STK39 Polymorphism Is Associated with Essential Hypertension: A Systematic Review and Meta-Analysis

Xi, Bo; Chen, Man; Chandak, Giriraj Ratan; Shen, Yue; Li, Yan; He, Jian‐Qing; Mou, Sihua

doi:10.1371/journal.pone.0059584

Cited by 23 publications

(26 citation statements)

References 26 publications

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“…[22][23][24] We report that the rs3754777 knockin cell lines exhibited increases in STK39 mRNA and protein expression and increased phosphorylation of SPAK, leading to increased phosphorylation of NKCC1. These findings suggest that the common SNP rs3754777 in STK39 intron 5, with allele frequency as high as 10% to 30% globally, 4,[9][10][11][12][13][14][15][16] increases BP via activation of SPAK and target cation-chloride cotransporters. To the best of our knowledge, this study is the first to clarify the biochemical function of the essential hypertension-associated polymorphism rs3754777 by the generation of knockin human cell lines using the CRISPR/Cas9 system.…”

Section: December 2015mentioning

confidence: 88%

“…These underlying diseases can be strong confounders that influence BP and affect results of GWAS analyses. STK39, encoding SPAK, was implicated as one of the limited number of hypertension susceptibility genes, 4 and a recent meta-analysis 16 revealed the association of the intronic SNP rs3754777 in STK39 with essential hypertension among the previously reported hypertension-associated STK39 polymorphisms. 4,9 However, the biological function of this SNP and the mechanism of BP elevation were previously unknown.…”

Section: Discussionmentioning

confidence: 99%

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Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System

et al. 2015

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Abstract-Previous genome-wide association studies identified serine threonine kinase 39 (STK39), encoding STE20/SPS1-related proline/alanine-rich kinase, as one of a limited number of hypertension susceptibility genes. A recent meta-analysis confirmed the association of STK39 intronic polymorphism rs3754777 with essential hypertension, among previously reported hypertension-associated STK39 polymorphisms. However, the biochemical function of this polymorphism in the mechanism responsible for hypertension is yet to be clarified. We generated rs3754777G>A knockin human cell lines with clustered regularly interspaced short palindromic repeats-mediated genome engineering. Homozygous (A/A) and heterozygous (G/A) knockin human embryonic kidney cell lines were generated using a double nickase, singleguide RNAs targeting STK39 intron 5 around single-nucleotide polymorphism, and a 100-bp donor single-stranded DNA oligonucleotide. Reverse transcription polymerase chain reaction with sequencing analyses revealed the identical STK39 transcripts among the wild-type and both knockin cell lines. Quantitative reverse transcription polymerase chain reaction showed increased STK39 mRNA expression, and immunoblot analysis revealed increases in total and phosphorylated STE20/SPS1-related proline/alanine-rich kinase with increased phosphorylated Na-K-Cl cotransporter isoform 1 in both knockin cell lines. The largest increases in these molecules were observed in the homozygous cell line. These findings indicated that this intronic polymorphism increases STK39 transcription, leading to activation of the STE20/ SPS1-related proline/alanine-rich kinase-solute carrier family 12A signaling cascade. Increased interactions between STE20/SPS1-related proline/alanine-rich kinase and the target cation-chloride cotransporters may be responsible for hypertension susceptibility in individuals with this polymorphism.

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Section: December 2015mentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System

et al. 2015

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“…It is related to the diastolic pressure and systolic pressure of the patient (Xi et al, 2013). We amplified STK39 gene SNP (rs6433027) segment and analyzed the genetic variation of the segment, and investigated the association between the variations and the blood pressure of hypertension patients.…”

Section: Discussionmentioning

confidence: 99%

Expression of STK39 in peripheral blood of hypertension patients and the relationship between its genetic polymorphism and blood pressure

Yang

2015

Genet. Mol. Res.

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ABSTRACT. This study investigated the STK39 expression in peripheral blood of hypertension patients and the relation between its genetic polymorphism and blood pressure. The observation group comprised of 42 primary hypertension patients admitted to our hospital, and the control group comprised of 30 healthy individuals who underwent physical examination in our hospital during the same period. Fasting venous blood was collected from both groups in the morning to determine the STK39 mRNA and protein levels in peripheral blood using quantitative real-time PCR and western blot. STK39 gene SNP (rs6433027) was sequenced using PCR and its genetic variation was analyzed. The relationship between STK39 protein level, genetic variation, and diastolic and systolic blood pressure was also analyzed. The observation group showed increased STK39 mRNA and protein levels in peripheral blood compared to the control group, and the difference was statistically significant (P < 0.05), suggesting C/T mutation 16461-16468 (2015) in STK39 gene SNP (rs6433027). Correlation analysis showed positive association between STK39 protein level and diastolic and systolic blood pressure (P < 0.05), indicating a positive association between C/T genetic mutation and diastolic and systolic blood pressure (P < 0.05). In conclusion, STK39 mRNA and protein express abnormally in primary hypertension patients with genetic variation, which is related to the blood pressure.

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“…A meta-analysis shows the significant association of STK39 polymorphism with susceptibility to hypertension in Europeans and East Asians [41].…”

Section: Genetics Of Hypertensionmentioning

confidence: 99%

Genes associated with metabolic syndrome and hyperuricemia: An overview

Pokharel¹,

Acharya²,

Chowdhury³

2015

Clin Case Rep Rev

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Purposes:Recently, different studies have found genetic basis for hyperuricemia, metabolic syndrome and different components of it. The purpose of our review is to overview the different genes that have been studied with regard to hyperuricemia, metabolic syndrome and its components. Method:We made this review by systematically searching relevant literatures using multiple keywords and standardized terminology on PubMed, Nature.com, Hindawi.com, Plosone.com etc and other online resources related to the topic of our study. Findings:Serum uric acid level is influenced by diet, cellular breakdown, renal elimination and correlates with metabolic syndrome, diabetes mellitus, blood pressure, gout, and cardiovascular disease. Metabolic syndrome has strong association with the development of type II diabetes and risk of cardiovascular morbidity and mortality.We found associations of different genes regarding hyperuricemia, metabolic syndrome and its components like diabetes mellitus, obesity, dyslipidemia, and hypertension.Conclusions: This review provides evidence that different genes are responsible for the causation of Metabolic syndrome and its each component. Further genetic studies with different population groups and races in different parts of the world need to be carried out to find specific relation and effect of each gene in each specific component of our study.

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STK39 Polymorphism Is Associated with Essential Hypertension: A Systematic Review and Meta-Analysis

Cited by 23 publications

References 26 publications

Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System

Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System

Expression of STK39 in peripheral blood of hypertension patients and the relationship between its genetic polymorphism and blood pressure

Genes associated with metabolic syndrome and hyperuricemia: An overview

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