Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Positive association between KCNJ5 rs2604204 (A/C) polymorphism and plasma aldosterone levels, but also plasma renin and angiotensin I and II levels, in newly diagnosed hypertensive Chinese: a case–control study

Journal of Human Hypertension volume 31, pages 457–461 (2017)Cite this article

Subjects

Abstract

Variants in G protein-coupled inward rectifier K+ channels 4 (GIRK4 also known as KCNJ5) gene are associated with primary aldosteronism, which is the most common cause of secondary hypertension. The KCNJ5 rs2604204 variant was shown to be common (minor allele frequency=32.5%) in Chinese patients with essential hypertension (EH). The relationship between KCNJ5 variant and plasma aldosterone (ALD) levels in EH patients has not been reported. We collected 229 patients with newly diagnosed EH without any antihypertensive agents. According to the median standing plasma ALD, high-ALD and control groups were divided. Clinical data and blood samples were collected. KCNJ5 rs2604204 genotype was determined by PCR. The results showed that the levels of triglyceride, uric acid, insulin, insulin resistance (IR) index, renin, angiotensin I (Ang I), angiotensin II (Ang II), cortisol, 24 h mean systolic blood pressure (SBP) and daytime mean SBP were significantly increased in the high-ALD group than those in the control group, as well as 24 h s.d. of SBP and diastolic BP (DBP), and 24 h coefficient of variance of SBP and DBP. Notably, the distribution frequency of AC and CC genotypes, and the C allele of KCNJ5 were also significantly higher in the high-ALD group. Logistic regression analysis showed that the C allele of KCNJ5 rs2604204 was one risk factor for increased plasma ALD in Chinese EH patients (P=0.008, odds ratio=2.2 (95% confidence interval 1.2–4.1)). Our findings indicated that the variation of plasma ALD might be associated with increased IR and BP variability. Moreover, KCNJ5 rs2604204 polymorphism was related to increased plasma ALD level, but also plasma renin, Ang I and II levels in newly diagnosed, never-treated EH patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Calhoun DA . Aldosteronism and hypertension. Clin J Am Soc Nephrol 2006; 1: 1039–1045.

    Article  CAS  Google Scholar 

  2. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004; 351: 33–41.

    Article  CAS  Google Scholar 

  3. Newton-Cheh C, Guo CY, Gona P, Larson GM, Emalia JB, Wang TJ et al. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample. Hypertension 2007; 49: 846–856.

    Article  CAS  Google Scholar 

  4. Vaidya A, Underwood PC, Hopkins PN, Jeunemaitre X, Ferri C, Williams GH et al. Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension 2013; 61 (4): 886–893.

    Article  CAS  Google Scholar 

  5. Savard S, Amar L, Plouin PF, Steichen O . Cardiovascular complications associated with primary aldosteronism: a controlled crosssectional study. Hypertension 2013; 62: 331–336.

    Article  CAS  Google Scholar 

  6. Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab 2013; 98: 4826–4833.

    Article  CAS  Google Scholar 

  7. Zhang YJ, Li NF, Zhang JH, Xing WH, Li B . Correlation between plasma aldosterone concentration and left ventricular structure in hypertensive patients. Zhonghua Xin Xue Guan Bing Za Zhi 2013; 41 (7): 583–586.

    CAS  PubMed  Google Scholar 

  8. Mulè G, Nardi E, Cusimano P, Cottone S, Seddio G, Geraci C et al. Plasma aldosterone and its relationships with left ventricular mass in essential hypertensive patients with metabolic syndrome. Am J Hypertens 2008; 21: 1055–1061.

    Article  Google Scholar 

  9. Garg R, Hurwitz S, Williams GH, Hopkins PN, Adler GK . Aldosterone production and insulin resistance in healthy adults. J Clin Endocrinol Metab 2010; 95: 1986–1990.

    Article  CAS  Google Scholar 

  10. Hannemann A, Wallaschofski H, Lüdemann J, Völzke H, Markus MR, Rettig R et al. Plasma aldosterone levels and aldosterone-to-renin ratios are associated with endothelial dysfunction in young to middle-aged subjects. Atherosclerosis 2011; 219: 875–879.

    Article  CAS  Google Scholar 

  11. Deo R, Yang W, Khan AM, Bansal N, Zhang X, Leonard MB et al. Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. Hypertension 2014; 64 (1): 103–110.

    Article  CAS  Google Scholar 

  12. Tomaschitz A, Pilz S, Ritz E, Meinitzer A, Boehm BO, März W . Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Eur Heart J 2010; 31 (10): 1237–1247.

    Article  CAS  Google Scholar 

  13. Ross DF . Recent milestones on the long and winding road from electrocortin to KCNJ5, GPER, and beyond. Hypertension 2014; 63: 19–21.

    Article  Google Scholar 

  14. Li NF, Li HJ, Zhang DL, Zhang JH, Yao XG, Wang HM et al. Genetic variations in the KCNJ5 gene in primary aldosteronism patients from Xinjiang, China. PLoS ONE 2013; 8 (1): e54051.

    Article  CAS  Google Scholar 

  15. Liu LS Writing Group of 2010 Chinese Guidelines for the Management of Hypertension. 2010 Chinese guidelines for the management of hypertension. Zhonghua Xin Xue Guan Bing Za Zhi 2011; 39 (7): 579–615.

    PubMed  Google Scholar 

  16. JCS Joint Working Group. Guidelines for the clinical use of 24-h ambulatory blood pressure monitoring (ABPM) (JCS 2010):–digest version. Circ J 2012; 76 (2): 508–519.

    Article  Google Scholar 

  17. Kumagai E, Adachi H, Jacobs DR Jr, Hirai Y, Enomoto M, Fukami A et al. Plasma aldosterone levels and development of insulin resistance: prospective study in a general population. Hypertension 2011; 58 (6): 1043–1048.

    Article  CAS  Google Scholar 

  18. Briet M, Schiffrin EL . The role of aldosterone in the metabolic syndrome. Curr Hypertens Rep 2011; 13 (2): 163–172.

    Article  CAS  Google Scholar 

  19. Miura R, Nakamura K, Miura D, Miura A, Hisamatsu K, Kajiya M et al. Aldosterone synthesis and cytokine production in human peripheral blood mononuclear cells. J Pharmacol Sci 2006; 102 (3): 288–295.

    Article  CAS  Google Scholar 

  20. Rutkowska-Zapała M, Suski M, Szatanek R, Lenart M, Węglarczyk K, Olszanecki R et al. Human monocyte subsets exhibit divergent angiotensin I-converting activity. Clin Exp Immunol 2015; 181 (1): 126–132.

    Article  Google Scholar 

  21. Tatasciore A, Renda G, Zimarino M, Soccio M, Bilo G, Parati G et al. Awake systolic blood pressure variability correlates with target organ damage in hypertensive subjects. Hypertension 2007; 50: 325–332.

    Article  CAS  Google Scholar 

  22. Hansen TW, Thijs L, Li Y, Boggia J, Kikuya M, Björklund-Bodegård K et al. Prognostic value of reading-to-reading blood pressure variability over 24 h in 8938 subjects from 11 populations. Hypertension 2010; 55 (4): 1049–1057.

    Article  CAS  Google Scholar 

  23. Ozkayar N, Dede F, Akyel F, Yildirim T, Ateş I, Turhan T et al. Relationship between blood pressure varıability and renal activity of the renin-angiotensin system. J Hum Hypertens 2016; 30 (5): 297–302.

    Article  CAS  Google Scholar 

  24. Grillo A, Bernardi S, Rebellato A, Fabris B, Bardelli M, Burrello J et al. Ambulatory blood pressure monitoring-derived short-term blood pressure variability in primary aldosteronism. J Clin Hypertens 2015; 17 (8): 603–608.

    Article  CAS  Google Scholar 

  25. Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331: 768–772.

    Article  CAS  Google Scholar 

  26. Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension 2012; 59: 592–598.

    Article  CAS  Google Scholar 

  27. Zheng FF, Zhu LM, Nie AF, Li XY, Lin JR, Zhang K et al. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension 2015; 65 (3): 622–628.

    Article  CAS  Google Scholar 

  28. van Leeuwen N, Caprio M, Blaya C, Fumeron F, Sartorato P, Ronconi V et al. The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels. Hypertension 2010; 56: 995–1002.

    Article  CAS  Google Scholar 

  29. Ketsawatsomkron P, Stepp DW, Fulton DJ, Marrero MB . Molecular mechanism of angiotensin II-induced insulin resistance in aortic vascular smooth muscle cells: roles of protein tyrosine phosphatase-1B. Vascul Pharmacol 2010; 53 (3–4): 160–168.

    Article  CAS  Google Scholar 

  30. Härdtner C, Mörke C, Walther R, Wolke C, Lendeckel U . High glucose activates the alternative ACE2/Ang-(1-7)/Mas and APN/Ang IV/IRAP RAS axes in pancreatic β-cells. Int J Mol Med 2013; 32 (4): 795–804.

    Article  Google Scholar 

  31. Li NF, Kang YA, Zhang DL, Wang HM, Zhang JH, Hu YR et al. Association between GIRK4 gene polymorphisms and insulin resistance in Xinjiang Uygur population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012; 29 (6): 715–719.

    CAS  PubMed  Google Scholar 

  32. Li N, Zhang D, Zhang J, Guo Y, Yan Z, Wang H et al. Influence of age on the association of GIRK4 with metabolic syndrome. Ann Clin Biochem 2012; 49: 369–376.

    Article  Google Scholar 

  33. Hattangady NG, Karashima S, Yuan L, Ponce-Balbuena D, Jalife J, Gomez-Sanchez CE et al. Mutated KCNJ5 activates the acute and chronic regulatory steps in aldosterone production. J Mol Endocrinol 2016; 57 (1): 1–11.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to express their sincere gratitude to all the study subjects for their voluntary participation and to all the staff of Hypertension Laboratory in Fujian Provincial Cardiovascular Disease Institute for their excellent assistance in data collection and conservation of samples. This work was supported by the Natural Science Foundation of Fujian Province (no 2014Y01010261) and Health Innovation Fund of Fujian (no 2012-CXB-5). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Conceived and designed the experiments: HC. Performed the experiments: HW, CW and HC. Analysed the data: HW and CW. Contributed reagents/materials/analysis tools: HW and CW. Wrote the paper: HW, CW and HC.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Hypertension Laboratory, Fujian Provincial Cardiovascular Disease Institute, The Shengli Clinical Medical College of Fujian Medical University, Fujian, China

    H Wang & H Chen

  2. Department of Cardiology, The First Hospital of Putian City, Fujian, China

    C Weng

Authors
  1. H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Chen.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., Weng, C. & Chen, H. Positive association between KCNJ5 rs2604204 (A/C) polymorphism and plasma aldosterone levels, but also plasma renin and angiotensin I and II levels, in newly diagnosed hypertensive Chinese: a case–control study. J Hum Hypertens 31, 457–461 (2017). https://doi.org/10.1038/jhh.2016.97

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2016.97

Search

Advanced search

Quick links