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.

  • Article
  • Published:

Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension

Hypertension Research volume 43, pages 220–226 (2020)Cite this article

Abstract

We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Miura K, Nagai M, Ohkubo T. Epidemiology of hypertension in Japan: where are we now? Circ J. 2013;77:2226–31.

    Article  Google Scholar 

  2. Ministry of Health, Labour and Welfare: National Health and Nutrition Survey Japan 2013, Ministry of Health, Health, Labour and Welfare, 2013 (in Japanese).

  3. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension. Hypertens Res. 2014;37:253–390.

    Article  Google Scholar 

  4. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13–e115.

    CAS  PubMed  Google Scholar 

  5. Mancia G1, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219.

    Article  Google Scholar 

  6. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA. 1997;277:739–45.

    Article  CAS  Google Scholar 

  7. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255–64.

    Article  Google Scholar 

  8. Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension. 2003;42:247–52.

    Article  CAS  Google Scholar 

  9. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7–13.

    Article  CAS  Google Scholar 

  10. OhtaY TsuchihashiT, Kiyohara K, Oniki H. Increased uric acid promotes the decline of renal function in hypertensive patients-a 10-years observational study. Intern Med. 2013;52:1467–72.

    Article  Google Scholar 

  11. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature. 2007;447:661–78.

    Article  Google Scholar 

  12. Kamide K, Asayama K, Katsuya T, Ohkubo T, Hirose T, Inoue R, et al. HOMED-BP study group: Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study. Pharmacogenomics. 2013;14:1709–21. GEANE study group

    Article  CAS  Google Scholar 

  13. Turner ST, Bailey KR, Fridley BL, Chapman AB, Schwartz GL, Chai HS, et al. Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension. 2008;52:359–65.

    Article  CAS  Google Scholar 

  14. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension. 2005;46:758–65.

    Article  CAS  Google Scholar 

  15. Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML. Lys418Asn polymorphism of the alpha2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity. Hypertension. 2005;46:144–50.

    Article  CAS  Google Scholar 

  16. Stark K, Reinhard W, Neureuther K, Wiedmann S, Sedlacek K, Baessler A, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS ONE. 2008;3:1–9.

    Article  Google Scholar 

  17. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Collaborators developing the Japanese equation for estimated GFR: Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.

    Article  CAS  Google Scholar 

  18. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41.

    Article  Google Scholar 

  19. Gosse P, Sheridan DJ, Zannad F, Dubourg O, Guéret P, Karpov Y, et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study. J Hypertens. 2000;18:1465–75.

    Article  CAS  Google Scholar 

  20. Marre M, Puig JG, Kokot F, Fernandez M, Jermendy G, Opie L, et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study. J Hypertens. 2004;22:1613–22.

    Article  CAS  Google Scholar 

  21. Pickkers P, Hughes AD, Russel FG, Thien T, Smits P. Thiazide-induced vasodilation in humans is mediated by potassium channel activation. Hypertension. 1998;32:1071–6.

    Article  CAS  Google Scholar 

  22. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. Br Med J. 2003;326:1427–31.

    Article  CAS  Google Scholar 

  23. Carlsen JE, Køber L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. Br Med J. 1990;300:975–8.

    Article  CAS  Google Scholar 

  24. Ueda S, Morimoto T, Ando S, Takishita S, Kawano Y, Shimamoto K, et al. DIME Investigators: A randomised controlled trial for the evaluation of risk for type 2 diabetes in hypertensive patients receiving thiazide diuretics: Diuretics In the Management of Essential hypertension (DIME) study. BMJ Open 2014;4:e004576 https://doi.org/10.1136/bmjopen-2013-004576.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158:741–51.

    Article  CAS  Google Scholar 

  26. Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension. 2000;36:1072–8.

    Article  CAS  Google Scholar 

  27. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens. 2000;18:1149–54.

    Article  CAS  Google Scholar 

  28. Jutabha P, Anzai N, Kitamura K, Taniguchi A, Kaneko S, Yan K, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem. 2010;285:35123–32.

    Article  CAS  Google Scholar 

  29. Vandell AG, McDonough CW, Gong Y, Langaee TY, Lucas AM, Chapman AB, et al. Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study. J Intern Med. 2014;276:486–97.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The GEANE study was supported by grants-in-aid from the Ministry of Health, Labor and Health. There is no conflict of interest for all authors in the GEANE study.

Author information

Authors and Affiliations

  1. Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, Osaka, Japan

    Yuko Ohta, Kei Kamide, Yoshio Iwashima, Fumiki Yoshihara, Takeshi Horio, Satoko Nakamura, Hajime Nakahama & Yuhei Kawano

  2. Department of General Internal Medicine, Kyushu Dental University, Fukuoka, Japan

    Yuko Ohta

  3. Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan

    Kei Kamide

  4. Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan

    Hironori Hanada & Toshiyuki Miyata

  5. Department of Geriatric Medicine, Kanazawa Medical University, Ishishikawa, Japan

    Shigeto Morimoto & Takeshi Nakahashi

  6. Department of Cardiology, Higashi-Takarazuka Satoh Hospital, Hyogo, Japan

    Shin Takiuchi

  7. Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Tochigi, Japan

    Toshihiko Ishimitsu

  8. Steel Memorial Yawata Hospital, Fukuoka, Japan

    Takuya Tsuchihashi

  9. Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    Masayoshi Soma

  10. Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    T. Tomohiro Katsuya, Ken Sugimoto & Hiromi Rakugi

  11. Department of Integrated Medicine and Informatics, University Graduate School of Medicine, Ehime, Japan

    Takafumi Oukura & Jitsuo Higaki

  12. Saiseikai Kure Hospital, Hiroshima, Japan

    Hideo Matsuura

  13. Japanese Red Cross Nagasaki Atomic Bomb Hospital, Nagasaki, Japan

    Tatsuo Shinagawa

  14. Departments of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Fukuoka, Japan

    Yosikazu Miwa & Toshiyuki Sasaguri

  15. Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan

    Michiya Igase & Tetsuro Miki

  16. Kyotokojohokenkai Hospital, Kyoto, Japan

    Kazuo Takeda

  17. Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Hokkaido, Japan

    Katsuhiro Higashiura & Kazuaki Shimamoto

  18. National Fukuoka-Higashi Medical Center, Fukuoka, Japan

    Ritsuko Katabuchi & Michio Ueno

  19. Department of Neurology, Hiroshima University Graduate School of Medicine, Hiroshima, Japan

    Naonaga Hosomi

  20. Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan

    Johji Kato

  21. Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan

    Norio Komai

  22. National Hospital Organization Shizuoka Medical Center, Shizuoka, Japan

    Shunichi Kojima

  23. Clinical Pharmacology, Juntendo University, Tokyo, Japan

    Kazuhiro Sase

Authors
  1. Yuko Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kei Kamide
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hironori Hanada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shigeto Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takeshi Nakahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shin Takiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshihiko Ishimitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takuya Tsuchihashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masayoshi Soma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T. Tomohiro Katsuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ken Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiromi Rakugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Takafumi Oukura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jitsuo Higaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hideo Matsuura
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tatsuo Shinagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yosikazu Miwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Toshiyuki Sasaguri
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Michiya Igase
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Tetsuro Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kazuo Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Katsuhiro Higashiura
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Kazuaki Shimamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Ritsuko Katabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Michio Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Naonaga Hosomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Johji Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Norio Komai
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Shunichi Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Kazuhiro Sase
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Yoshio Iwashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Fumiki Yoshihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Takeshi Horio
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Satoko Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Hajime Nakahama
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Toshiyuki Miyata
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Yuhei Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kei Kamide.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ohta, Y., Kamide, K., Hanada, H. et al. Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension. Hypertens Res 43, 220–226 (2020). https://doi.org/10.1038/s41440-019-0356-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-019-0356-x

Keywords

Search

Advanced search

Quick links