Rare independent mutations in renal salt handling genes contribute to blood pressure variation

Ji, Weizhen; Foo, Jia Nee; O’Roak, Brian J.; Zhao, Hongyu; Larson, Martin G.; Simon, David B.; Newton‐Cheh, Christopher; State, Matthew W.; Levy, Daniel; Lifton, Richard P.

doi:10.1038/ng.118

Cited by 745 publications

(628 citation statements)

References 46 publications

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“…Bartter's syndrome type II patients (KCNJ1 homozygotes), who lack ROMK expression, have a phenotype characterized by renal salt wasting, hypotension, and mild hypokalemia. 10 Similar observations have also been reported from studies with the ROMK knock out mice. 11,12 In addition, KCNJ1 heterozygote carriers from the Framingham heart study exhibit reduced blood pressure and a reduced risk of hypertension at age 60, when compared with matched controls.…”

supporting

confidence: 80%

Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

Tang

Walsh

Yan

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:The renal outer medullary potassium channel (ROMK or K ir 1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal highthroughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure−activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.

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supporting

confidence: 80%

Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

Tang

Walsh

Yan

et al. 2012

ACS Med. Chem. Lett.

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“…7,8 Bartter's syndrome type II patients (KCNJ1 homozygotes) lack functional ROMK expression and have a phenotype characterized by renal salt wasting, hypotension, and mild hypokalemia. 9 A similar phenotype has been reported from studies with the ROMK knockout mice. 9,10 In addition, KCNJ1 heterozygote carriers from the Framingham Heart Study exhibited reduced blood pressure and a reduced risk of hypertension at age 60 when compared with matched controls.…”

supporting

confidence: 72%

Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

Walsh

Shahripour

Tang

et al. 2015

ACS Med. Chem. Lett.

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“…Another hypothesis is that rarer variants in genes implicated in Mendelian forms of stroke may have larger effects. It has already been shown that carriers of genetic variants in genes implicated in Mendelian forms of hyper-or hypotension, are associated with huge variation in BP 40,41 as compared with common SNPs. 21 In the same manner, rare mutations implicated in Mendelian forms of stroke, as well as maternally inherited mitrochondrial mutations, could contribute more than common SNPs to the occurrence of cerebrovascular events.…”

Section: Discussionmentioning

confidence: 99%

A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case–control study

et al. 2014

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Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P = 0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P = 0.25), MDC (1.168 (1.060-1.288); P = 0.002) and SAHLSIS (1.124 (0.997-1.267); P = 0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension. INTRODUCTIONStroke is one of the leading causes of mortality, morbidity and disability worldwide. 1 Thanks to genome-wide association studies (GWAS), genetics of complex diseases has made dramatic steps forward in the last few years 2 but very few single-nucleotide polymorphisms (SNPs) have been invariantly associated with ischemic stroke. [3][4][5][6][7] Moreover, the relative risk conferred by individual genetic variants is usually low. Thus, in an attempt to estimate the aggregate effect of several gene variants, different genetic risk scores (GRS) have been constructed including a few studies on stroke with inconsistent results. [8][9][10][11][12][13][14][15] Interestingly, the selection of the SNPs to be included in GRS calculation have been based on different criteria: SNPs detected by GWAS either associated or not associated with known cardiovascular risk factors, as well as SNPs in candidate genes or pathways. [8][9][10][11][12][13][14][15] High blood pressure (BP) is the major risk factors for stroke and among the most important ones for other cardiovascular events. 16,17 Despite BP and hypertension being heritable traits, 18 the search for genetic variants associated with these traits has been more challenging compared with other cardiovascular risk factors. Only in recent years, GWAS have discovered several genetic variants which associate with BP-related ...

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Rare independent mutations in renal salt handling genes contribute to blood pressure variation

Cited by 745 publications

References 46 publications

Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case–control study

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