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Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

ABSTRACT: WNK1--a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control--is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23-4.9), DBP 1.9 mmHg (95%CI:0.7-3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0-1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10(-7)). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.

SUBMITTER: Newhouse S

PROVIDER: S-EPMC2661139 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

Newhouse Stephen S Farrall Martin M Wallace Chris C Hoti Mimoza M Burke Beverley B Howard Philip P Onipinla Abiodun A Lee Kate K Shaw-Hawkins Sue S Dobson Richard R Brown Morris M Samani Nilesh J NJ Dominiczak Anna F AF Connell John M JM Lathrop G Mark GM Kooner Jaspal J Chambers John J Elliott Paul P Clarke Robert R Collins Rory R Laan Maris M Org Elin E Org Elin E Juhanson Peeter P Veldre Gudrun G Viigimaa Margus M Eyheramendy Susana S Cappuccio Francesco P FP Ji Chen C Iacone Roberto R Strazzullo Pasquale P Kumari Meena M Marmot Michael M Brunner Eric E Caulfield Mark M Munroe Patricia B PB

PloS one 20090404 4

WNK1--a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control--is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-con ...[more]

PMID: 19347040

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Project description:IntroductionSodium homeostasis is intimately associated with blood pressure (BP) rhythm, and potassium excretion is closely associated with sodium excretion in the general population. However, the association between circadian sodium and potassium pattern excretion and nocturnal BP in patients with chronic kidney disease (CKD) is not elucidated.MethodsWe evaluated the correlation between the day-to-night ratio of urinary sodium and potassium excretion rate, nocturnal blood pressure, and nocturnal BP dipping in a CKD cohort.ResultsA total of 3152 (56.76% males, mean age 47.63 years) individuals with CKD were included in the study. Patients in quartile 1 (with the lowest ratio) exhibited a 12 mmHg or 9 mmHg higher nocturnal systolic blood pressure (SBP) and blunted SBP dipping than those in quartile 4 when urinary sodium or potassium excretion rate was divided into day-to-night ratios (both P < 0.001). In multivariate analyses, lower day-to-night ratio of urinary sodium was independently linked to higher nocturnal SBP and blunted SBP dipping (linear regression coefficient (95% confidence interval [CI]): -6.89 (-9.48 to -4.31), and -3.64 (-5.48 to -1.80), respectively; both P < 0.001). Similarly, compared with the highest quartile of day-to-night ratio of urinary potassium excretion rate, linear regression coefficient (95% CI) for the lowest quartile was -5.60 (-8.13 to -3.07) for nocturnal SBP, and -2.47 (-4.28 to -0.67) for SBP dipping (both P < 0.001). Moreover, urine flow rate and concentrates of sodium or potassium in the urine were positively associated with urinary sodium or potassium excretion during daytime (P < 0.001).ConclusionA higher nocturnal BP and a blunted nocturnal BP dipping were both independently linked to a lower excretion of sodium or potassium during the day in patients with CKD. Furthermore, a decreased urine flow rate and a diminished capacity to concentrate sodium or potassium in the urine appear to be the key contributors to a low day-to-night ratio of urinary sodium excretion or potassium rate.

Project description:The direction and magnitude of the association between sodium and potassium excretion and blood pressure (BP) may differ depending on the characteristics of the study participant or the intake assessment method. Our objective was to assess the relationship between BP, hypertension and 24-h urinary sodium and potassium excretion among Chinese adults. A total of 1424 provincially representative Chinese residents aged 18 to 69 years participated in a cross-sectional survey in 2017 that included demographic data, physical measurements and 24-h urine collection. In this study, the average 24-h urinary sodium and potassium excretion and sodium-to-potassium ratio were 3811.4 mg/day, 1449.3 mg/day, and 4.9, respectively. After multivariable adjustment, each 1000 mg difference in 24-h urinary sodium excretion was significantly associated with systolic BP (0.64 mm Hg; 95% confidence interval [CI] 0.05-1.24) and diastolic BP (0.45 mm Hg; 95% CI 0.08-0.81), and each 1000 mg difference in 24-h urinary potassium excretion was inversely associated with systolic BP (- 3.07 mm Hg; 95% CI - 4.57 to - 1.57) and diastolic BP (- 0.94 mm Hg; 95% CI - 1.87 to - 0.02). The sodium-to-potassium ratio was significantly associated with systolic BP (0.78 mm Hg; 95% CI 0.42-1.13) and diastolic BP (0.31 mm Hg; 95% CI 0.10-0.53) per 1-unit increase. These associations were mainly driven by the hypertensive group. Those with a sodium intake above about 4900 mg/24 h or with a potassium intake below about 1000 mg/24 h had a higher risk of hypertension. At higher but not lower levels of 24-h urinary sodium excretion, potassium can better blunt the sodium-BP relationship. The adjusted odds ratios (ORs) of hypertension in the highest quartile compared with the lowest quartile of excretion were 0.54 (95% CI 0.35-0.84) for potassium and 1.71 (95% CI 1.16-2.51) for the sodium-to-potassium ratio, while the corresponding OR for sodium was not significant (OR, 1.28; 95% CI 0.83-1.98). Our results showed that the sodium intake was significantly associated with BP among hypertensive patients and the inverse association between potassium intake and BP was stronger and involved a larger fraction of the population, especially those with a potassium intake below 1000 mg/24 h should probably increase their potassium intake.

Dataset Information

Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

Publications

Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

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