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4 results on '"Kwakernaak, A.J."'

3. Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Author

Padmanabhan, S., Melander, O., Johnson, T., Blasio, A.M. di, Lee, W.K., Gentilini, D., Hastie, C.E., Menni, C., Monti, M.C., Delles, C., Laing, S., Corso, B., Navis, G., Kwakernaak, A.J., Harst, P. van der, Bochud, M., Maillard, M., Burnier, M., Hedner, T., Kjeldsen, S., Wahlstrand, B., Sjogren, M., Fava, C., Montagnana, M., Danese, E., Torffvit, O., Hedblad, B., Snieder, H., Connell, J.M.C., Brown, M., Samani, N.J., Farrall, M., Cesana, G., Mancia, G., Signorini, S., Grassi, G., Eyheramendy, S., Wichmann, H.E., Laan, M., Strachan, D.P., Sever, P., Shields, D.C., Stanton, A., Vollenweider, P., Teumer, A., Volzke, H., Rettig, R., Newton-Cheh, C., Arora, P., Zhang, F., Soranzo, N., Spector, T.D., Lucas, G., Kathiresan, S., Siscovick, D.S., Luan, J.A., Loos, R.J.F., Wareham, N.J., Penninx, B.W., Nolte, I.M., McBride, M., Miller, W.H., Nicklin, S.A., Baker, A.H., Graham, D., McDonald, R.A., Pell, J.P., Sattar, N., Welsh, P., Munroe, P., Caulfield, M.J., Zanchetti, A., Dominiczak, A.F., and Global BPgen Consortium

Subjects
tamm-horsfall protein chronic kidney-disease urinary-excretion risk-factors loci nephropathy feasibility mutations mortality burden
Abstract

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Published
2010

4. Concordance of dietary sodium intake and concomitant phosphate load: Implications for sodium interventions.

Author

Humalda, J.K., Keyzer, C.A., Binnenmars, S.H., Kwakernaak, A.J., Slagman, M.C.J., Laverman, G.D., Bakker, S.J.L., de Borst, M.H., and Navis, G.J.

Abstract

Background and Aims: Both a high dietary sodium and high phosphate load are associated with an increased cardiovascular risk in patients with chronic kidney disease (CKD), and possibly also in non-CKD populations. Sodium and phosphate are abundantly present in processed food. We hypothesized that (modulation of) dietary sodium is accompanied by changes in phosphate load across populations with normal and impaired renal function.Methods and Results: We first investigated the association between sodium and phosphate load in 24-h urine samples from healthy controls (n = 252), patients with type 2 diabetes mellitus (DM, n = 255) and renal transplant recipients (RTR, n = 705). Secondly, we assessed the effect of sodium restriction on phosphate excretion in a nondiabetic CKD cohort (ND-CKD: n = 43) and a diabetic CKD cohort (D-CKD: n = 39). Sodium excretion correlated with phosphate excretion in healthy controls (R = 0.386, P < 0.001), DM (R = 0.490, P < 0.001), and RTR (R = 0.519, P < 0.001). This correlation was also present during regular sodium intake in the intervention studies (ND-CKD: R = 0.491, P < 0.001; D-CKD: R = 0.729, P < 0.001). In multivariable regression analysis, sodium excretion remained significantly correlated with phosphate excretion after adjustment for age, gender, BMI, and eGFR in all observational cohorts. In ND-CKD and D-CKD moderate sodium restriction reduced phosphate excretion (31 ± 10 to 28 ± 10 mmol/d; P = 0.04 and 26 ± 11 to 23 ± 9 mmol/d; P = 0.02 respectively).Conclusions: Dietary exposure to sodium and phosphate are correlated across the spectrum of renal function impairment. The concomitant reduction in phosphate intake accompanying sodium restriction underlines the off-target effects on other nutritional components, which may contribute to the beneficial cardiovascular effects of sodium restriction. (f) Registration numbers: Dutch Trial Register NTR675, NTR2366. [ABSTRACT FROM AUTHOR]

Published
2016
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