STK39 is an independent risk factor for male hypertension in Han Chinese

Chen, Liyan; Zhao, Weihua; Tian, Wen; Guo, Jian; Jiang, Feng; Li-juan, Jin; Sun, Yingxian; Chen, Kaiming; An, Lili; Li, Guodong; Li, Qing; Li, Yang; Wu, Chong; Zhao, Ling; Wang, Wenjing; Zheng, Gu-Yan; Li, Bing; Li, Xueqi; Hu, Jian; Tian, Xiao-Li

doi:10.1016/j.ijcard.2010.09.007

Cited by 25 publications

(26 citation statements)

References 37 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%

“…Subsequently, a third polymorphism, rs35929607 in STK39 intron 2, was identified as a hypertension-associated variant, 9 and this SNP was in complete linkage disequilibrium with rs3754777. 4 After several replicating [10][11][12][13] and conflicting 14,15 findings reporting the link between these SNPs and hypertension in various races or populations, a meta-analysis confirmed that rs3754777 is significantly associated with essential hypertension after adjustments for multiple confounders.…”

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confidence: 95%

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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%

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confidence: 95%

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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“…7 Second, in a study performed with 5808 Han Chinese (2746 hypertensives (1665 males) and 3062 normotensives (2006 males)), two STK39 variants were identified as risk factors for male hypertension. 9 Third, in a study conducted in two Swedish cohorts consisting of over 20 000 participants, the rs35929607 variant in STK39 was associated with hypertension, especially in women (n413000). 10 Some evidence of a role for STK39 variants in salt sensitivity was also obtained from this study when the salt sensitivity was studied in 39 Swedish normotensive subjects 10 and from a study of 101 Korean subjects (73 salt-resistant and 28 salt-sensitive).…”

Section: Discussionmentioning

confidence: 98%

“…6 Three recent studies have provided additional evidence for the role of STK39 in hypertension. 7,9,10 First, a study performed in 1017 African Americans (509 hypertensives and 508 normotensives) was able to provide supporting evidence for the association of STK39 variants and office SBP and DBP levels. 7 Second, in a study performed with 5808 Han Chinese (2746 hypertensives (1665 males) and 3062 normotensives (2006 males)), two STK39 variants were identified as risk factors for male hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5][6] Certain progress is supported by the facts that some of these studies have identified concordant chromosomal loci and that additional evidence has been obtained by replication and functional studies. 3,4,[6][7][8][9][10] The increased risk of cardiovascular morbidity and mortality brought up by elevated blood pressure (BP) can be alleviated by effective antihypertensive drug therapy. 11 However, only one-third of hypertensive patients on antihypertensive medication are adequately controlled for their hypertension.…”

Section: Introductionmentioning

confidence: 99%

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STK39 variation predicts the ambulatory blood pressure response to losartan in hypertensive men

et al. 2011

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Large-scale genome-wide association studies (GWASs) have identified significant associations of common genetic variants with blood pressure (BP) levels. To obtain more evidence for the role of these variants in BP regulation, we studied their association with BP responses to four different antihypertensive drug monotherapies. We selected 19 single-nucleotide variants based on data from five GWASs. The study group consisted of more than 200 hypertensive Finnish men from the GENRES study. Ambulatory BP responses to 4-week treatments with losartan, bisoprolol, hydrochlorothiazide and amlodipine were the primary targets of the study. Secondarily, baseline indicators of the activity of the renin-angiotensin-aldosterone system were studied. After correction for multiple comparisons, the variant rs6749447 in the STK39 gene was significantly associated with BP responses. Thus, the minor rs6749447 allele was associated with a lower systolic and diastolic BP response to losartan (P¼0.0005 and 0.0002, respectively). rs6749447 minor allele homozygotes had marginally higher serum aldosterone/plasma renin activity (PRA) ratios (P¼0.04) than those without this allele. In a replication study on aldosterone and renin levels, another cohort of hypertensive patients (n¼311) showed a similar trend. When the two cohorts were combined, the aldosterone level (P¼0.02) and the aldosterone/PRA ratio (P¼0.01) were higher in subjects homozygous for the minor rs6749447 allele than in other subjects. The present study shows that pharmacogenetic approaches may provide evidence that complements systematic genome-wide strategies by identifying gene loci that not only affect the BP level but also might modify its response to pharmacologic interventions.

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Towards k-vertex connected component discovery from large networks

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et al. 2019

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STK39 is an independent risk factor for male hypertension in Han Chinese

Cited by 25 publications

References 37 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

STK39 variation predicts the ambulatory blood pressure response to losartan in hypertensive men

Towards k-vertex connected component discovery from large networks

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