Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs.
There is little data on genetic predictors of loop diuretic efficacy in humans. Therefore, we investigated the diuretic effects of single oral doses of bumetanide, frusemide, and torsemide in a crossover study in 97 healthy Caucasians in relation to genetic variation in the renal sodium transporters NKCC2 (coded by SLC12A1), NCC (SLC12A3), and ENaC (three subunits coded by SCNN1A, SCNN1B, and SCNN1G). The NCC alanine 264 allele (Gly264Ala) and the most frequent SCNN1B haplotype were associated with stronger diuresis, indicating lower reabsorbing function of these alleles. The variant alleles of the tightly coupled polymorphisms rs5723 (Leu649Leu) and rs5729 in SCNN1G were associated with weaker diuresis, indicating higher activity. Extended haplotype homozygosity implied evolutionary selection of the NCC alanine 264 allele. In conclusion, acute diuretic effects of loop diuretics were affected by genetic variation in sodium transporters that, in the nephron, are located distally from NKCC2.
Vormfelde
S V
SV
Department of Clinical Pharmacology, University Medical Centre, Georg-August-University Göttingen, Göttingen, Germany. svormfe@gwdg.de
Sehrt
D
D
Toliat
M R
MR
Schirmer
M
M
Meineke
I
I
Tzvetkov
M
M
Nürnberg
P
P
Brockmöller
J
J
D000328:Adult; D002034:Bumetanide / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D004232:Diuretics / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000235:genetics*; D005665:Furosemide / Q000493:pharmacokinetics / Q000494:pharmacology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011188:Potassium / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology; D027981:Symporters / Q000235:genetics*; D049971:Thiazides / Q000494:pharmacology; D000077786:Torsemide
D004232:Diuretics; D053503:Epithelial Sodium Channels; D011955:Receptors, Drug; C578714:SLC12A1 protein, human; C578874:SLC12A3 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D013449:Sulfonamides; D027981:Symporters; D049971:Thiazides; D002034:Bumetanide; D005665:Furosemide; D011188:Potassium; D000077786:Torsemide