Pharmacol Ther. 1998 Nov;80(2):149-82
references.pmid: 9839770
references.citation: Am J Physiol. 1995 Jan;268(1 Pt 1):E1-5
references.pmid: 7840165
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 May;290(5):R1153-67
references.pmid: 16603656
references.citation: Am J Hypertens. 2004 Dec;17(12 Pt 1):1184-7
references.pmid: 15607627
references.citation: Am J Hypertens. 2006 Aug;19(8):832-6
references.pmid: 16876683
references.citation: Hypertension. 2000 Aug;36(2):183-6
references.pmid: 10948075
references.citation: Curr Opin Nephrol Hypertens. 2002 Jan;11(1):87-92
references.pmid: 11753092
references.citation: J Hypertens. 1988 Aug;6(8):665-9
references.pmid: 2903190
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H551-69
references.pmid: 18083900
references.citation: Behav Res Methods. 2007 May;39(2):175-91
references.pmid: 17695343
references.citation: Klin Wochenschr. 1991 Sep 3;69(13):587-96
references.pmid: 1753681
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Cell Mol Life Sci. 2008 Oct;65(20):3168-81
references.pmid: 18581050
references.citation: Hypertension. 2007 Jan;49(1):155-61
references.pmid: 17116755
references.citation: Br J Clin Pharmacol. 1986 Jan;21(1):53-61
references.pmid: 2868748
references.citation: J Cell Biochem. 2002;87(1):58-64
references.pmid: 12210722
references.citation: Hypertension. 1997 Jan;29(1 Pt 1):115-22
references.pmid: 9039090
references.citation: Am J Physiol. 1987 Aug;253(2 Pt 2):H358-64
references.pmid: 3039860
references.citation: Hypertension. 2007 May;49(5):1015-31
references.pmid: 17353515
references.citation: J Cell Biochem. 2003 May 1;89(1):144-51
references.pmid: 12682915
references.citation: Hypertension. 2005 Oct;46(4):799-805
references.pmid: 16172423
references.citation: Hypertension. 2005 Jan;45(1):80-5
references.pmid: 15557390
references.citation: Nephrol Dial Transplant. 1999 Mar;14(3):581-7
references.pmid: 10193803
references.citation: Hypertension. 2003 Jun;41(6):1183-90
references.pmid: 12707287
references.citation: Br J Clin Pharmacol. 1985 Jan;19(1):21-7
references.pmid: 2858215