WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic.
Single nucleotide polymorphisms (SNPs) in genes encoding or influencing renal sodium transport systems were investigated as potential predictors of blood pressure (BP) response to a thiazide diuretic. A sample of 585 adults with essential hypertension (30 to 59.9 years of age; 50% blacks; 47% women) were treated with hydrochlorothiazide for 4 weeks (25 mg daily, orally) to determine office BP responses. Ambulatory BP responses were measured in a subset of 228 subjects. After adjustment for ethnicity, sex, age, and waist-to-hip ratio, 3 SNPs in WNK1 (rs2107614, rs2277869, and rs1159744), encoding a lysine-deficient protein kinase that regulates thiazide-sensitive sodium-potassium cotransport, made statistically significant contributions to predicting ambulatory BP responses, accounting for 2% to 4% of variation in systolic and diastolic responses (P<0.05). SNPs in the beta2-adrenoceptor (rs2400707) and the epithelial sodium channel gamma-subunit (rs5723 and rs5729) were associated with similar magnitude of variation in ambulatory systolic BP response (P=0.028) or office diastolic BP response (P<0.05), respectively. However, SNPs evaluated in the furosemide-sensitive sodium-potassium chloride cotransporter, potassium inwardly rectifying channel, chloride channel, thiazide-sensitive sodium chloride cotransporter, epithelial sodium channel beta-subunit, and the mineralocorticoid receptor were not associated with significant variation in ambulatory or office BP responses. Polymorphisms in genes regulating renal sodium transport, in particular WNK1, predict interindividual differences in antihypertensive responses to hydrochlorothiazide.
Turner
Stephen T
ST
Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA. turner.stephen@mayo.edu
Schwartz
Gary L
GL
Chapman
Arlene B
AB
Boerwinkle
Eric
E
D000328:Adult; D001692:Biological Transport / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D018660:Blood Pressure Monitoring, Ambulatory; D003971:Diastole; D053503:Epithelial Sodium Channels; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*; D013599:Systole; D000076204:WNK Lysine-Deficient Protein Kinase 1
D053503:Epithelial Sodium Channels; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D018343:Receptors, Adrenergic, beta-2; D015222:Sodium Channels; D049993:Sodium Chloride Symporter Inhibitors; D006852:Hydrochlorothiazide; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human