Genetics of Resistant Hypertension: a Novel Pharmacogenomics Phenotype

Current Hypertension Reports

Volumn 17, Issue 9, 2015, Pages

  El Rouby, Nihal ^a   Cooper DeHoff, Rhonda M ^a,b  

^a UNIVERSITY OF FLORIDA   (United States)

^b UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Aldosterone; Blood pressure; Pharmacogenomics; Resistant hypertension

Indexed keywords

ALDOSTERONE; ALDOSTERONE SYNTHASE; ALPHA ADDUCIN; AMILORIDE; CYTOCHROME P450 4A11; DIURETIC AGENT; ENDOTHELIAL NITRIC OXIDE SYNTHASE; EPITHELIAL SODIUM CHANNEL; GUANINE NUCLEOTIDE BINDING PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN BETA POLYPEPTIDE 3; HYDROCHLOROTHIAZIDE; ISOSORBIDE MONONITRATE; MINERALOCORTICOID ANTAGONIST; NEURAL PRECURSOR CELL EXPRESSED DEVELOPMENTALLY DOWNREGULATED 4 LIKE PROTEIN; PHOSPHODIESTERASE V INHIBITOR; PLACEBO; SILDENAFIL; SPIRONOLACTONE; THIAZIDE DIURETIC AGENT; UBIQUITIN PROTEIN LIGASE; UNCLASSIFIED DRUG; ANTIHYPERTENSIVE AGENT;

BLOOD PRESSURE REGULATION; DRUG EFFICACY; ENDOTHELIAL DYSFUNCTION; GENETIC ASSOCIATION; GENETIC VARIABILITY; HORMONE ACTION; HUMAN; HYPERALDOSTERONISM; OUTCOME ASSESSMENT; PATHOPHYSIOLOGY; PHARMACOGENETICS; PHARMACOGENOMICS; PHENOTYPE; PLURIPOTENT STEM CELL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RESISTANT HYPERTENSION; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SODIUM METABOLISM; SODIUM RESTRICTION; TREATMENT DURATION; TREATMENT RESPONSE; VASCULITIS; BLOOD PRESSURE; DRUG EFFECTS; GENETICS; HYPERTENSION; PROCEDURES;

ANTIHYPERTENSIVE AGENTS; BLOOD PRESSURE; GENETIC VARIATION; HUMANS; HYPERTENSION; PHARMACOGENETICS; PHENOTYPE;

EID: 84937855028     PISSN: 15226417     EISSN: 15343111     Source Type: Journal    
DOI: 10.1007/s11906-015-0583-8     Document Type: Review

References (94)

1. Nwankwo S, Yoon S, Burt V, Gu Q. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011–2012. NCHS Data Brief. 2013;133:1–8.
2. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M. Executive summary: Heart Disease and Stroke Statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):434–41.
3. Joffres M, Falaschetti E, Gillespie C, Robitaille C, Loustalot F, Poulter N, et al. Hypertension prevalence, awareness, treatment and control in national surveys from England, the USA and Canada, and correlation with stroke and ischaemic heart disease mortality: a cross-sectional study. BMJ Open. 2013;3(8):e003423.
4. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510–26.
5. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002;40(6):892–6.
6. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159–64.
7. Oliva RV, Bakris GL. Sympathetic activation in resistant hypertension: theory and therapy. Semin Nephrol. 2014;34(5):550–9.
8. Tsioufis C, Kordalis A, Flessas D, Anastasopoulos I, Tsiachris D, Papademetriou V, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens. 2011;2011:642416.
9. R. Modolo, A. P. de Faria, and H. Moreno, “Resistant hypertension: a volemic or nervous matter?” J. Am. Soc. Hypertens., Feb. 2015.
10. N. R. Barbaro, V. Fontana, R. Modolo, A. P. De Faria, A. R. Sabbatini, F. H. Fonseca, G. F. Anhê, and H. Moreno, “Increased arterial stiffness in resistant hypertension is associated with inflammatory biomarkers.,” Blood Press., pp. 1–7, Jul. 2014.
11. Salles GF, Fiszman R, Cardoso CRL, Muxfeldt ES. Relation of left ventricular hypertrophy with systemic inflammation and endothelial damage in resistant hypertension. Hypertension. 2007;50(4):723–8.
12. A. Whaley-Connell, M. S. Johnson, and J. R. Sowers, “Aldosterone: role in the cardiometabolic syndrome and resistant hypertension.,” Prog. Cardiovasc. Dis., vol. 52, no. 5, pp. 401–9, Jan.
13. Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside. Nat Rev Drug Discov. 2004;3(9):739–48.
14. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348(6):529–37.
15. Duarte JD, Turner ST, Tran B, Chapman AB, Bailey KR, Gong Y, et al. Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression. Pharmacogenom J. 2013;13(3):257–63.
16. Turner ST, Bailey KR, Schwartz GL, Chapman AB, Chai HS, Boerwinkle E. Genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker. Hypertension. 2012;59(6):1204–11.
17. Gong Y, McDonough CW, Wang Z, Hou W, Cooper-DeHoff RM, Langaee TY, et al. Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study. Circ Cardiovasc Genet. 2012;5(6):686–91.
18. Turner ST, Boerwinkle E, O’Connell JR, Bailey KR, Gong Y, Chapman AB, et al. Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension. 2013;62(2):391–7.
19. Hiltunen TP, Donner KM, Sarin A-P, Saarela J, Ripatti S, Chapman AB, et al. Pharmacogenomics of hypertension: a genome-wide, placebo-controlled cross-over study, using four classes of antihypertensive drugs. J Am Heart Assoc. 2015;4(1):e001521.
20. Bubien JK. Epithelial Na+ channel (ENaC), hormones, and hypertension. J Biol Chem. 2010;285(31):23527–31.
21. Studer RA, Person E, Robinson-Rechavi M, Rossier BC. Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport. Physiol Genomics. 2011;43(13):844–54.
22. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150(11):776–83.
23. Hummler E. Epithelial sodium channel, salt intake, and hypertension. Curr Hypertens Rep. 2003;5(1):11–8.
24. Garty H, Palmer LG. Epithelial sodium channels: function, structure, and regulation. Physiol Rev. 1997;77(2):359–96.
25. Rayner BL, Owen EP, King JA, Soule SG, Vreede H, Opie LH, et al. A new mutation, R563Q, of the beta subunit of the epithelial sodium channel associated with low-renin, low-aldosterone hypertension. J Hypertens. 2003;21(5):921–6.
26. Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens. 2004;22(11):2217–26.
27. Spence JD. Physiologic tailoring of treatment in resistant hypertension. Curr Cardiol Rev. 2010;6(2):119–23.
28. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003;16(11 Pt 1):925–30.
29. Ori Y, Chagnac A, Korzets A, Zingerman B, Herman-Edelstein M, Bergman M, et al. Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone. Nephrol Dial Transplant. 2013;28(7):1787–93.
30. Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens. 2013;31(10):2094–102.
31. Spence JD. Lessons from Africa: the importance of measuring plasma renin and aldosterone in resistant hypertension. Can J Cardiol. 2012;28(3):254–7.
32. Jones ESW, Owen EP, Rayner BL. The association of the R563Q genotype of the ENaC with phenotypic variation in Southern Africa. Am J Hypertens. 2012;25(12):1286–91.
33. Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, et al. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol Endocrinol. 2013;27(2):315–24.
34. Alvarez-Madrazo S, Mackenzie SM, Davies E, Fraser R, Lee W-K, Brown M, et al. Common polymorphisms in the CYP11B1 and CYP11B2 genes: evidence for a digenic influence on hypertension. Hypertension. 2013;61(1):232–9.
35. Fontana V, de Faria APC, Barbaro NR, Sabbatini AR, Modolo R, Lacchini R, et al. Modulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension. J Am Soc Hypertens. 2014;8(3):146–51.
36. Ubaid-Girioli S, de Souza LA, Yugar-Toledo JC, Cláudio Martins L, Ferreira-Melo S, Rizzi Coelho O, et al. Aldosterone excess or escape: treating resistant hypertension. J Clin Hypertens. 2009;11(5):245–52.
37. Zordoky BNM, El-Kadi AOS. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol Ther. 2010;125(3):446–63.
38. Laffer CL, Elijovich F, Eckert GJ, Tu W, Pratt JH, Brown NJ. Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans. J Am Soc Hypertens. 2014;8(7):475–80. A recent research evaluating the effect of variants in CYP4A11 on the effectiveness of spironolactone and amiloride.
39. Kumar N, Calhoun DA, Dudenbostel T. Management of patients with resistant hypertension: current treatment options. Integr Blood Press Control. 2013;6:139–51.
40. Vongpatanasin W. Resistant hypertension. JAMA. 2014;311(21):2216.
41. Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell’Italia LJ, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension. 2009;54(3):475–81.
42. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, et al. Comprehensive physiology, vol. 2, no. 4. Hoboken: Wiley; 2012.
43. Armando I, Villar VAM, Jose PA. Genomics and pharmacogenomics of salt-sensitive hypertension. Curr Hypertens Rev. 2015;11(1):49–56.
44. Sanada H, Jones JE, Jose PA. Genetics of salt-sensitive hypertension. Curr Hypertens Rep. 2010;13(1):55–66.
45. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet (London, England). 1997;349(9062):1353–7.
46. Kelly TN, Rice TK, Gu D, Hixson JE, Chen J, Liu D, et al. Novel genetic variants in the alpha-adducin and guanine nucleotide binding protein beta-polypeptide 3 genes and salt sensitivity of blood pressure. Am J Hypertens. 2009;22(9):985–92.
47. Schunkert H, Hense HW, Döring A, Riegger GA, Siffert W. Association between a polymorphism in the G protein beta3 subunit gene and lower renin and elevated diastolic blood pressure levels. Hypertension. 1998;32(3):510–3.
48. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. C825T polymorphism of the G protein 3-subunit and antihypertensive response to a thiazide diuretic. Hypertension. 2001;37(2):739–43.
49. Schelleman H, Stricker BHC, Verschuren WMM, de Boer A, Kroon AA, de Leeuw PW, et al. Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. Pharmacogenom J. 2005;6(1):22–6.
50. Y. Gong, C. W. Mcdonough, S. Padmanabhan, and J. A. Johnson, Handbook of pharmacogenomics and stratified medicine. Elsevier, 2014.
51. Dahlberg J, Nilsson LO, von Wowern F, Melander O. Polymorphism in NEDD4L is associated with increased salt sensitivity, reduced levels of P-renin and increased levels of Nt-proANP. PLoS One. 2007;2(5):e432.
52. Svensson-Färbom P, Wahlstrand B, Almgren P, Dahlberg J, Fava C, Kjeldsen S, et al. A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients. J Hypertens. 2011;29(2):388–95.
53. McDonough CW, Burbage SE, Duarte JD, Gong Y, Langaee TY, Turner ST, et al. Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics. J Hypertens. 2013;31(4):698–704.
54. J. C. Yugar-Toledo, J. F. V. Martin, J. E. Krieger, A. C. Pereira, C. Demacq, O. R. Coelho, E. Pimenta, D. A. Calhoun, and H. M. Júnior, “Gene variation in resistant hypertension: multilocus analysis of the angiotensin 1-converting enzyme, angiotensinogen, and endothelial nitric oxide synthase genes,” Jul. 2011.
55. Sandrim VC, de Syllos RWC, Lisboa HRK, Tres GS, Tanus-Santos JE. Influence of eNOS haplotypes on the plasma nitric oxide products concentrations in hypertensive and type 2 diabetes mellitus patients. Nitric Oxide. 2007;16(3):348–55.
56. Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (Greenwich). 2012;14(4):198–205.
57. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol. 1997;17(11):2479–88.
58. Ballinger SW, Patterson C, Yan C-N, Doan R, Burow DL, Young CG, et al. Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ Res. 2000;86(9):960–6.
59. Oliveira-Paula GH, Lacchini R, Coeli-Lacchini FB, Junior HM, Tanus-Santos JE. Inducible nitric oxide synthase haplotype associated with hypertension and responsiveness to antihypertensive drug therapy. Gene. 2013;515(2):391–5.
60. Wang SS, Davis S, Cerhan JR, Hartge P, Severson RK, Cozen W, et al. Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma. Carcinogenesis. 2006;27(9):1828–34.
61. Kaise M, Miwa J, Suzuki N, Mishiro S, Ohta Y, Yamasaki T, et al. Inducible nitric oxide synthase gene promoter polymorphism is associated with increased gastric mRNA expression of inducible nitric oxide synthase and increased risk of gastric carcinoma. Eur J Gastroenterol Hepatol. 2007;19(2):139–45.
62. Fu L, Zhao Y, Lu J, Shi J, Li C, Liu H, et al. Functional single nucleotide polymorphism-1026C/A of inducible nitric oxide synthase gene with increased YY1-binding affinity is associated with hypertension in a Chinese Han population. J Hypertens. 2009;27(5):991–1000.
63. Li W, Liu H, Fu L, Li D, Zhao Y. Identification of Yin Yang 1-interacting partners at -1026C/A in the human iNOS promoter. Arch Biochem Biophys. 2010;498(2):119–26.
64. Brown KE, Dhaun N, Goddard J, Webb DJ. Potential therapeutic role of phosphodiesterase type 5 inhibition in hypertension and chronic kidney disease. Hypertension. 2014;63(1):5–11.
65. Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase type 5 inhibition in hypertension. Hypertension. 2006;48(4):622–7.
66. Oliver JJ, Hughes VEC, Dear JW, Webb DJ. Clinical potential of combined organic nitrate and phosphodiesterase type 5 inhibitor in treatment-resistant hypertension. Hypertension. 2010;56(1):62–7.
67. Safarinejad MR, Khoshdel A, Shekarchi B, Taghva A, Safarinejad S. Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects. BJU Int. 2011;107(12):1994–2001.
68. Sinici I, Güven EO, Serefoğlu E, Hayran M. T-786C polymorphism in promoter of eNOS gene as genetic risk factor in patients with erectile dysfunction in Turkish population. Urology. 2010;75(4):955–60.
69. H. Rosas-Vargas, R. M. Coral-Vazquez, R. Tapia, J. L. Borja, R. A. Salas, and F. Salamanca, “Glu298Asp endothelial nitric oxide synthase polymorphism is a risk factor for erectile dysfunction in the Mexican Mestizo population.,” J. Androl., vol. 25, no. 5, pp. 728–32, Jan.
70. Lee Y-C, Wu W-J, Liu C-C, Wang C-J, Li W-M, Huang C-H, et al. The associations among eNOS G894T gene polymorphism, erectile dysfunction, and benign prostate hyperplasia-related lower urinary tract symptoms. J Sex Med. 2009;6(11):3158–65.
71. Metzger IF, Sertório JTC, Tanus-Santos JE. Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes. Free Radic Biol Med. 2007;43(6):987–92.
72. Metzger IF, Ishizawa MH, Rios-Santos F, Carvalho WA, Tanus-Santos JE. Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenom J. 2011;11(6):393–9.
73. Metzger IF, Souza-Costa DC, Marroni AS, Nagassaki S, Desta Z, Flockhart DA, et al. Endothelial nitric oxide synthase gene haplotypes associated with circulating concentrations of nitric oxide products in healthy men. Pharmacogenet Genomics. 2005;15(8):565–70.
74. Souza-Costa DC, Belo VA, Silva PS, Metzger IF, Lanna CM, Machado MA, et al. eNOS haplotype associated with hypertension in obese children and adolescents. Int J Obes. 2010;35(3):387–92.
75. Miyamoto Y, Saito Y, Nakayama M, Shimasaki Y, Yoshimura T, Yoshimura M, et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786TC mutation associated with coronary spastic angina. Hum Mol Genet. 2000;9(18):2629–37.
76. Quinaglia T, de Faria APC, Fontana V, Barbaro NR, Sabbatini AR, Sertório JT, et al. Acute cardiac and hemodynamic effects of sildenafil on resistant hypertension. Eur J Clin Pharmacol. 2013;69(12):2027–36.
77. Lynch AI, Irvin MR, Davis BR, Ford CE, Eckfeldt JH, Arnett DK. Genetic and adverse health outcome associations with treatment resistant hypertension in GenHAT. Int J Hypertens. 2013;2013:578578. A recent analysis from the Genetics of Hypertension Associated Treatment Study assessing the association of 78 candidate gene polymorphism with RHTN.
78. D. Arnett, E. Boerwinkle, and B. Davis, “Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study,” …, 2002.
79. B. Davis, J. Cutler, and D. Gordon, “Rationale and design for the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT),” Am. J. …, 1996.
80. Barbaro NR, Fontana V, Moreno H. Angiotensinogen variants among resistant hypertensive patients. Int J Hypertens. 2014;2014:424793.
81. Fontana V, McDonough CW, Gong Y, El Rouby NM, Sá ACC, Taylor KD, et al. Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension. J Am Heart Assoc. 2014;3:6. An analysis from the INVEST-Genetic substudy assessing the association of approximately 50,000 SNPs in genes implicated in CV, metabolic and inflammatory processes with RHTN in 1,714 participants.
82. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al. A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21):2805–16.
83. Smith SM, Gong Y, Handberg E, Messerli FH, Bakris GL, Ahmed A, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32(3):635–43.
84. C. Merz and S. Kelsey, “The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report,” J. …, 1999.
85. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A. Nat Genet. 2009;41(6):677–87.
86. Ganesh SK, Tragante V, Guo W, Guo Y, Lanktree MB, Smith EN. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum Mol Genet. 2013;22(8):1663–78.
87. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449(7164):851–61.
88. Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65.
89. Krieger EM, Drager LF, Giorgi DMA, Krieger JE, Pereira AC, Barreto-Filho JAS, et al. Resistant hypertension optimal treatment trial: a randomized controlled trial. Clin Cardiol. 2014;37(1):1–6.
90. Gupta AK, Nasothimiou EG, Chang CL, Sever PS, Dahlöf B, Poulter NR. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens. 2011;29(10):2004–13.
91. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators. J Hypertens. 2001;19(6):1139–47.
92. McCarthy JJ, McLeod HL, Ginsburg GS. Genomic medicine: a decade of successes, challenges, and opportunities. Sci Transl Med. 2013;5(189):189sr4.
93. Hankowski KE, Hamazaki T, Umezawa A, Terada N. Induced pluripotent stem cells as a next-generation biomedical interface. Lab Invest. 2011;91(7):972–7.
94. Zhu H, Lensch MW, Cahan P, Daley GQ. Investigating monogenic and complex diseases with pluripotent stem cells. Nat Rev Genet. 2011;12(4):266–75.