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Pharmacogenetics of Thiazide Diuretics: An Update on Inter-individual Variations

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Springer Science Reviews

Abstract

Hypertension is a common disorder, representing a leading cause of cardiovascular mortality worldwide. Thiazide diuretics, mainly hydrochlorothiazide, are among the most widely prescribed antihypertensive agents. Treatment with thiazide diuretics has reported large inter-individual differences in blood pressure (BP) responses, assuring the great need for pharmacogenetic studies. Over the past decade, significant advances have been made in the field of cardiovascular pharmacogenomics. This narrative review summarizes the current state of knowledge regarding the pharmacogenetic effects of thiazide diuretics on BP-lowering efficacy and safety. After performing a MEDLINE search, relevant literature was collected until September 2015, thus several inter-individual variations were highlighted. We provided clarity for single-nucleotide polymorphisms of genes that have been extensively studied relative to thiazide diuretics. Genetic polymorphisms in many candidate genes like alpha-adducin 1, G protein β3-subunit, subunit of sodium channel, and others were suggested to affect BP response and toxicity to thiazide diuretic therapy. Many inter-individual variations presented differences in efficacy and adverse events between different ethnicities and genders necessitating the tailoring of thiazide diuretic therapy and the targeting of new sites of action.

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References

  1. ALLHAT Collaborative Research Group (2002) Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Am Med Assoc. doi:10.1001/jama.288.23.2981

    Google Scholar 

  2. Arnett DK, Claas SA, Glasser SP (2006) Pharmacogenetics of antihypertensive treatment. Vasc Pharmacol. doi:10.1016/jvph.2005.09.010

    Google Scholar 

  3. Bozec E, Fassot C, Tropeano AI, Boutouyrie P, Jeunemaitre X, Lacolley P, Dabire H (2003) Angiotensinogen gene M235T polymorphism and reduction in wall thickness in response to antihypertensive treatment. Clin Sci 105(5):637

    Article  CAS  PubMed  Google Scholar 

  4. Bozkurt O, de Boer A, Grobbee DE, de Leeuw PW, Kroon AA, Schiffers P (2009) Variation in renin–angiotensin system and salt-sensitivity genes and the risk of diabetes mellitus associated with the use of thiazide diuretics. Am J Hypertens 22:545–551

    Article  CAS  PubMed  Google Scholar 

  5. Chobanian AV, Bakris GL, Black HR (2003) The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289(19):2560–2572. doi:10.1161/01.HYP.0000107251.49515.c2

    Article  CAS  PubMed  Google Scholar 

  6. Conway J, Lauwers P (1960) Hemodynamic and hypotensive effects of long term therapy with chlorothiazide. Circulation 21:21

    Article  CAS  PubMed  Google Scholar 

  7. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, Glorioso N, Lanzani C, Manunta P, Righetti M, Rivera R, Stella P, Troffa C, Zagato L, Bianchi G (1997) Polymorphisms of α-adducin and salt sensitivity in patients with essential hypertension. Lancet 349:1353–1357

    Article  CAS  PubMed  Google Scholar 

  8. Del-Aguila JL, Beitelshees AL, Cooper-DeHoff RM, Chapman AB, Gums JG, Bailey K, Gong Y, Turner ST, Johnson JA, Boerwinkle E (2014) Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. The. Pharmacogenomics. doi:10.1038/tpj.2013.3

    Google Scholar 

  9. Del-Aguila JL, Cooper-DeHoff RM, Chapman AB, Gums JG, Beitelshees AL, Bailey K, Turner ST, Johnson JA, Boerwinkle E (2014) Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide. Pharmacogenomics. doi:10.1038/tpj.2014.46

    Google Scholar 

  10. Duarte J, Cooper-DeHoff RM (2010) Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide- like diuretics. Expert Rev Cardiovasc Ther. doi:10.1586/erc.10.27

    PubMed  PubMed Central  Google Scholar 

  11. Duarte JD, Turner ST, Tran B, Chapman AB, Bailey KR, Gong Y, Gums JG, Langaee TY, Beitelshees AL, Cooper-Dehoff RM, Boerwinkle E, Johnson JA (2013) Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression. Pharmacogenomics J. doi:10.1038/tpj.2012.4

    PubMed  Google Scholar 

  12. Duarte JD, Zineh I, Burkley I, Gong Y, Langaee TY, Turner ST, Chapman AB, Boerwinkle E, Gums JG, Cooper-DeHoff RM, Beitelshees AL, Bailey KR, Fillingim RB, Kone BC, Johnson JA (2012) Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide. J Transl Med. doi:10.1186/1479-5876-10-56

    PubMed  PubMed Central  Google Scholar 

  13. Dunn DM, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt SC, Leppert MF, Lalouel JM, Weiss RB (2002) Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. J Hum Genet 47:665–676

    Article  CAS  PubMed  Google Scholar 

  14. Elliott WJ, Meyer PM (2007) Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 369(9557):201–207

    Article  CAS  PubMed  Google Scholar 

  15. Eriksson JW, Jansson PA, Carlberg B, Hagg A, Kurland L, Svensson MK (2008) Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study. Hypertension 52:1030–1037

    Article  CAS  PubMed  Google Scholar 

  16. Fontana V, Luizon MR, Sandrim VC (2014) An update on the pharmacogenetics of treating hypertension. J Hum Hypertens. doi:10.1038/jhh.2014.76

    Google Scholar 

  17. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW (2007) A second-generation human haplotype map of over 3.1 million SNPs. Nature 449(7164):851–861

    Article  CAS  PubMed  Google Scholar 

  18. Frazier L, Turner ST, Schwartz GL, Chapman AB, Boerwinkle E (2004) Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic. Pharmacogenomics J. doi:10.1038/sj.tpj.6500215

    PubMed  Google Scholar 

  19. Freis ED (1962) Veterans Administration Cooperative Study on Antihypertensive Agents. Double blind control study of antihypertensive agents: III. Chlorothiazide alone and in combination with other agents; preliminary results. Arch Intern Med 110:230–236

    Article  CAS  Google Scholar 

  20. Gamba G (2009) The thiazide-sensitive Na+-Cl− cotransporter: molecular biology, functional properties, and regulation by WNKs. Am J Physiol Renal Physiol 297:F838–F848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gerhard T, Gong Y, Beitelshees AL (2008) Alpha-adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: results from genetic sub study of the international verapamil SR-trandolapril study (INVEST-GENES). Am Heart J 156(2):397–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gorden P (1973) Glucose intolerance with hypokalemia. Failure of short-term potassium depletion in normal subjects to reproduce the glucose and insulin abnormalities of clinical hypokalemia. Diabetes 22:544–551

    Article  CAS  PubMed  Google Scholar 

  23. Hajjar I, Kotchen TA (2003) Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 290(2):199–206

    Article  PubMed  Google Scholar 

  24. Hughes CA, Bennett V (1995) Adducin: a physical model with implications for function in assembly of spectrin-actin complexes. J Biol Chem 270:18990–18996

    Article  CAS  PubMed  Google Scholar 

  25. Irvin MR, Lynch AI, Kabagambe EK (2010) Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study. J Hypertens 28(10):2076–2083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E (2014) 2014 Evidence-based guideline for the management of high blood pressure in adults report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311(5):507–520. doi:10.1001/jama.2013.284427

    Article  CAS  PubMed  Google Scholar 

  27. Johnson JA (2012) Advancing management of hypertension through pharmacogenomics. Ann Med 44(Suppl 1):S17–S22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M (2012) Kegg for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. doi:10.1093/nar/gkr988

    Google Scholar 

  29. Khullar M, Sharma S (2012) Pharmacogenetics of essential hypertension. In: Khullar M (ed) Genetics and pathophysiology of essential hypertension. InTech. ISBN: 978-953-51-0282-3

  30. Kone BC (2013) Epigenetics and the control of the collecting duct epithelial sodium channel. Semin Nephrol. doi:10.1016/j.semnephrol.2013.05.010

    PubMed  PubMed Central  Google Scholar 

  31. Laragh JH, Sealey JE (2011) The plasma renin test reveals the contribution of body sodium-volume content (V) and renin-angiotensin ® vasoconstriction to long-term blood pressure. Am J Hypertens 24:1164–1180

    Article  CAS  PubMed  Google Scholar 

  32. Laragh JH, Lamport B, Sealey J, Alderman MH (1988) Individual response patterns to drugs reveal hypertension mechanisms and simplify treatment. Hypertension 12:223–226

    Article  CAS  PubMed  Google Scholar 

  33. Liamis G, Milionis H, Elisaf M (2008) Blood pressure drug therapy and electrolyte disturbances. Int J Clin Pract 62:1572–1580

    Article  CAS  PubMed  Google Scholar 

  34. Lifton RP, Gharavi AG, Geller DS (2001) Molecular mechanisms of human hypertension. Cell 104:545–556

    Article  CAS  PubMed  Google Scholar 

  35. Lindpaintner K (2003) Pharmacogenetics and the future of medical practice. J Mol Med (Berl) 81(3):141–153

    Google Scholar 

  36. Liu J, Liu ZQ, Yu BN, Xu FH, Mo W, Zhou G, Liu YZ (2006) β1-adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin Pharmacol Ther 80(1):23–32

    Article  CAS  PubMed  Google Scholar 

  37. Luo F, Wang Y, Wang X, Sun K, Zhou X, Hui R (2009) A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension. Hypertension 54(4):796–801

    Article  CAS  PubMed  Google Scholar 

  38. Ma Q, Lu A (2011) Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev 63(437–459):2011

    Google Scholar 

  39. Manunta P, Cusi D, Barlassina C (1998) Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients. Kidney Int 53(6):1471–1478

    Article  CAS  PubMed  Google Scholar 

  40. Matsuoka Y, Hughes CA, Bennett V (1996) Definition of the calmodulin-binding domain and sites of phosphorylation by protein kinases A and C. J Biol Chem 271:25157–25166

    Article  CAS  PubMed  Google Scholar 

  41. McDonough C, Burbage S, Duarte J, Gong Y, Langaee T, Turner S, Gums J, Chapman A, Bailey K, Beitelshees A, Boerwinkle E, Pepine C, Cooper-DeHoff R, Johnson J (2013) Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics. J Hypertens. doi:10.1097/HJH.0b013e32835e2a71

    PubMed  PubMed Central  Google Scholar 

  42. Meissner I, Whisnant JP, Sheps SG, Schwartz GL, O’Fallon WM, Covalt JL, Sicks JD, Bailey KR, Wiebers DO (1999) Detection and control of high blood pressure in the community: do we need a wake-up call? Hypertension 34:466–471. doi:10.1161/01.HYP.34.3.466

    Article  CAS  PubMed  Google Scholar 

  43. Nordestgaard BG, Kontula K, Benn M, Dahlf B, de Faire U, Edelman JM, Eliasson E (2010) Effect of ACE insertion/deletion and 12 other polymorphisms on clinical outcomes and response to treatment in the LIFE study. Pharmacogenet Genom 20(2):77–85. doi:10.1097/FPC.0b013e328333f70b

    Article  CAS  Google Scholar 

  44. Pasty BM, Smith NL, Heckbert SR, Vos HL, Lemaitre RN, Reiner AP, Siscovick DS, Lumley T, JrWT Longstreth, Rosendaal FR (2002) Diuretic therapy, the alpha-adducin gene variant, the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA 287(13):1680–1689

    Article  Google Scholar 

  45. Piatkov I, Jones T, Mclean M (2000) Drug interactions, pharmacogenomics and cardiovascular complication. doi:10.5772/48423

  46. Province MA, Arnett DK, Hunt SC, Leiendecker-Foster C, Eckfeldt JH, Oberman A, Ellison RC, Heiss G, Mockrin SC, Williams RR (2000) Association between the a-adducin gene and hypertension in the HyperGEN Study. Am J Hypertens 13:710–718

    Article  CAS  PubMed  Google Scholar 

  47. Rowe JW, Tobin JD, Rosa RM, Andres R (1980) Effect of experimental potassium deficiency on glucose and insulin metabolism. Metabolism 29:498–502

    Article  CAS  PubMed  Google Scholar 

  48. Schelleman H, Klungel OH, Witteman JCM, Breteler MMB, Hofman A, van Duijn CM, Boer A, Stricker BHCh (2007) Diuretic–gene interaction and the risk of myocardial infarction and stroke. Pharmacogenomics J. doi:10.1038/sj.tpj.6500428

    PubMed  Google Scholar 

  49. Schelleman H, Stricker BHch, Vershuren WMM, Boer A, Kroon A, Leeuw PW, Kromhout D, Klungel OH (2006) Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. Pharmacogenomics J 6:22–26. doi:10.1038/sj.tpj.6500339

    Article  CAS  PubMed  Google Scholar 

  50. Schelleman H, Klungel OH, Witteman JCM, Breteler MMB, Yazdanpanah M, Danser AHJ, Hofman A (2007) Angiotensinogen M235T polymorphism and the risk of myocardial infarction and stroke among hypertensive patients on ACE-inhibitors or beta-blockers. Eur J Hum Genet 15(4):478–484

    Article  CAS  PubMed  Google Scholar 

  51. Sciarrone MT, Stella P, Barlassina C, Manunta P, Lanzani C, Bianchi G, Cusi D (2003) ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension. doi:10.1161/01.HYP.0000057010.27011.2C

    PubMed  Google Scholar 

  52. Sethi AA, Nordestgaard BG, Agerholm-Larsen B, Frandsen E, Jensen G, Tybjaerg-Hansen A (2001) Angiotensinogen polymorphisms and elevated blood pressure in the general population the Copenhagen City Heart Study. Hypertension 37:875–881

    Article  CAS  PubMed  Google Scholar 

  53. Shafi T, Appel LJ, Miller ER III, Klag MJ, Parekh RS (2008) Changes in serum potassium mediate thiazide-induced diabetes. Hypertension 52:1022–1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sidawy AN, Sumpio BE, DePalma RG (1997) The basic science of vascular biology. Futura Publishing Company Inc, Armonk

    Google Scholar 

  55. Su X, Lee L, Li X, Lv J, Hu Y, Zhan S, Cao W (2007) Association between angiotensinogen, angiotensin II receptor genes, and blood pressure response to an angiotensin-converting enzyme inhibitor. Circulation 115(6):725–732. doi:10.1161/CIRCULATIONAHA.106.642058

    Article  CAS  PubMed  Google Scholar 

  56. Suonsyrjä T, Hannila-Handelberg T, Fodstad H (2009) Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study. Am J Hypertens 22(2):169–175. doi:10.1038/ajh.2008.343

    Article  PubMed  Google Scholar 

  57. Svensson-Farbom P, Wahlstrand B, Almgren P (2011) A functional variant of the NEDD4L gene is associated with beneficial treatment response with beta-blockers and diuretics in hypertensive patients. J Hypertens 29(2):388–395. doi:10.1097/HJH.0b013e3283410390

    Article  PubMed  Google Scholar 

  58. Thoenes M, Neuberger H-R, Volpe M, Khan BV, Kirch W, Böhm M (2010) Antihypertensive drug therapy and blood pressure control in men and women: an international perspective. J Hum Hypertens 24:336–344. doi:10.1038/jhh.2009.76

    Article  CAS  PubMed  Google Scholar 

  59. Tripodi G, Valtorta F, Torielli L (1996) Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 97:2815–2822. doi:10.1172/JCI118737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Turner ST, Bailey KR, Fridley BL, Chapman AB, Schwartz GL, Chai HS (2008) Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension 52(2):359–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Turner ST, Boerwinkle E, O’Connell JR, Bailey KR, Gong Y, Chapman AB, McDonough CW, Beitelshees AL, Schwartz GL, Gums JG, Padmanabhan S, Hiltunen TP, Citterio L, Donner KM, Hedner T, Lanzani C, Melander O, Saarela J, Ripatti S, Wahlstrand B, Manunta P, Kontula K, Dominiczak AF, Cooper-DeHoff RM, Johnson JA (2013) Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension 62:391–397. doi:10.1161/HYPERTENSIONAHA.111.00436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E (2005) WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension. 36:758–765. doi:10.1161/01.HYP.0000186240.81996.57

    Article  Google Scholar 

  63. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E (2001) C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension 37(2 part 2):739–743. doi:10.1038/ajh.2010.98

    Article  CAS  PubMed  Google Scholar 

  64. Vandel AG, McDonough CW, Gong Y, Langaee TY, Lucas AM, Chapman AB, Gums JG, Beitelshees AL, Bailey KR, Johnson RJ, Boerwinkle E, Turner ST, Cooper-DeHoff RM, Johnson JA (2014) Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study. J Intern Med. doi:10.1111/joim.12215

    Google Scholar 

  65. Wang YL, Liang HY, Gao YH, Wu XJ, Chen X, Pan BY, Yang XX, Liu HZ (2013) A functional variant of NEDD4L is associated with obesity and related phenotypes in a Han population of Southern China. Int J Mol Sci. doi:10.3390/ijms14047433

    Google Scholar 

  66. Xiao X, Du HJ, Hu WJ, Shaw P (2013) The influence of long term hydrochlorothiazide administration on the relationship between renin-angiotensin-aldosterone system activity and plasma glucose in patients with hypertension. Oxid Med Cell Longev. doi:10.1155/2013/434618

    Google Scholar 

Useful Internet Resources and Databases

  1. FDA: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics

  2. FDA: Table of Pharmacogenomic Biomarkers in Drug Labels: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

  3. NCBI, Individual SNP information, such as genetic location, nucleotide and amino acid changes, and allele frequencies in diverse populations, can be obtained from dbSNP: www.ncbi.nlm.nih.gov/sites/entrez?db=snp

  4. PharmGKB (The Pharmacogenetics and Pharmacogenomics Knowledge Base): www.pharmgkb.org/#public

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  1. Pharmacology and Therapeutics Department, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon

    Safaa Hammoud & Asser Ghoneim

  2. Faculty of Pharmacy, Damanhour University, Damanhour, Egypt

    Asser Ghoneim

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  1. Safaa Hammoud
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Correspondence to Safaa Hammoud.

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Hammoud, S., Ghoneim, A. Pharmacogenetics of Thiazide Diuretics: An Update on Inter-individual Variations. Springer Science Reviews 4, 15–23 (2016). https://doi.org/10.1007/s40362-016-0038-x

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