Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricemia in a German Caucasian population.
OBJECTIVE
Human urate transporter 1 (hURAT1) is a member of the organic anion transporter family (SLC22A12) that mainly regulates tubular urate reabsorption. Loss-of-function mutations result in idiopathic hypouricemia. The present case-control study was designed to analyze whether hURAT1 might also be a candidate gene for hyperuricemia with primary reduced renal urate excretion.


METHODS
DNA samples from 389 individuals with reduced fractional excretion of uric acid (FEUA) (< or =6.5%) and from 263 controls (FEUA >6.5%) were sequenced. Genotype frequencies between groups were compared by Cochran-Armitage trend test.


RESULTS
Significantly different genotype distributions could be demonstrated for the -788 T >A (promoter; P = 0.014), the C258T (exon 1; P = 0.006), and the C426T (exon 2; P = 0.0002) polymorphisms, but not for the T1309C (exon 8) and the +18 C >T (intron 9) polymorphisms. The strongest association with reduced FEUA was observed for the C426T polymorphism, with odds ratios (ORs) of 1.59 and 2.54 (P = 0.0002) for the CT and TT genotypes, respectively. Adjusted values for FEUA in the C426T genotype, were significantly reduced decreasing to 7.3%, 6.7%, and 6.3% in individuals with the CC, CT, and TT genotypes, respectively (P = 0.004). Haplotypes were constructed from the -788 T >A, C258T, and C426T polymorphisms. Individuals carrying at least 1 ACT haplotype (n = 349) had a significantly higher risk for reduced FEUA than individuals without any ACT haplotype (n = 303) (OR 1.39, P = 0.041).


CONCLUSIONS
These results indicate that polymorphisms in the N-terminus of the hURAT1 gene were significantly associated with reduced renal uric acid excretion. The main regulating factor seems to be located close to the C426T polymorphism or is in strong linkage disequilibrium.
Graessler
Juergen
J
Department of Pathological Biochemistry, Clinic of Internal Medicine III, Carl Gustav Carus Medical School, University of Technology-Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany. Juergen.Graessler@mailbox.tu-dresden.de
Graessler
Anett
A
Unger
Susette
S
Kopprasch
Steffi
S
Tausche
Anne-Kathrin
AK
Kuhlisch
Eberhard
E
Schroeder
Hans-Egbert
HE
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D005260:Female; D005858:Germany; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000502:physiology; D027701:Organic Cation Transport Proteins; D011110:Polymorphism, Genetic; D014527:Uric Acid / Q000652:urine*; D044465:White People
D002352:Carrier Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014527:Uric Acid