STK39、OXSR1、SLC12A3与中国东北地区汉族人群高血压相关性的研究
|
摘要
目的
原发性高血压是一类复杂的疾病,约占世界成人数量的25-30%。高血压促发了卒中、心肌梗死、充血性心力衰竭和终末期肾病的发病率和死亡率的提高,因此,研究其发病机制显得尤为重要。在高血压的发病机制中,遗传和环境因素扮演了非常重要的作用。据估计,人类血压变异度30%-50%由遗传因素决定。因此,高血压遗传易感基因和遗传标记的鉴别对高血压的发病机制和治疗有很好的理解和指导作用。
在高血压的发病机制中,肾脏离子转运系统备受人们的关注。最近,人们得到了令人振奋的结果,Ste20蛋白相关的富含脯氨酸丙氨酸激酶(SPAK,基因符号：STK39)和氧化应激反应激酶1(OSR1,基因符号：OXSR1)相互作用,共同磷酸化钠-氯协同转运体(NCC,基因符号：SLC12A3),调节肾脏的水盐平衡,进而参与血压的调节。然而,关于该信号通路与人类高血压的遗传相关性研究目前还没有充分的报道。SPAK蛋白基因-STK39,最近在阿米士人群中通过全基因组关联分析的方法鉴别出与原发性高血压相关,该发现揭开了STK39参与高血压发病机制的序幕。但考虑到遗传因素的种族异质性,很有必要研究STK39及其下游通路的基因在中国汉族高血压人群中的作用。
高血压是一种多基因遗传性疾病,受多种危险因素的影响,如年龄、体重指数(BMI)、糖尿病及吸烟等。因此,研究基因-基因及基因-危险因素间的相互作用对理解遗传因素对高血压发病的贡献是至关重要的。在本研究中,我们探讨了STK39, OXSR1和SLC12A3是否参与了中国东北地区(沈阳和哈尔滨)汉族高血压人群的发病,以及基因-基因、基因-危险因素是否相互作用共同促进高血压的发生和发展。
我们于2005年-2008年募集来自沈阳和哈尔滨的汉族人群1210人(高血压601人,正常血压609人)和4598人(高血压2145人,正常血压2453人),分别作为人群1和人群2。采用标准的水银血压计测量受试者的右臂血压。调查问卷的方式获取入选者的其它相关信息,如身高、体重、高血压病家族史、吸烟和饮酒等。高血压的入选标准为收缩压≥140 mmHg,和／或舒张压≥90 mmHg,和／或目前应用抗高血压药物治疗。正常对照组(正常血压)人群均没有高血压家族史,并且在过去的5年内进行规律的物理锻炼,且血压<140/90 mmHg,从未应用过抗高血压药物。糖尿病的入选标准根据美国糖尿病协会(ADA)的诊断标准。
我们根据如下标准选择STK39, OXSR1和SLC12A3共11个标签SNPs:1)所有的标签SNPs均尽可能涵盖较多的SNPs位点；2)具有功能性；3)最小等位基因频率(MAF)>10%。在入选的11个标签SNPs中,STK39包括rs3754777,rs6749447, rs6433027, rsl448827, rs7595310; OXSR1包括rs4955408,rs12629406; SLC12A3包括rs5804, rs6499857, rs711747, rs8063291.
我们运用蛋白酶K的方法提取血液基因组DNA。在人群1(沈阳)中对入选的11个标签SNPs运用等位基因特异性PCR (AS-PCR)的方法进行分型,分型差的样品用基因测序的方法来鉴别,比较这11个标签SNPs在高血压组和正常对照组间最小等位基因频率(MAF)的差异以及与性别的相关性。这些有差异的SNPs,即和高血压相关SNPs位点进一步在另一个人群-哈尔滨人群中验证。进一步运用Logistic回归分析SNPs与高血压危险因素的相关性：年龄、体重指数、糖尿病、吸烟、饮酒等及基因-基因间的相互作用。
结果
一、沈阳人群的等位基因相关性分析
在入选的11个标签SNPs中,所有的SNPs均符合哈迪-温伯格平衡。STK39的两个SNPs, rs6433027和rs3754777,与人群1(沈阳)的高血压病相关,尤其与男性高血压相关(P=0.008-0.024),与女性不相关。其它的SNPs与高血压及性别均不相关。
二、哈尔滨人群的等位基因相关性分析
两个相关SNPs, rs6433027和rs3754777,在人群2(哈尔滨)中的相关性得到验证,仍显示与男性高血压相关(P=0.0001-0.004),与女性不相关。在男性的相对危险性(95%置信区间,P值)分别为1.269(1.131-1.424；P=0.0001),1.231(1.078-1.405；P=0.004)。在高血压的危险因素校正后,如年龄、体重指数、糖尿病、吸烟、饮酒,仍显示与男性高血压相关。
三、STK39与高血压相关的遗传模式
为了研究SNPs rs6433027和rs3754777与高血压相关的遗传模式,我们对人群2(哈尔滨)中的男性在显性、隐性、共显性三种遗传模式下进行了基因型的关联分析,以及在危险因素的校正下,如：年龄,BMI,糖尿病,吸烟,饮酒。我们发现SNPrs6433027在隐性、共显性遗传模式下与男性高血压相关(校正P=3.18×10-6-5.30×10-5)。SNPrs3754777在显性、共显性遗传模式下与男性高血压相关(校正p=0.007-0.002)。
四、SNPs与危险因素的相互作用
在人群2(哈尔滨)男性中,SNPs rs6433027和rs3754777基因型分布对年龄、BMI的影响通过方差分析来评估,继以Post-hoc test LSD (Fisher's least significant difference)评估,糖尿病三种基因型(AA, Aa, aa)的不同流行率通过皮尔森卡方检验来分析。我们发现,年龄、BMI、糖尿病的流行率在三种基因型中未见明显差异,SNPs rs6433027和rs3754777与年龄、BMI、糖尿病均不相关。
五、SNP-SNP的相互作用
SNPs rs6433027和rs3754777的等位基因分别是T/c和G/a(最大等位基因／最小等位基因)。为了评估这两个SNPs间是否有相互作用,我们对比了人群2男性中携带T-T/G-G, T-T/a-a, c-c/G-G, c-c/a-a这四种基因型中的高血压病流行率。在T-T/G-G和T-T/a-a组中,我们并没有发现高血压病流行率的不同,但是,与携带基因型T-T/G-G的群体相比,携带基因型c-c/G-G的群体高血压流行率迅速增加。携带基因型c-c/a-a群体在四组中展示了最高的高血压流行率。
结论
STK39与中国汉族人群男性高血压相关,与年龄、体重指数、糖尿病均不相关,是男性高血压发病的独立危险因素。STK39基因内SNPs rs6433027和rs3754777相互作用,SNP rs6433027的等位基因T对SNP rs3754777的等位基因A在男性高血压人群中具有上位性,共同参与血压的调节。
Background
Essential hypertension is a complex disease and affects 25% to 30% of the adult population worldwide. It contributes to morbidity and mortality related to stroke, myocardial infarction, congestive heart failure, and end-stage renal disease. Genetic and multiple environmental determinants play important roles in the etiology and pathogenesis of essential hypertension. An estimated 30% to 50% of blood pressure variation in the general population is determined by genetic factors. Therefore, identifying or establishing genetic susceptibility genes and genetic markers for hypertension can lead to a better understanding of regulatory mechanisms of blood pressure and help with prevention and therapy.
Among the pathogenesis of essential hypertension, renal transporters play an important role in regulating salt/water balance. Recently, studies showed that Sterile-20 like related praline alanine rich kinase (SPAK, gene symbol:STK39) interacts with oxidative stress-responsive kinase 1 (OSR1, gene symbol:OXSR1) and phosphorylates the sodium-chloride co-transporter (NCC, gene symbol:SLC12A3), which plays a critical role in regulating the salt/water balance and blood pressure. However, it has not been studied the association of this pathway with hypertension in Han Chinese. Recently, a new hypertension susceptibility gene, STK39, was identified in an Amish population by a genome-wide association study. Given the fact that the heterogeneity in the etiology of hypertension or the confounding in genetic association studies caused by population stratification, it is necessary to estimate the association of STK39 and its downstream molecular with hypertension in Han Chinese.
Hypertension is a complex multigenic disease and is affected by a number of risk factors, such as age, gender, race, obesity, diabetes, life style, and heredity. Therefore, it is important to determine "gene-gene" or "gene-other risk factors" interactions in the contribution of genetic factors to hypertension. In our study, we investigated how STK39,OXSR1, SLC12A3 (three components of the SPAK/OSR1-NCC pathway) and other major risk factors contribute to essential hypertension in Northeast Han Chinese.
Methods
We recruited Han Chinese participants from two medical centers in Shenyang and Harbin in China between January 2005 and December 2008. The standard mercury sphygmomanometers were used to measure the systolic and diastolic blood pressure (SBP and DBP, respectively) from an individual's right arm. A questionnaire was used for collecting other related information such as family history, smoking, and alcoholic intake. The inclusion criteria for the essential hypertension were SBP≥140 mmHg, and/or DBP≥90 mmHg, and/or current under antihypertensive treatment. Normotensive subjects were selected from those who had regular physical exam over the past 5 years in the two centers based on three criteria:1) SBP and DBP were never above 140 and 90 mmHg,2) no family history of hypertension was reported, and 3) one never received antihypertensive treatments. Type 2 diabetes mellitus (T2DM) was diagnosed according to 1997 American Diabetes Association criteria.
In this study, we selected 11 tagging SNPs based on three criteria 1) tagging SNPs with maximum coverage; 2) functional if possible; and 3) minor allele frequency (MAF) >10% from the International HapMap project (CHB). Of selected tagging SNPs,5 were for STK39,2 for OXSR1, and 4 for SLC12A3, respectively.
Genomic DNA was isolated by the proteinase K method. SNP genotyping was performed by Allelic Specific PCR and direct sequencing. We compared the differences in allele and genotype distributions between cases and controls in two populations. We also analyzed the "gene-gene" and "gene-other risk factors" interactions in this study.
Results
Two SNPs of STK39, rs6433027 and rs3754777, were found to be associated with hypertension in population 1 (Shenyang) males (P=0.008-0.024). All other SNPs were not associated with hypertension in either gender. The association of rs6433027 and rs3754777 with male hypertension was validated by genotyping another 4598 hypertensive and healthy individuals (Harbin). The odds ratios (95% confidence interval, P value) in males were 1.269 (1.13-1.43; P=0.0001) and 1.231 (1.078-1.41; P =0.004) of rs6433027 and rs3754777, respectively. The allele T of rs6433027 presented a strong epistatic effect on the allele A of rs3754777 in hypertensive trait. The minor allele frequencies of two SNPs were not stratified by age, BMI, or diabetes, the three major risk factors for hypertension.
Conclusion
Our results suggest that STK39 is an independent risk factor for male hypertension and that its intragenic SNPs can interact and function in the control of blood pressure.
原发性高血压是一类复杂的疾病,约占世界成人数量的25-30%。高血压促发了卒中、心肌梗死、充血性心力衰竭和终末期肾病的发病率和死亡率的提高,因此,研究其发病机制显得尤为重要。在高血压的发病机制中,遗传和环境因素扮演了非常重要的作用。据估计,人类血压变异度30%-50%由遗传因素决定。因此,高血压遗传易感基因和遗传标记的鉴别对高血压的发病机制和治疗有很好的理解和指导作用。
在高血压的发病机制中,肾脏离子转运系统备受人们的关注。最近,人们得到了令人振奋的结果,Ste20蛋白相关的富含脯氨酸丙氨酸激酶(SPAK,基因符号：STK39)和氧化应激反应激酶1(OSR1,基因符号：OXSR1)相互作用,共同磷酸化钠-氯协同转运体(NCC,基因符号：SLC12A3),调节肾脏的水盐平衡,进而参与血压的调节。然而,关于该信号通路与人类高血压的遗传相关性研究目前还没有充分的报道。SPAK蛋白基因-STK39,最近在阿米士人群中通过全基因组关联分析的方法鉴别出与原发性高血压相关,该发现揭开了STK39参与高血压发病机制的序幕。但考虑到遗传因素的种族异质性,很有必要研究STK39及其下游通路的基因在中国汉族高血压人群中的作用。
高血压是一种多基因遗传性疾病,受多种危险因素的影响,如年龄、体重指数(BMI)、糖尿病及吸烟等。因此,研究基因-基因及基因-危险因素间的相互作用对理解遗传因素对高血压发病的贡献是至关重要的。在本研究中,我们探讨了STK39, OXSR1和SLC12A3是否参与了中国东北地区(沈阳和哈尔滨)汉族高血压人群的发病,以及基因-基因、基因-危险因素是否相互作用共同促进高血压的发生和发展。
我们于2005年-2008年募集来自沈阳和哈尔滨的汉族人群1210人(高血压601人,正常血压609人)和4598人(高血压2145人,正常血压2453人),分别作为人群1和人群2。采用标准的水银血压计测量受试者的右臂血压。调查问卷的方式获取入选者的其它相关信息,如身高、体重、高血压病家族史、吸烟和饮酒等。高血压的入选标准为收缩压≥140 mmHg,和／或舒张压≥90 mmHg,和／或目前应用抗高血压药物治疗。正常对照组(正常血压)人群均没有高血压家族史,并且在过去的5年内进行规律的物理锻炼,且血压<140/90 mmHg,从未应用过抗高血压药物。糖尿病的入选标准根据美国糖尿病协会(ADA)的诊断标准。
我们根据如下标准选择STK39, OXSR1和SLC12A3共11个标签SNPs:1)所有的标签SNPs均尽可能涵盖较多的SNPs位点；2)具有功能性；3)最小等位基因频率(MAF)>10%。在入选的11个标签SNPs中,STK39包括rs3754777,rs6749447, rs6433027, rsl448827, rs7595310; OXSR1包括rs4955408,rs12629406; SLC12A3包括rs5804, rs6499857, rs711747, rs8063291.
我们运用蛋白酶K的方法提取血液基因组DNA。在人群1(沈阳)中对入选的11个标签SNPs运用等位基因特异性PCR (AS-PCR)的方法进行分型,分型差的样品用基因测序的方法来鉴别,比较这11个标签SNPs在高血压组和正常对照组间最小等位基因频率(MAF)的差异以及与性别的相关性。这些有差异的SNPs,即和高血压相关SNPs位点进一步在另一个人群-哈尔滨人群中验证。进一步运用Logistic回归分析SNPs与高血压危险因素的相关性：年龄、体重指数、糖尿病、吸烟、饮酒等及基因-基因间的相互作用。
结果
一、沈阳人群的等位基因相关性分析
在入选的11个标签SNPs中,所有的SNPs均符合哈迪-温伯格平衡。STK39的两个SNPs, rs6433027和rs3754777,与人群1(沈阳)的高血压病相关,尤其与男性高血压相关(P=0.008-0.024),与女性不相关。其它的SNPs与高血压及性别均不相关。
二、哈尔滨人群的等位基因相关性分析
两个相关SNPs, rs6433027和rs3754777,在人群2(哈尔滨)中的相关性得到验证,仍显示与男性高血压相关(P=0.0001-0.004),与女性不相关。在男性的相对危险性(95%置信区间,P值)分别为1.269(1.131-1.424；P=0.0001),1.231(1.078-1.405；P=0.004)。在高血压的危险因素校正后,如年龄、体重指数、糖尿病、吸烟、饮酒,仍显示与男性高血压相关。
三、STK39与高血压相关的遗传模式
为了研究SNPs rs6433027和rs3754777与高血压相关的遗传模式,我们对人群2(哈尔滨)中的男性在显性、隐性、共显性三种遗传模式下进行了基因型的关联分析,以及在危险因素的校正下,如：年龄,BMI,糖尿病,吸烟,饮酒。我们发现SNPrs6433027在隐性、共显性遗传模式下与男性高血压相关(校正P=3.18×10-6-5.30×10-5)。SNPrs3754777在显性、共显性遗传模式下与男性高血压相关(校正p=0.007-0.002)。
四、SNPs与危险因素的相互作用
在人群2(哈尔滨)男性中,SNPs rs6433027和rs3754777基因型分布对年龄、BMI的影响通过方差分析来评估,继以Post-hoc test LSD (Fisher's least significant difference)评估,糖尿病三种基因型(AA, Aa, aa)的不同流行率通过皮尔森卡方检验来分析。我们发现,年龄、BMI、糖尿病的流行率在三种基因型中未见明显差异,SNPs rs6433027和rs3754777与年龄、BMI、糖尿病均不相关。
五、SNP-SNP的相互作用
SNPs rs6433027和rs3754777的等位基因分别是T/c和G/a(最大等位基因／最小等位基因)。为了评估这两个SNPs间是否有相互作用,我们对比了人群2男性中携带T-T/G-G, T-T/a-a, c-c/G-G, c-c/a-a这四种基因型中的高血压病流行率。在T-T/G-G和T-T/a-a组中,我们并没有发现高血压病流行率的不同,但是,与携带基因型T-T/G-G的群体相比,携带基因型c-c/G-G的群体高血压流行率迅速增加。携带基因型c-c/a-a群体在四组中展示了最高的高血压流行率。
结论
STK39与中国汉族人群男性高血压相关,与年龄、体重指数、糖尿病均不相关,是男性高血压发病的独立危险因素。STK39基因内SNPs rs6433027和rs3754777相互作用,SNP rs6433027的等位基因T对SNP rs3754777的等位基因A在男性高血压人群中具有上位性,共同参与血压的调节。
Background
Essential hypertension is a complex disease and affects 25% to 30% of the adult population worldwide. It contributes to morbidity and mortality related to stroke, myocardial infarction, congestive heart failure, and end-stage renal disease. Genetic and multiple environmental determinants play important roles in the etiology and pathogenesis of essential hypertension. An estimated 30% to 50% of blood pressure variation in the general population is determined by genetic factors. Therefore, identifying or establishing genetic susceptibility genes and genetic markers for hypertension can lead to a better understanding of regulatory mechanisms of blood pressure and help with prevention and therapy.
Among the pathogenesis of essential hypertension, renal transporters play an important role in regulating salt/water balance. Recently, studies showed that Sterile-20 like related praline alanine rich kinase (SPAK, gene symbol:STK39) interacts with oxidative stress-responsive kinase 1 (OSR1, gene symbol:OXSR1) and phosphorylates the sodium-chloride co-transporter (NCC, gene symbol:SLC12A3), which plays a critical role in regulating the salt/water balance and blood pressure. However, it has not been studied the association of this pathway with hypertension in Han Chinese. Recently, a new hypertension susceptibility gene, STK39, was identified in an Amish population by a genome-wide association study. Given the fact that the heterogeneity in the etiology of hypertension or the confounding in genetic association studies caused by population stratification, it is necessary to estimate the association of STK39 and its downstream molecular with hypertension in Han Chinese.
Hypertension is a complex multigenic disease and is affected by a number of risk factors, such as age, gender, race, obesity, diabetes, life style, and heredity. Therefore, it is important to determine "gene-gene" or "gene-other risk factors" interactions in the contribution of genetic factors to hypertension. In our study, we investigated how STK39,OXSR1, SLC12A3 (three components of the SPAK/OSR1-NCC pathway) and other major risk factors contribute to essential hypertension in Northeast Han Chinese.
Methods
We recruited Han Chinese participants from two medical centers in Shenyang and Harbin in China between January 2005 and December 2008. The standard mercury sphygmomanometers were used to measure the systolic and diastolic blood pressure (SBP and DBP, respectively) from an individual's right arm. A questionnaire was used for collecting other related information such as family history, smoking, and alcoholic intake. The inclusion criteria for the essential hypertension were SBP≥140 mmHg, and/or DBP≥90 mmHg, and/or current under antihypertensive treatment. Normotensive subjects were selected from those who had regular physical exam over the past 5 years in the two centers based on three criteria:1) SBP and DBP were never above 140 and 90 mmHg,2) no family history of hypertension was reported, and 3) one never received antihypertensive treatments. Type 2 diabetes mellitus (T2DM) was diagnosed according to 1997 American Diabetes Association criteria.
In this study, we selected 11 tagging SNPs based on three criteria 1) tagging SNPs with maximum coverage; 2) functional if possible; and 3) minor allele frequency (MAF) >10% from the International HapMap project (CHB). Of selected tagging SNPs,5 were for STK39,2 for OXSR1, and 4 for SLC12A3, respectively.
Genomic DNA was isolated by the proteinase K method. SNP genotyping was performed by Allelic Specific PCR and direct sequencing. We compared the differences in allele and genotype distributions between cases and controls in two populations. We also analyzed the "gene-gene" and "gene-other risk factors" interactions in this study.
Results
Two SNPs of STK39, rs6433027 and rs3754777, were found to be associated with hypertension in population 1 (Shenyang) males (P=0.008-0.024). All other SNPs were not associated with hypertension in either gender. The association of rs6433027 and rs3754777 with male hypertension was validated by genotyping another 4598 hypertensive and healthy individuals (Harbin). The odds ratios (95% confidence interval, P value) in males were 1.269 (1.13-1.43; P=0.0001) and 1.231 (1.078-1.41; P =0.004) of rs6433027 and rs3754777, respectively. The allele T of rs6433027 presented a strong epistatic effect on the allele A of rs3754777 in hypertensive trait. The minor allele frequencies of two SNPs were not stratified by age, BMI, or diabetes, the three major risk factors for hypertension.
Conclusion
Our results suggest that STK39 is an independent risk factor for male hypertension and that its intragenic SNPs can interact and function in the control of blood pressure.
引文
1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension:analysis of worldwide data. Lancet.2005;365:217-223.
2. Whelton PK. Epidemiology of hypertension. Lancet.1994;344:101-106.
3. Tanira MO, Al Balushi KA. Genetic variations related to hypertension:a review. J Hum Hypertens.2005;19:7-19.
4. Newhouse S, Farrall M, Wallace C, et al. Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion. PLoS One.2009;4:e5003.
5. Das M, Pal S, Ghosh A. Angiotensin converting enzyme gene polymorphism (insertion/deletion) and hypertension in adult Asian Indians:a population-based study from Calcutta, India. Hum Biol.2008;80:303-312.
6. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet.2009.
7. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet.2009.
8. Wang Y, O'Connell JR, McArdle PF, et al. From the Cover:Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009; 106:226-231.
9. Richardson C, Rafiqi FH, Karlsson HK, et al. Activation of the thiazide-sensitive Na+-Cl-cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675-684.
10. Delpire E, Gagnon KB. SPAK and OSR1:STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J.2008;409:321-331.
11. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet.1996;12:24-30.
12. Melander O, Orho-Melander M, Bengtsson K, et al. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000;36:389-394.
13. Matsuo A, Katsuya T, Ishikawa K, et al. G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women. J Hypertens. 2004;22:2123-2127.
14. Wang XF, Lin RY, Wang SZ, et al. Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China. Clin Chim Acta.2008;388:95-98.
15. Moriguchi T, Urushiyama S, Hisamoto N, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem.2005;280:42685-42693.
16. Nielsen R, Hubisz MJ, Clark AG. Reconstituting the frequency spectrum of ascertained single-nucleotide polymorphism data. Genetics.2004; 168:2373-2382.
17. Fisher ND, Ferri C, Bellini C, et al. Age, gender, and non-modulation. A sexual dimorphism in essential hypertension. Hypertension.1997;29:980-985.
18. Dasgupta K, O'Loughlin J, Chen S, et al. Emergence of sex differences in prevalence of high systolic blood pressure:analysis of a longitudinal adolescent cohort. Circulation. 2006;114:2663-2670.
19. Wenger NK. Hypertension and other cardiovascular risk factors in women. Am J Hypertens. 1995;8:94s-99s.
20. Narkiewicz K, Phillips BG, Kato M, et al. Gender-selective interaction between aging, blood pressure, and sympathetic nerve activity. Hypertension.2005;45:522-525.
21. Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency:Ⅲ. Cardiovascular disease. J Androl.2009;30:477-494.
22. Wong SY, Chan DC, Hong A, Woo J. Prevalence of and risk factors for androgen deficiency in middle-aged men in Hong Kong. Metabolism.2006;55:1488-1494.
23. Fogari R, Preti P, Zoppi A, et al. Serum testosterone levels and arterial blood pressure in the elderly. Hypertens Res.2005;28:625-630.
24. Qi H, Labrie Y, Grenier J, et al. Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. Mol Cell Endocrinol. 2001;182:181-192.
25. Arici M, Turgan C, Altun B, et al. Hypertension incidence in Turkey (HinT):a population-based study. J Hypertens;28:240-244.
26. Hu FB, Stampfer MJ. Insulin resistance and hypertension:the chicken-egg question revisited. Circulation.2005;112:1678-1680.
27. Riddle EL, Rana BK, Murthy KK, et al. Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Hypertension. 2006;47:415-420.
28. Yang J, Kamide K, Kokubo Y, et al. Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population. J Hypertens.2005;23:1497-1505.
29. Sober S, Org E, Kepp K, et al. Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array. PLoS One.2009;4:e6034.
30. Rana BK, Insel PA, Payne SH, et al. Population-based sample reveals gene-gender interactions in blood pressure in White Americans. Hypertension.2007;49:96-106.
31. Lackland DT, Egan BM, Mountford WK, et al. Thirty-year Survival for Black and White Hypertensive Individuals in the Evans County Heart Study and the Hypertension Detection and Follow-up Program. J Am Soc Hypertens.2008;2:448-454.
32. Reynolds K, Gu D, Muntner P, et al. A population-based, prospective study of blood pressure and risk for end-stage renal disease in China. J Am Soc Nephrol. 2007;18:1928-1935.
33. Ganten U, Schroder G, Witt M, et al. Sexual dimorphism of blood pressure in spontaneously hypertensive rats:effects of anti-androgen treatment. J Hypertens. 1989;7:721-726.
34. Langille DB, Joffres MR, MacPherson KM, et al. Prevalence of risk factors for cardiovascular disease in Canadians 55 to 74 years of age:results from the Canadian Heart Health Surveys,1986-1992. CMAJ.1999;161:S3-9.
35. Mendez-Chacon E, Santamaria-Ulloa C, Rosero-Bixby L. Factors associated with hypertension prevalence, unawareness and treatment among Costa Rican elderly. BMC Public Health.2008;8:275.
36. Pickering TG. Mental stress as a causal factor in the development of hypertension and cardiovascular disease. Curr Hypertens Rep.2001;3:249-254.
37. Ruixing Y, Jinzhen W, Shangling P, et al. Sex differences in environmental and genetic factors for hypertension. Am J Med.2008;121:811-819.
38. Gainer JV, Lipkowitz MS, Yu C, et al. Association of a CYP4A11 variant and blood pressure in black men. J Am Soc Nephrol.2008;19:1606-1612.
39. Ong KL, Leung RY, Wong LY, et al. Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men. Am J Hypertens.2008;21:539-545.
40. Zhao W, Wang Y, Wang L, et al. Gender-specific association between the kininogen 1 gene variants and essential hypertension in Chinese Han population. J Hypertens. 2009;27:484-490.
41. Holla VR, Adas F, Imig JD, et al. Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension. Proc Natl Acad Sci U S A.2001;98:5211-5216.
42. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency:Ⅱ. Type 2 diabetes and insulin resistance. J Androl.2009;30:23-32.
1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension:analysis of worldwide data. Lancet.2005;365:217-223.
2. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545-556.
3. Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science.2001;293:1107-1112.
4. Kupper N, Ge D, Treiber FA, Snieder H. Emergence of novel genetic effects on blood pressure and hemodynamics in adolescence:the Georgia Cardiovascular Twin Study. Hypertension.2006;47:948-954.
5. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature.1992;355:262-265.
6. Pascoe L, Curnow KM, Slutsker L, et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci U S A.1992;89:8327-8331.
7. Mune T, Rogerson FM, Nikkila H, et al. Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet.1995;10:394-399.
8. Li A, Li KX, Marui S, et al. Apparent mineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygote state. J Hypertens.1997; 15:1397-1402.
9. Wilson RC, Dave-Sharma S, Wei JQ, et al. A genetic defect resulting in mild low-renin hypertension. Proc Natl Acad Sci U S A.1998;95:10200-10205.
10. Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science.2000;289:119-123.
11. Botero-Velez M, Curtis JJ, Warnock DG Brief report:Liddle's syndrome revisited--a disorder of sodium reabsorption in the distal tubule. N Engl J Med.1994;330:178-181.
12. Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit:genetic heterogeneity of Liddle syndrome. Nat Genet.1995; 11:76-82.
13. Hansson JH, Schild L, Lu Y, et al. A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci U S A. 1995;92:11495-11499.
14. Shimkets RA, Warnock DG, Bositis CM, et al. Liddle's syndrome:heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79:407-414.
15. Inoue J, Iwaoka T, Tokunaga H, et al. A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. J Clin Endocrinol Metab.1998;83:2210-2213.
16. Schild L, Lu Y, Gautschi I, et al. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J.1996;15:2381-2387.
17. Snyder PM, Price MP, McDonald FJ, et al. Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+channel. Cell.1995;83:969-978.
18. Shimkets RA, Lifton RP, Canessa CM. The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis. J Biol Chem.1997;272:25537-25541.
19. Nagy Z, Busjahn A, Bahring S, et al. Quantitative trait loci for blood pressure exist near the IGF-1, the Liddle syndrome, the angiotensin II-receptor gene and the renin loci in man. J Am Soc Nephrol.1999;10:1709-1716.
20. Disse-Nicodeme S, Achard JM, Desitter I, et al. A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Am J Hum Genet.2000;67:302-310.
21. Nkeh B, Samani NJ, Badenhorst D, et al. T594M variant of the epithelial sodium channel beta-subunit gene and hypertension in individuals of African ancestry in South Africa. Am J Hypertens.2003; 16:847-852.
22. Hollier JM, Martin DF, Bell DM, et al. Epithelial sodium channel allele T594M is not associated with blood pressure or blood pressure response to amiloride. Hypertension. 2006;47:428-433.
23. Mansfield TA, Simon DB, Farfel Z, et al. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1 q31-42 and 17p11-q21. Nat Genet.1997;16:202-205.
24. Schuster H, Wienker TF, Toka HR, et al. Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension. Hypertension. 1996;28:1085-1092.
25. Schuster H, Toka O, Toka HR, et al. A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly. Kidney Int.1998;53:167-172.
26. Jordan J, Toka HR, Heusser K, et al. Severely impaired baroreflex-buffering in patients with monogenic hypertension and neurovascular contact. Circulation.2000;102:2611-2618.
27. Bahring S, Nagai T, Toka HR, et al. Deletion at 12p in a Japanese child with brachydactyly overlaps the assigned locus of brachydactyly with hypertension in a Turkish family. Am J Hum Genet.1997;60:732-735.
28. Bahring S, Rauch A, Toka O, et al. Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. Hypertension.2004;43:471-476.
29. Dickson ME, Zimmerman MB, Rahmouni K, Sigmund CD. The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells. Hypertension.2007;49:631-639.
30. Dickson ME, Sigmund CD. Genetic basis of hypertension:revisiting angiotensinogen. Hypertension.2006;48:14-20.
31. Smithies O, Kim HS. Targeted gene duplication and disruption for analyzing quantitative genetic traits in mice. Proc Natl Acad Sci U S A.1994;91:3612-3615.
32. Pereira AC, Mota GF, Cunha RS, et al. Angiotensinogen 235T allele "dosage" is associated with blood pressure phenotypes. Hypertension.2003;41:25-30.
33. Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A. Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease:a meta-analysis. Arterioscler Thromb Vasc Biol.2003;23:1269-1275.
34. Kumar A, Li Y, Patil S, Jain S. A haplotype of the angiotensinogen gene is associated with hypertension in african americans. Clin Exp Pharmacol Physiol.2005;32:495-502.
35. Hasimu B, Nakayama T, Mizutani Y, et al. Haplotype analysis of the human renin gene and essential hypertension. Hypertension.2003;41:308-312.
36. Fuchs S, Philippe J, Germain S, et al. Functionality of two new polymorphisms in the human renin gene enhancer region. J Hypertens.2002;20:2391-2398.
37. Mansego ML, Redon J, Marin R, et al. Renin polymorphisms and haplotypes are associated with blood pressure levels and hypertension risk in postmenopausal women. J Hypertens. 2008;26:230-237.
38. Rieder MJ, Taylor SL, Clark AG, Nickerson DA. Sequence variation in the human angiotensin converting enzyme. Nat Genet.1999;22:59-62.
39. Zhu X, Bouzekri N, Southam L, et al. Linkage and association analysis of angiotensin Ⅰ-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet.2001;68:1139-1148.
40. Sethupathy P, Borel C, Gagnebin M, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3'untranslated region:a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet.2007;81:405-413.
41. Ge D, Zhu H, Huang Y, et al. Multilocus analyses of Renin-Angiotensin-aldosterone system gene variants on blood pressure at rest and during behavioral stress in young normotensive subjects. Hypertension.2007;49:107-112.
42. Riddle EL, Rana BK, Murthy KK, et al. Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Hypertension. 2006;47:415-420.
43. Etzel JP, Rana BK, Wen G, et al. Genetic variation at the human alpha2B-adrenergic receptor locus:role in blood pressure variation and yohimbine response. Hypertension. 2005;45:1207-1213.
44. Li JL, Canham RM, Vongpatanasin W, et al. Do allelic variants in alpha2A and alpha2C adrenergic receptors predispose to hypertension in blacks? Hypertension. 2006;47:1140-1146.
45. Bao X, Mills PJ, Rana BK, et al. Interactive effects of common beta2-adrenoceptor haplotypes and age on susceptibility to hypertension and receptor function. Hypertension. 2005;46:301-307.
46. Xu B, English JM, Wilsbacher JL, et al. WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem. 2000;275:16795-16801.
47. Verissimo F, Jordan P. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene.2001;20:5562-5569.
48. Vitari AC, Deak M, Morrice NA, Alessi DR. The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J.2005;391:17-24.
49. Delaloy C, Lu J, Houot AM, et al. Multiple promoters in the WNK1 gene:one controls expression of a kidney-specific kinase-defective isoform. Mol Cell Biol. 2003;23:9208-9221.
50. O'Reilly M, Marshall E, Speirs HJ, Brown RW. WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain. J Am Soc Nephrol.2003; 14:2447-2456.
51. Lazrak A, Liu Z, Huang CL. Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proc Natl Acad Sci U S A.2006;103:1615-1620.
52. Subramanya AR, Yang CL, McCormick JA, Ellison DH. WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. Kidney Int. 2006;70:630-634.
53. Wade JB, Fang L, Liu J, et al. WNK1 kinase isoform switch regulates renal potassium excretion. Proc Natl Acad Sci U S A.2006;103:8558-8563.
54. Huang CL, Cha SK, Wang HR, et al. WNKs:protein kinases with a unique kinase domain. Exp Mol Med.2007;39:565-573.
55. Kahle KT, Ring AM, Lifton RP. Molecular physiology of the WNK kinases. Annu Rev Physiol.2008;70:329-355.
56. Moniz S, Verissimo F,Matos P, et al. Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Oncogene.2007;26:6071-6081.
57. Verissimo F, Silva E, Morris JD, et al. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Oncogene.2006;25:4172-4182.
58. Hong C, Moorefield KS, Jun P, et al. Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Proc Natl Acad Sci U S A.2007;104:10974-10979.
59. Zambrowicz BP, Abuin A, Ramirez-Solis R, et al. Wnkl kinase deficiency lowers blood pressure in mice:a gene-trap screen to identify potential targets for therapeutic intervention. Proc Natl Acad Sci U S A.2003;100:14109-14114.
60. Lenertz LY, Lee BH, Min X, et al. Properties of WNK1 and implications for other family members. J Biol Chem.2005;280:26653-26658.
61. Xu BE, Min X, Stippec S, et al. Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. J Biol Chem.2002;277:48456-48462.
62. Zagorska A, Pozo-Guisado E, Boudeau J, et al. Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. J Cell Biol.2007;176:89-100.
63. Moriguchi T, Urushiyama S, Hisamoto N, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem.2005;280:42685-42693.
64. Richardson C, Rafiqi FH, Karlsson HK, et al. Activation of the thiazide-sensitive Na+-Cl-cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675-684.
65. Gordon RD. The syndrome of hypertension and hyperkalemia with normal glomerular filtration rate:Gordon's syndrome. Aust N Z J Med.1986; 16:183-184.
66. Yang CL, Zhu X, Ellison DH. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest.2007;117:3403-3411.
67. Chiga M, Rai T, Yang SS, et al. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 2008;74:1403-1409.
68. O'Reilly M, Marshall E, Macgillivray T, et al. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. J Am Soc Nephrol.2006; 17:2402-2413.
69. Kamel KS, Oh MS, Halperin ML. Bartter's, Gitelman's, and Gordon's syndromes. From physiology to molecular biology and back, yet still some unanswered questions. Nephron. 2002;92Suppl 1:18-27.
70. Levy D, DeStefano AL, Larson MQ et al. Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study. Hypertension.2000;36:477-483.
71. Baima J, Nicolaou M, Schwartz F, et al. Evidence for linkage between essential hypertension and a putative locus on human chromosome 17. Hypertension.1999;34:4-7.
72. Julier C, Delepine M, Keavney B, et al. Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. Hum Mol Genet.1997;6:2077-2085.
73. Benjafield AV, Katyk K, Morris BJ. Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. Clin Genet.2003;64:433-438.
74. Erlich PM, Cui J, Chazaro I, et al. Genetic variants of WNK4 in whites and African Americans with hypertension. Hypertension.2003;41:1191-1195.
75. Speirs HJ, Morris BJ. WNK4 intron 10 polymorphism is not associated with hypertension. Hypertension.2004;43:766-768.
76. Kokubo Y, Kamide K, Inamoto N, et al. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. J Hum Genet.2004;49:507-515.
77. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation.2005; 112:627-635.
78. Tobin MD, Timpson NJ, Wain LV, et al. Common variation in the WNK1 gene and blood pressure in childhood:the Avon Longitudinal Study of Parents and Children. Hypertension. 2008;52:974-979.
79. Newhouse SJ, Wallace C, Dobson R, et al. Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study. Hum Mol Genet.2005;14:1805-1814.
80. Ushiro H, Tsutsumi T, Suzuki K, et al. Molecular cloning and characterization of a novel Ste20-related protein kinase enriched in neurons and transporting epithelia. Arch Biochem Biophys.1998;355:233-240.
81. Johnston AM, Naselli G, Gonez LJ, et al. SPAK, a STE20/SPS1-related kinase that activates thep38 pathway. Oncogene.2000; 19:4290-4297.
82. Miao N, Fung B, Sanchez R, et al. Isolation and expression of PASK, a serine/threonine kinase, during rat embryonic development, with special emphasis on the pancreas. J Histochem Cytochem.2000;48:1391-1400.
83. Chen W, Yazicioglu M, Cobb MH. Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. J Biol Chem.2004;279:11129-11136.
84. Dan I, Watanabe NM, Kusumi A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol.2001;11:220-230.
85. Li Y, Hu J, Vita R, et al. SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. EMBO J.2004;23:1112-1122.
86. Tsutsumi T, Ushiro H, Kosaka T, et al. Proline-and alanine-rich Ste20-related kinase associates with F-actin and translocates from the cytosol to cytoskeleton upon cellular stresses. J Biol Chem.2000;275:9157-9162.
87. Anselmo AN, Earnest S, Chen W, et al. WNK1 and OSR1 regulate the Na+, K+,2C1-cotransporter in HeLa cells. Proc Natl Acad Sci U S A.2006;103:10883-10888.
88. Gagnon KB, England R, Delpire E. Volume sensitivity of cation-Cl-cotransporters is modulated by the interaction of two kinases:Ste20-related proline-alanine-rich kinase and WNK4. Am J Physiol Cell Physiol.2006;290:C134-142.
89. Vitari AC, Thastrup J, Rafiqi FH, et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J. 2006;397:223-231.
90. Dowd BF, Forbush B. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of theNa-K-Cl cotransporter (NKCC1). J Biol Chem.2003;278:27347-27353.
91. Piechotta K, Lu J, Delpire E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem.2002;277:50812-50819.
92. Piechotta K, Garbarini N, England R, Delpire E. Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2C1-cotransporter in the nervous system:evidence for a scaffolding role of the kinase. J Biol Chem.2003;278:52848-52856.
93. Delpire E, Rauchman MI, Beier DR, et al. Molecular cloning and chromosome localization of a putative basolateral Na(+)-K(+)-2Cl-cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells. J Biol Chem.1994;269:25677-25683.
94. Gerelsaikhan T, Turner RJ. Transmembrane topology of the secretory Na+-K+-2C1-cotransporter NKCC1 studied by in vitro translation. J Biol Chem.2000;275:40471-40477.
95. Flatman PW. Cotransporters, WNKs and hypertension:important leads from the study of monogenetic disorders of blood pressure regulation. Clin Sci (Lond).2007; 112:203-216.
96. Gamba G Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev.2005;85:423-493.
97. Gagnon KB, England R, Delpire E. A single binding motif is required for SPAK activation of the Na-K-2Cl cotransporter. Cell Physiol Biochem.2007;20:131-142.
98. Gamba G, Miyanoshita A, Lombardi M, et al. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem. 1994;269:17713-17722.
99. Gamba G, Saltzberg SN, Lombardi M, et al. Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci U S A.1993;90:2749-2753.
100. Payne JA, Forbush B,3rd. Alternatively spliced isoforms of the putative renal Na-K-Cl cotransporter are differentially distributed within the rabbit kidney. Proc Natl Acad Sci U S A.1994;91:4544-4548.
101. Lin SH, Shiang JC, Huang CC, et al. Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome. J Clin Endocrinol Metab.2005;90:2500-2507.
102. Maki N, Komatsuda A, Wakui H, et al. Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant.2004;19:1761-1766.
103. Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman's syndrome. Nephron Physiol.2008;108:p29-36.
104. Cai H, Cebotaru V, Wang YH, et al. WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney Int.2006;69:2162-2170.
105. Golbang AP, Murthy M, Hamad A, et al. A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension.2005;46:295-300.
106. Wilson FH, Kahle KT, Sabath E, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia:the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A.2003; 100:680-684.
107. Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest.2003;111:1039-1045.
108. Kahle KT, Rinehart J, Ring A, et al. WNK protein kinases modulate cellular Cl-flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters. Physiology (Bethesda).2006;21:326-335.
109. Garzon-Muvdi T, Pacheco-Alvarez D, Gagnon KB, et al. WNK4 kinase is a negative regulator of K+-Cl-cotransporters. Am J Physiol Renal Physiol.2007;292:F1197-1207.
110. Kahle KT, Rinehart J, de Los Heros P, et al. WNK3 modulates transport of Cl-in and out of cells:implications for control of cell volume and neuronal excitability. Proc Natl Acad Sci U S A.2005;102:16783-16788.
111. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet.1996; 12:24-30.
112. Lemmink HH, Knoers NV, Karolyi L, et al. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int.1998;54:720-730.
113. Cruz DN, Simon DB, Nelson-Williams C, et al. Mutations in the Na-Cl cotransporter reduce blood pressure in humans. Hypertension.2001;37:1458-1464.
114. Melander O, Orho-Melander M, Bengtsson K, et al. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000;36:389-394.
115. Song Y, Herrera VL, Filigheddu F, et al. Non-association of the thiazide-sensitive Na,Cl-cotransporter gene with polygenic hypertension in both rats and humans. J Hypertens.2001; 19:1547-1551.
116. Matsuo A, Katsuya T, Ishikawa K, et al. G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women. J Hypertens. 2004;22:2123-2127.
117. Wang XF, Lin RY, Wang SZ, et al. Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China. Clin Chim Acta.2008;388:95-98.
118. Kim JH, Shin HD, Park BL, et al. SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Diabetes.2006;55:843-848.
119. Keszei AP, Tisler A, Backx PH, et al. Molecular variants of the thiazide-sensitive Na+-Cl-cotransporter in hypertensive families. J Hypertens.2007;25:2074-2081.
120. Wang Y, O'Connell JR, McArdle PF, et al. From the Cover:Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009; 106:226-231.
121. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet.2009.
122. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet.2009.
123. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature.2007;447:661-678.
124. Cho YS, Go MJ, Kim YJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527-534.
2. Whelton PK. Epidemiology of hypertension. Lancet.1994;344:101-106.
3. Tanira MO, Al Balushi KA. Genetic variations related to hypertension:a review. J Hum Hypertens.2005;19:7-19.
4. Newhouse S, Farrall M, Wallace C, et al. Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion. PLoS One.2009;4:e5003.
5. Das M, Pal S, Ghosh A. Angiotensin converting enzyme gene polymorphism (insertion/deletion) and hypertension in adult Asian Indians:a population-based study from Calcutta, India. Hum Biol.2008;80:303-312.
6. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet.2009.
7. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet.2009.
8. Wang Y, O'Connell JR, McArdle PF, et al. From the Cover:Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009; 106:226-231.
9. Richardson C, Rafiqi FH, Karlsson HK, et al. Activation of the thiazide-sensitive Na+-Cl-cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675-684.
10. Delpire E, Gagnon KB. SPAK and OSR1:STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J.2008;409:321-331.
11. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet.1996;12:24-30.
12. Melander O, Orho-Melander M, Bengtsson K, et al. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000;36:389-394.
13. Matsuo A, Katsuya T, Ishikawa K, et al. G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women. J Hypertens. 2004;22:2123-2127.
14. Wang XF, Lin RY, Wang SZ, et al. Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China. Clin Chim Acta.2008;388:95-98.
15. Moriguchi T, Urushiyama S, Hisamoto N, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem.2005;280:42685-42693.
16. Nielsen R, Hubisz MJ, Clark AG. Reconstituting the frequency spectrum of ascertained single-nucleotide polymorphism data. Genetics.2004; 168:2373-2382.
17. Fisher ND, Ferri C, Bellini C, et al. Age, gender, and non-modulation. A sexual dimorphism in essential hypertension. Hypertension.1997;29:980-985.
18. Dasgupta K, O'Loughlin J, Chen S, et al. Emergence of sex differences in prevalence of high systolic blood pressure:analysis of a longitudinal adolescent cohort. Circulation. 2006;114:2663-2670.
19. Wenger NK. Hypertension and other cardiovascular risk factors in women. Am J Hypertens. 1995;8:94s-99s.
20. Narkiewicz K, Phillips BG, Kato M, et al. Gender-selective interaction between aging, blood pressure, and sympathetic nerve activity. Hypertension.2005;45:522-525.
21. Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency:Ⅲ. Cardiovascular disease. J Androl.2009;30:477-494.
22. Wong SY, Chan DC, Hong A, Woo J. Prevalence of and risk factors for androgen deficiency in middle-aged men in Hong Kong. Metabolism.2006;55:1488-1494.
23. Fogari R, Preti P, Zoppi A, et al. Serum testosterone levels and arterial blood pressure in the elderly. Hypertens Res.2005;28:625-630.
24. Qi H, Labrie Y, Grenier J, et al. Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. Mol Cell Endocrinol. 2001;182:181-192.
25. Arici M, Turgan C, Altun B, et al. Hypertension incidence in Turkey (HinT):a population-based study. J Hypertens;28:240-244.
26. Hu FB, Stampfer MJ. Insulin resistance and hypertension:the chicken-egg question revisited. Circulation.2005;112:1678-1680.
27. Riddle EL, Rana BK, Murthy KK, et al. Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Hypertension. 2006;47:415-420.
28. Yang J, Kamide K, Kokubo Y, et al. Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population. J Hypertens.2005;23:1497-1505.
29. Sober S, Org E, Kepp K, et al. Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array. PLoS One.2009;4:e6034.
30. Rana BK, Insel PA, Payne SH, et al. Population-based sample reveals gene-gender interactions in blood pressure in White Americans. Hypertension.2007;49:96-106.
31. Lackland DT, Egan BM, Mountford WK, et al. Thirty-year Survival for Black and White Hypertensive Individuals in the Evans County Heart Study and the Hypertension Detection and Follow-up Program. J Am Soc Hypertens.2008;2:448-454.
32. Reynolds K, Gu D, Muntner P, et al. A population-based, prospective study of blood pressure and risk for end-stage renal disease in China. J Am Soc Nephrol. 2007;18:1928-1935.
33. Ganten U, Schroder G, Witt M, et al. Sexual dimorphism of blood pressure in spontaneously hypertensive rats:effects of anti-androgen treatment. J Hypertens. 1989;7:721-726.
34. Langille DB, Joffres MR, MacPherson KM, et al. Prevalence of risk factors for cardiovascular disease in Canadians 55 to 74 years of age:results from the Canadian Heart Health Surveys,1986-1992. CMAJ.1999;161:S3-9.
35. Mendez-Chacon E, Santamaria-Ulloa C, Rosero-Bixby L. Factors associated with hypertension prevalence, unawareness and treatment among Costa Rican elderly. BMC Public Health.2008;8:275.
36. Pickering TG. Mental stress as a causal factor in the development of hypertension and cardiovascular disease. Curr Hypertens Rep.2001;3:249-254.
37. Ruixing Y, Jinzhen W, Shangling P, et al. Sex differences in environmental and genetic factors for hypertension. Am J Med.2008;121:811-819.
38. Gainer JV, Lipkowitz MS, Yu C, et al. Association of a CYP4A11 variant and blood pressure in black men. J Am Soc Nephrol.2008;19:1606-1612.
39. Ong KL, Leung RY, Wong LY, et al. Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men. Am J Hypertens.2008;21:539-545.
40. Zhao W, Wang Y, Wang L, et al. Gender-specific association between the kininogen 1 gene variants and essential hypertension in Chinese Han population. J Hypertens. 2009;27:484-490.
41. Holla VR, Adas F, Imig JD, et al. Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension. Proc Natl Acad Sci U S A.2001;98:5211-5216.
42. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency:Ⅱ. Type 2 diabetes and insulin resistance. J Androl.2009;30:23-32.
1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension:analysis of worldwide data. Lancet.2005;365:217-223.
2. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545-556.
3. Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science.2001;293:1107-1112.
4. Kupper N, Ge D, Treiber FA, Snieder H. Emergence of novel genetic effects on blood pressure and hemodynamics in adolescence:the Georgia Cardiovascular Twin Study. Hypertension.2006;47:948-954.
5. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature.1992;355:262-265.
6. Pascoe L, Curnow KM, Slutsker L, et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci U S A.1992;89:8327-8331.
7. Mune T, Rogerson FM, Nikkila H, et al. Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet.1995;10:394-399.
8. Li A, Li KX, Marui S, et al. Apparent mineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygote state. J Hypertens.1997; 15:1397-1402.
9. Wilson RC, Dave-Sharma S, Wei JQ, et al. A genetic defect resulting in mild low-renin hypertension. Proc Natl Acad Sci U S A.1998;95:10200-10205.
10. Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science.2000;289:119-123.
11. Botero-Velez M, Curtis JJ, Warnock DG Brief report:Liddle's syndrome revisited--a disorder of sodium reabsorption in the distal tubule. N Engl J Med.1994;330:178-181.
12. Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit:genetic heterogeneity of Liddle syndrome. Nat Genet.1995; 11:76-82.
13. Hansson JH, Schild L, Lu Y, et al. A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci U S A. 1995;92:11495-11499.
14. Shimkets RA, Warnock DG, Bositis CM, et al. Liddle's syndrome:heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79:407-414.
15. Inoue J, Iwaoka T, Tokunaga H, et al. A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. J Clin Endocrinol Metab.1998;83:2210-2213.
16. Schild L, Lu Y, Gautschi I, et al. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J.1996;15:2381-2387.
17. Snyder PM, Price MP, McDonald FJ, et al. Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+channel. Cell.1995;83:969-978.
18. Shimkets RA, Lifton RP, Canessa CM. The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis. J Biol Chem.1997;272:25537-25541.
19. Nagy Z, Busjahn A, Bahring S, et al. Quantitative trait loci for blood pressure exist near the IGF-1, the Liddle syndrome, the angiotensin II-receptor gene and the renin loci in man. J Am Soc Nephrol.1999;10:1709-1716.
20. Disse-Nicodeme S, Achard JM, Desitter I, et al. A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Am J Hum Genet.2000;67:302-310.
21. Nkeh B, Samani NJ, Badenhorst D, et al. T594M variant of the epithelial sodium channel beta-subunit gene and hypertension in individuals of African ancestry in South Africa. Am J Hypertens.2003; 16:847-852.
22. Hollier JM, Martin DF, Bell DM, et al. Epithelial sodium channel allele T594M is not associated with blood pressure or blood pressure response to amiloride. Hypertension. 2006;47:428-433.
23. Mansfield TA, Simon DB, Farfel Z, et al. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1 q31-42 and 17p11-q21. Nat Genet.1997;16:202-205.
24. Schuster H, Wienker TF, Toka HR, et al. Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension. Hypertension. 1996;28:1085-1092.
25. Schuster H, Toka O, Toka HR, et al. A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly. Kidney Int.1998;53:167-172.
26. Jordan J, Toka HR, Heusser K, et al. Severely impaired baroreflex-buffering in patients with monogenic hypertension and neurovascular contact. Circulation.2000;102:2611-2618.
27. Bahring S, Nagai T, Toka HR, et al. Deletion at 12p in a Japanese child with brachydactyly overlaps the assigned locus of brachydactyly with hypertension in a Turkish family. Am J Hum Genet.1997;60:732-735.
28. Bahring S, Rauch A, Toka O, et al. Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. Hypertension.2004;43:471-476.
29. Dickson ME, Zimmerman MB, Rahmouni K, Sigmund CD. The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells. Hypertension.2007;49:631-639.
30. Dickson ME, Sigmund CD. Genetic basis of hypertension:revisiting angiotensinogen. Hypertension.2006;48:14-20.
31. Smithies O, Kim HS. Targeted gene duplication and disruption for analyzing quantitative genetic traits in mice. Proc Natl Acad Sci U S A.1994;91:3612-3615.
32. Pereira AC, Mota GF, Cunha RS, et al. Angiotensinogen 235T allele "dosage" is associated with blood pressure phenotypes. Hypertension.2003;41:25-30.
33. Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A. Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease:a meta-analysis. Arterioscler Thromb Vasc Biol.2003;23:1269-1275.
34. Kumar A, Li Y, Patil S, Jain S. A haplotype of the angiotensinogen gene is associated with hypertension in african americans. Clin Exp Pharmacol Physiol.2005;32:495-502.
35. Hasimu B, Nakayama T, Mizutani Y, et al. Haplotype analysis of the human renin gene and essential hypertension. Hypertension.2003;41:308-312.
36. Fuchs S, Philippe J, Germain S, et al. Functionality of two new polymorphisms in the human renin gene enhancer region. J Hypertens.2002;20:2391-2398.
37. Mansego ML, Redon J, Marin R, et al. Renin polymorphisms and haplotypes are associated with blood pressure levels and hypertension risk in postmenopausal women. J Hypertens. 2008;26:230-237.
38. Rieder MJ, Taylor SL, Clark AG, Nickerson DA. Sequence variation in the human angiotensin converting enzyme. Nat Genet.1999;22:59-62.
39. Zhu X, Bouzekri N, Southam L, et al. Linkage and association analysis of angiotensin Ⅰ-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet.2001;68:1139-1148.
40. Sethupathy P, Borel C, Gagnebin M, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3'untranslated region:a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet.2007;81:405-413.
41. Ge D, Zhu H, Huang Y, et al. Multilocus analyses of Renin-Angiotensin-aldosterone system gene variants on blood pressure at rest and during behavioral stress in young normotensive subjects. Hypertension.2007;49:107-112.
42. Riddle EL, Rana BK, Murthy KK, et al. Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Hypertension. 2006;47:415-420.
43. Etzel JP, Rana BK, Wen G, et al. Genetic variation at the human alpha2B-adrenergic receptor locus:role in blood pressure variation and yohimbine response. Hypertension. 2005;45:1207-1213.
44. Li JL, Canham RM, Vongpatanasin W, et al. Do allelic variants in alpha2A and alpha2C adrenergic receptors predispose to hypertension in blacks? Hypertension. 2006;47:1140-1146.
45. Bao X, Mills PJ, Rana BK, et al. Interactive effects of common beta2-adrenoceptor haplotypes and age on susceptibility to hypertension and receptor function. Hypertension. 2005;46:301-307.
46. Xu B, English JM, Wilsbacher JL, et al. WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem. 2000;275:16795-16801.
47. Verissimo F, Jordan P. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene.2001;20:5562-5569.
48. Vitari AC, Deak M, Morrice NA, Alessi DR. The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J.2005;391:17-24.
49. Delaloy C, Lu J, Houot AM, et al. Multiple promoters in the WNK1 gene:one controls expression of a kidney-specific kinase-defective isoform. Mol Cell Biol. 2003;23:9208-9221.
50. O'Reilly M, Marshall E, Speirs HJ, Brown RW. WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain. J Am Soc Nephrol.2003; 14:2447-2456.
51. Lazrak A, Liu Z, Huang CL. Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proc Natl Acad Sci U S A.2006;103:1615-1620.
52. Subramanya AR, Yang CL, McCormick JA, Ellison DH. WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. Kidney Int. 2006;70:630-634.
53. Wade JB, Fang L, Liu J, et al. WNK1 kinase isoform switch regulates renal potassium excretion. Proc Natl Acad Sci U S A.2006;103:8558-8563.
54. Huang CL, Cha SK, Wang HR, et al. WNKs:protein kinases with a unique kinase domain. Exp Mol Med.2007;39:565-573.
55. Kahle KT, Ring AM, Lifton RP. Molecular physiology of the WNK kinases. Annu Rev Physiol.2008;70:329-355.
56. Moniz S, Verissimo F,Matos P, et al. Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Oncogene.2007;26:6071-6081.
57. Verissimo F, Silva E, Morris JD, et al. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Oncogene.2006;25:4172-4182.
58. Hong C, Moorefield KS, Jun P, et al. Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Proc Natl Acad Sci U S A.2007;104:10974-10979.
59. Zambrowicz BP, Abuin A, Ramirez-Solis R, et al. Wnkl kinase deficiency lowers blood pressure in mice:a gene-trap screen to identify potential targets for therapeutic intervention. Proc Natl Acad Sci U S A.2003;100:14109-14114.
60. Lenertz LY, Lee BH, Min X, et al. Properties of WNK1 and implications for other family members. J Biol Chem.2005;280:26653-26658.
61. Xu BE, Min X, Stippec S, et al. Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. J Biol Chem.2002;277:48456-48462.
62. Zagorska A, Pozo-Guisado E, Boudeau J, et al. Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. J Cell Biol.2007;176:89-100.
63. Moriguchi T, Urushiyama S, Hisamoto N, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem.2005;280:42685-42693.
64. Richardson C, Rafiqi FH, Karlsson HK, et al. Activation of the thiazide-sensitive Na+-Cl-cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675-684.
65. Gordon RD. The syndrome of hypertension and hyperkalemia with normal glomerular filtration rate:Gordon's syndrome. Aust N Z J Med.1986; 16:183-184.
66. Yang CL, Zhu X, Ellison DH. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest.2007;117:3403-3411.
67. Chiga M, Rai T, Yang SS, et al. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 2008;74:1403-1409.
68. O'Reilly M, Marshall E, Macgillivray T, et al. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. J Am Soc Nephrol.2006; 17:2402-2413.
69. Kamel KS, Oh MS, Halperin ML. Bartter's, Gitelman's, and Gordon's syndromes. From physiology to molecular biology and back, yet still some unanswered questions. Nephron. 2002;92Suppl 1:18-27.
70. Levy D, DeStefano AL, Larson MQ et al. Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study. Hypertension.2000;36:477-483.
71. Baima J, Nicolaou M, Schwartz F, et al. Evidence for linkage between essential hypertension and a putative locus on human chromosome 17. Hypertension.1999;34:4-7.
72. Julier C, Delepine M, Keavney B, et al. Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. Hum Mol Genet.1997;6:2077-2085.
73. Benjafield AV, Katyk K, Morris BJ. Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. Clin Genet.2003;64:433-438.
74. Erlich PM, Cui J, Chazaro I, et al. Genetic variants of WNK4 in whites and African Americans with hypertension. Hypertension.2003;41:1191-1195.
75. Speirs HJ, Morris BJ. WNK4 intron 10 polymorphism is not associated with hypertension. Hypertension.2004;43:766-768.
76. Kokubo Y, Kamide K, Inamoto N, et al. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. J Hum Genet.2004;49:507-515.
77. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation.2005; 112:627-635.
78. Tobin MD, Timpson NJ, Wain LV, et al. Common variation in the WNK1 gene and blood pressure in childhood:the Avon Longitudinal Study of Parents and Children. Hypertension. 2008;52:974-979.
79. Newhouse SJ, Wallace C, Dobson R, et al. Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study. Hum Mol Genet.2005;14:1805-1814.
80. Ushiro H, Tsutsumi T, Suzuki K, et al. Molecular cloning and characterization of a novel Ste20-related protein kinase enriched in neurons and transporting epithelia. Arch Biochem Biophys.1998;355:233-240.
81. Johnston AM, Naselli G, Gonez LJ, et al. SPAK, a STE20/SPS1-related kinase that activates thep38 pathway. Oncogene.2000; 19:4290-4297.
82. Miao N, Fung B, Sanchez R, et al. Isolation and expression of PASK, a serine/threonine kinase, during rat embryonic development, with special emphasis on the pancreas. J Histochem Cytochem.2000;48:1391-1400.
83. Chen W, Yazicioglu M, Cobb MH. Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. J Biol Chem.2004;279:11129-11136.
84. Dan I, Watanabe NM, Kusumi A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol.2001;11:220-230.
85. Li Y, Hu J, Vita R, et al. SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. EMBO J.2004;23:1112-1122.
86. Tsutsumi T, Ushiro H, Kosaka T, et al. Proline-and alanine-rich Ste20-related kinase associates with F-actin and translocates from the cytosol to cytoskeleton upon cellular stresses. J Biol Chem.2000;275:9157-9162.
87. Anselmo AN, Earnest S, Chen W, et al. WNK1 and OSR1 regulate the Na+, K+,2C1-cotransporter in HeLa cells. Proc Natl Acad Sci U S A.2006;103:10883-10888.
88. Gagnon KB, England R, Delpire E. Volume sensitivity of cation-Cl-cotransporters is modulated by the interaction of two kinases:Ste20-related proline-alanine-rich kinase and WNK4. Am J Physiol Cell Physiol.2006;290:C134-142.
89. Vitari AC, Thastrup J, Rafiqi FH, et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J. 2006;397:223-231.
90. Dowd BF, Forbush B. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of theNa-K-Cl cotransporter (NKCC1). J Biol Chem.2003;278:27347-27353.
91. Piechotta K, Lu J, Delpire E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem.2002;277:50812-50819.
92. Piechotta K, Garbarini N, England R, Delpire E. Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2C1-cotransporter in the nervous system:evidence for a scaffolding role of the kinase. J Biol Chem.2003;278:52848-52856.
93. Delpire E, Rauchman MI, Beier DR, et al. Molecular cloning and chromosome localization of a putative basolateral Na(+)-K(+)-2Cl-cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells. J Biol Chem.1994;269:25677-25683.
94. Gerelsaikhan T, Turner RJ. Transmembrane topology of the secretory Na+-K+-2C1-cotransporter NKCC1 studied by in vitro translation. J Biol Chem.2000;275:40471-40477.
95. Flatman PW. Cotransporters, WNKs and hypertension:important leads from the study of monogenetic disorders of blood pressure regulation. Clin Sci (Lond).2007; 112:203-216.
96. Gamba G Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev.2005;85:423-493.
97. Gagnon KB, England R, Delpire E. A single binding motif is required for SPAK activation of the Na-K-2Cl cotransporter. Cell Physiol Biochem.2007;20:131-142.
98. Gamba G, Miyanoshita A, Lombardi M, et al. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem. 1994;269:17713-17722.
99. Gamba G, Saltzberg SN, Lombardi M, et al. Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci U S A.1993;90:2749-2753.
100. Payne JA, Forbush B,3rd. Alternatively spliced isoforms of the putative renal Na-K-Cl cotransporter are differentially distributed within the rabbit kidney. Proc Natl Acad Sci U S A.1994;91:4544-4548.
101. Lin SH, Shiang JC, Huang CC, et al. Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome. J Clin Endocrinol Metab.2005;90:2500-2507.
102. Maki N, Komatsuda A, Wakui H, et al. Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant.2004;19:1761-1766.
103. Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman's syndrome. Nephron Physiol.2008;108:p29-36.
104. Cai H, Cebotaru V, Wang YH, et al. WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney Int.2006;69:2162-2170.
105. Golbang AP, Murthy M, Hamad A, et al. A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension.2005;46:295-300.
106. Wilson FH, Kahle KT, Sabath E, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia:the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A.2003; 100:680-684.
107. Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest.2003;111:1039-1045.
108. Kahle KT, Rinehart J, Ring A, et al. WNK protein kinases modulate cellular Cl-flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters. Physiology (Bethesda).2006;21:326-335.
109. Garzon-Muvdi T, Pacheco-Alvarez D, Gagnon KB, et al. WNK4 kinase is a negative regulator of K+-Cl-cotransporters. Am J Physiol Renal Physiol.2007;292:F1197-1207.
110. Kahle KT, Rinehart J, de Los Heros P, et al. WNK3 modulates transport of Cl-in and out of cells:implications for control of cell volume and neuronal excitability. Proc Natl Acad Sci U S A.2005;102:16783-16788.
111. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet.1996; 12:24-30.
112. Lemmink HH, Knoers NV, Karolyi L, et al. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int.1998;54:720-730.
113. Cruz DN, Simon DB, Nelson-Williams C, et al. Mutations in the Na-Cl cotransporter reduce blood pressure in humans. Hypertension.2001;37:1458-1464.
114. Melander O, Orho-Melander M, Bengtsson K, et al. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000;36:389-394.
115. Song Y, Herrera VL, Filigheddu F, et al. Non-association of the thiazide-sensitive Na,Cl-cotransporter gene with polygenic hypertension in both rats and humans. J Hypertens.2001; 19:1547-1551.
116. Matsuo A, Katsuya T, Ishikawa K, et al. G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women. J Hypertens. 2004;22:2123-2127.
117. Wang XF, Lin RY, Wang SZ, et al. Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China. Clin Chim Acta.2008;388:95-98.
118. Kim JH, Shin HD, Park BL, et al. SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Diabetes.2006;55:843-848.
119. Keszei AP, Tisler A, Backx PH, et al. Molecular variants of the thiazide-sensitive Na+-Cl-cotransporter in hypertensive families. J Hypertens.2007;25:2074-2081.
120. Wang Y, O'Connell JR, McArdle PF, et al. From the Cover:Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009; 106:226-231.
121. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet.2009.
122. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet.2009.
123. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature.2007;447:661-678.
124. Cho YS, Go MJ, Kim YJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527-534.