Personalized Therapy of Hypertension: the Past and the Future

Current Hypertension Reports

Volumn 18, Issue 3, 2016, Pages 1-11

  Manunta, Paolo ^a   Ferrandi, Mara ^b   Cusi, Daniele ^c   Ferrari, Patrizia ^b   Staessen, Jan ^d,e   Bianchi, Giuseppe ^a,b  

^a VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^b CVie Therapeutics Limited   (Taiwan)

^c INSTITUTE OF BIOMEDICAL TECHNOLOGIES   (Italy)

^d UNIVERSITY OF LEUVEN   (Belgium)

^e MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

Adducin; Candidate gene; Endogenous ouabain; Genetics; GWAS; Hypertension; Kidney cross transplantation; Personalized therapy; Pharmacogenomics; Rostafuroxin

Indexed keywords

ADDUCIN; ANTIHYPERTENSIVE AGENT; DIURETIC AGENT; OUABAIN; ROSTAFUROXIN; SODIUM;

ESSENTIAL HYPERTENSION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC CODE; GENETIC VARIABILITY; GENETICS; HEREDITARY HYPERTENSION; HUMAN; HYPERTENSION; MOLECULAR MECHANICS; PERSONALIZED MEDICINE; PHARMACOGENOMICS; REVIEW; ANIMAL; GENETIC SCREENING; METABOLISM;

ANIMALS; ANTIHYPERTENSIVE AGENTS; GENETIC TESTING; HUMANS; HYPERTENSION; PRECISION MEDICINE; SODIUM;

EID: 84979619687     PISSN: 15226417     EISSN: 15343111     Source Type: Journal    
DOI: 10.1007/s11906-016-0632-y     Document Type: Review

References (148)

1. Polanyi M. Science, faith, and society. London: Oxford University Press; 1946.
2. Arwood MJ, Cavallari LH, Duarte JD. Pharmacogenomics of hypertension and heart disease. Curr Hypertens Rep. 2015;17:586.
3. Fontana V, Luizon MR, Sandrim VC. An update on the pharmacogenetics of treating hypertension. J Hum Hypertens. 2015;29:283–91.
4. El Rouby N, Cooper-DeHoff RM. Genetics of resistant hypertension: a novel pharmacogenomics henotype. Curr Hypertens Rep. 2015;17:583.
5. Franceschini N, Chasman DI, Cooper-DeHoff RM, Arnett DK. Genetics, ancestry, and hypertension: implications for targeted antihypertensive therapies. Curr Hypertens Rep. 2014;16:461.
6. Manunta P, Lavery G, Lanzani C, et al. Physiological interaction between alpha-adducin and WNK1-NEDD4L pathways on sodium-related blood pressure regulation. Hypertension. 2008;52:366–72.
7. Kurtz TW. Genome-wide association studies will unlock the genetic basis of hypertension: con side of the argument. Hypertension. 2010;56:1021–5.
8. Ganesh SK, Chasman DI, Larson MG, et al. Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. Am J Hum Genet. 2014;95:49–65. An association with blood pressure is found for these loci in 49,626 individuals of European ancestry.
9. Tragante V, Barnes MR, Ganesh SK, et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet. 2014;94:349–60.
10. Natekar A, Olds RL, Lau MW, et al. Elevated blood pressure: our family’s fault? The genetics of essential hypertension. World J Cardiol. 2014;6:327–37. A comprehensive review on genetic factors associated to arterial hypertension.
11. Padmanabhan S, Caulfield M, Dominiczak AF. Genetic and molecular aspects of hypertension. Circ Res. 2015;116:937–59. The current status of genetic hypertension is reviewed and two targets (NOS and Uromodulin) to be successfully used for drug development are illustrated.
12. Doaei S, Gholamalizadeh M. The association of genetic variations with sensitivity of blood pressure to dietary salt: a narrative literature review. ARYA Atheroscler. 2014;10:169–74.
13. Manolio TA. Bringing genome-wide association findings into clinical use. Nat Rev Genet. 2013;14:549–58.
14. Aronson SJ, Rehm HL. Building the foundation for genomics in precision medicine. Nature. 2015;526:336–42. A thorough discussion on the various issues to be addressed to develop a precision medicine.
15. Joyner MJ, Paneth N. Seven questions for personalized medicine. JAMA. 2015;314:999–1000.
16. Caro JJ, Salas M, Speckman JL, et al. Persistence with treatment for hypertension in actual practice. Can Med Assoc J. 1999;160:31–7. Withdrawal rate from hypertensive drugs is four times higher in newly discovered and never treated patients compared to the patients under therapy.
17. Barrett JC, Dunham I, Birney E. Using human genetics to make new medicines. Nat Rev Genet. 2015;16:561–2.
18. Rodriguez R, Miller KM. Unraveling the genomic targets of small molecules using high-throughput sequencing. Nat Rev Genet. 2014;15:783–96. A comprehensive review on genomic target application in the search for drug development.
19. Frye SV, Arkin MR, Arrowsmith CH, et al. Tackling reproducibility in academic preclinical drug discovery. Nat Rev Drug Discov. 2015;14:733–4. The problem related to the use of genetic targets discovered in Academic research applicable to drug development is discussed.
20. Noble D, Jablonka E, Joyner MJ, et al. Evolution evolves: physiology returns to centre stage. J Physiol. 2014;592:2237–44. The importance of considering physiological functions in discussing evolution is highlighted.
21. Milot E, Mayer FM, Nussey DH, et al. Evidence for evolution in response to natural selection in a contemporary human population. Proc Natl Acad Sci. 2011;108:17040–5.
22. Bianchi G, Fox U, Di Francesco GF, et al. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med. 1974;47:435–48.
23. Bianchi G, Fox U, Di Francesco GF, et al. The hypertensive role of the kidney in spontaneously hypertensive rats. Clin Sci Mol Med. 1973;45:135–9.
24. Guidi E, Bianchi G, Dallosta V, et al. Influence of familial hypertension of the donor on the blood pressure and antihypertensive therapy of kidney graft recipients. Nephron. 1982;30:318–23.
25. Guidi E, Bianchi G, Rivolta E, et al. Hypertension in man with a kidney transplant: role of familial versus other factors. Nephron. 1985;41:14–21.
26. Guidi E, Menghetti D, Milani S, et al. Hypertension may be transplanted with the kidney in humans: a long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in the family. J Am Soc Nephrol. 1996;7:1131–8.
27. Dahl LK, Heine M. Primary role of renal homografts in setting chronic blood pressure levels in rats. Circ Res. 1975;36:692–6.
28. Rettig R, Stauss H, Folberth C, et al. Hypertension transmitted by kidneys from stroke-prone spontaneously hypertensive rats. Am J Physiol. 1989;257:F197–203.
29. Bianchi G, Tenconi LT, Lucca R. Effect in the conscious dog of constriction of the renal artery to a sole remaining kidney on hemodynamics, sodium balance, body fluid volumes, plasma renin concentration and pressor responsiveness to angiotensin. Clin Sci. 1970;38:741–66.
30. Bing RF, Russell GI, Swales JD, Thurston H. Effect of 12-hour infusions of saralasin or captopril on blood pressure in hypertensive conscious rats. Relationship to plasma renin, duration of hypertension, and effect of unclipping. J Lab Clin Med. 1981;98:302–10.
31. Watkins BE, Davis JO, Freeman RH, et al. Continuous angiotensin II blockade throughout the acute phase of one-kidney hypertension in the dog. Circ Res. 1978;42:813–21.
32. Freeman RH, Davis JO, Watkins BE, et al. Effects of continuous converting enzyme blockade on renovascular hypertension in the rat. Am J Physiol. 1979;236:F21–4.
33. Edmunds ME, Russell GI, Bing RF. Reversal of experimental renovascular hypertension. J Hypertens. 1991;9:289–301.
34. Davis JO. The pathogenesis of chronic renovascular hypertension. Circ Res. 1977;40:439–44.
35. Bianchi G, Baer PG, Fox U, et al. Changes in renin, water balance, and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ Res. 1975;36&37:153–61.
36. Baer PG, Bianchi G. Micropuncture study of altered renal function in rats of the Milan hypertensive strain (MHS). Proceedings of: the Symposium on Spontaneous Genetic Hypertension in rats. Clin Exp Pharmacol Physiol. 1976;3:41s-5s.
37. Baer PG, Bianchi G, Duzzi L. Renal micropuncture study of normotensive and Milan hypertensive rats before and after development of hypertension. Kidney Int. 1978;13:452–66.
38. Ferrari P, Cusi D, Barber B, et al. Erythrocyte membrane and renal function in relation to hypertension in rats of the Milan hypertensive strain. Clin Sci. 1982;63:61–4.
39. Persson AE, Boberg U, Hahne B, et al. Interstitial pressure as a modulator of tubuloglomerular feedback control. Kidney Int. 1982;12:S122–8.
40. Persson AE, Bianchi G, Boberg U. Evidence of defective tubuloglomerular feedback control in rats of the Milan hypertensive strain (MHS). Acta Physiol Scand. 1984;122:217–19.
41. Persson AE, Bianchi G, Boberg U. Tubuloglomerular feedback in hypertensive rats of the Milan strain. Acta Physiol Scand. 1985;123:139–46.
42. Salvati P, Pinciroli GP, Bianchi G. Renal function of isolated perfused kidneys from hypertensive (MHS) and normotensive (MNS) rats of the Milan strain at different ages. J Hypertens. 1984;2:351–3.
43. Salvati P, Ferrario RG, Parenti P, Bianchi G. Renal function of isolated perfused kidneys from hypertensive (MHS) and normotensive (MNS) rats of the Milan strain: role of calcium. J Hypertens. 1987;5:31–8.
44. Capasso G, Rizzo M, Evangelista C, et al. Altered expression of renal apical plasma membrane Na + transporters in the early phase of genetic hypertension. Am J Physiol Renal Physiol. 2005;288:F1173–82.
45. Capasso G, Rizzo M, Garavaglia ML, et al. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol. 2008;295:F556–67.
46. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008;371:1921–6.
47. Young WF. Primary aldosteronism-one picture is not worth a thousand words. Ann Intern Med. 2009;151:357–8.
48. Monticone S, Else T, Mulatero P, et al. Understanding primary aldosteronism: impact of next generation sequencing and expression profiling. Mol Cell Endocrinol. 2015;399:311–20.
49. Beretta-Piccoli C, Fischbacher A, Rothenbühler A, et al. Body sodium/blood volume state in normotensive members of normotensive and hypertensive families. J Hypertens. 1986;4:229–34.
50. Bianchi G, Cusi D, Gatti M, et al. A renal abnormality as a possible cause of “essential” hypertension. Lancet. 1979;1:173–7.
51. Bianchi G, Staessen JA, Ferrari P. Pharmacogenomics of primary hypertension-the lessons from the past to look toward the future. Pharmacogenomics. 2003;4:279–96.
52. Huan T, Esko T, Peters MJ, et al. A meta-analysis of gene expression signatures of blood pressure and hypertension. PLoS Genet. 2015;11:e1005035.
53. Munroe PB, Tinker A. Genome-wide association studies and contribution to cardiovascular physiology. Physiol Genomics. 2015;47:365–75.
54. Chakravarti A. Genomics is not enough. Science. 2011;334:15.
55. Ryan CJ, Cimermančič P, Szpiech ZA, et al. High-resolution network biology: connecting sequence with function. Nat Rev Genet. 2013;14:865–79.
56. Le Novère N. Quantitative and logic modeling of molecular and gene networks. Nat Rev Genet. 2015;16:146–58.
57. Mooney MA, Nigg JT, McWeeney SK, Wilmot B. Functional and genomic context in pathway analysis of GWAS data. Trends Genet. 2014;30:390–400.
58. Ritchie MD, Holzinger ER, Li R, et al. Methods of integrating data to uncover genotype-phenotype interactions. Nat Rev Genet. 2015;16:85–97.
59. Sorrells TR, Johnson AD. Making sense of transcription networks. Cell. 2015;161:714–23.
60. Mazzocchi F. Could big data be the end of theory in science? A few remarks on the epistemology of data-driven science. EMBO Rep. 2015;16:1250–5.
61. Ségalat L. System crash. EMBO Rep. 2010;11:86–9.
62. Baddeley M. Herding, social influences and behavioral bias in scientific research: simple awareness of the hidden pressures and beliefs that influence our thinking can help to preserve objectivity. EMBO Rep. 2015;16:902–5. Many non scientific factors influence the choice of research approaches.
63. MacArthur DG, Manolio TA, Dimmock DP, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469–76.
64. Marian AJ. Causality in genetics: the gradient of genetic effects and back to Koch’s postulates of causality. Circ Res. 2014;114:e18–21.
65. Williams SM, Haines JL, Moore JH. The use of animal models in the study of complex disease: all else is never equal or why do so many human studies fail to replicate animal findings? Bioessays. 2004;26:170–9.
66. Romiguier J, Gayral P, Ballenghien M, et al. Comparative population genomics in animals uncovers the determinants of genetic diversity. Nature. 2014;515:261–3.
67. Editorial. Of men, not mice. Nat Med. 2013;19:379.
68. Bianchi G. Genetic variations of tubular sodium reabsorption leading to “primary” hypertension. Am J Physiol. 2005;289:R1536–49. In this review, the most peculiar aspects of our strategy have been indicated and discussed.
69. Bianchi G, Picotti GB, Bracchi G, et al. Familial hypertension and hormonal profile, renal haemodynamics and body fluids of young normotensive subjects. Clin Sci Mol Med. 1978;55:367–71.
70. + countertransport in the erythrocytes of “essential” hypertensive patients. Clin Sci. 1981;61:33s–6.
71. Cusi D, Barlassina C, Ferrandi M, et al. Erythrocyte membrane transport systems as possible markers for essential hypertension. Clin Sci. 1982;63:57–9.
72. Bianchi G, Cusi D, Guidi E. Renal hemodynamics in human subjects and in animals with genetic hypertension during the prehypertensive stage. Am J Nephrol. 1983;3:73–9.
73. Bianchi G, Cusi D, Barlassina C, et al. Renal dysfunction as a possible cause of essential hypertension in predisposed subjects. Kidney Int. 1983;23:870–5.
74. Beck F, Bianchi G, Dörge A, et al. Sodium and potassium concentrations of renal cortical cells in two animal models of primary arterial hypertension. J Hypertens. 1983;1:38–9.
75. Thurau K, Beck F, Borst M, et al. Intracellular electrolyte composition in various experimental models of hypertension: an electron microprobe study. J Cardiovasc Pharmacol. 1984;6:28–31.
76. Bianchi G, Ferrari P, Salvati P, et al. Relationship between red blood cell function, kidney function and blood pressure in genetic hypertension. Klin Wochenschr. 1985;63:59–60.
77. Cusi D, Alberghini E, Pati P, et al. Pathogenetic mechanisms in essential hypertension. Analogies between a rat model and the human disease. Int J Cardiol. 1989;25:29–36.
78. Bianchi G, Baldoli E, Lucca E, Barbin P. Pathogenesis of arterial hypertension after the constriction of the renal artery leaving the opposite kidney intact both in the anaesthetized and the conscious dog. Clin Sci. 1972;42:651–64.
79. Trizio D, Ferrari P, Ferrandi M, et al. Expression at the hemopoietic stem cell level of the genetically determined erythrocyte membrane defects in the Milan hypertensive rat strain (MHS). J Hypertens. 1983;1:S6–8.
80. Bianchi G, Ferrari P, Trizio D, et al. Red blood cell abnormalities and spontaneous hypertension in the rat: a genetically determined link. Hypertension. 1985;7:319–25.
81. Parenti P, Hanozet G, Bianchi G. Sodium and glucose transport across renal brush-border membranes of Milan hypertensive rats. Hypertension. 1986;8:932–9.
82. + transports in intact red blood cells, resealed ghosts and inside-out vesicles of Milan hypertensive rats. J Hypertens. 1986;4:379–81.
83. Ferrari P, Ferrandi M, Torielli L, et al. Relationship between erythrocyte volume and sodium transport in the Milan hypertensive rat and age-dependent changes. J Hypertens. 1987;5:199–206.
84. + fluxes in membrane vesicles from kidneys of normotensive and hypertensive rats. Biochim Biophys Acta. 1990;1021:13–20.
85. Ferrari P, Torielli L, Cirillo M, et al. Sodium transport kinetics in erythrocytes and inside-out vesicles from Milan rats. J Hypertens. 1991;9:703–11.
86. Parenti P, Ferrari P, Ferrandi M, et al. Effect of amiloride analogues on sodium transport in renal brush border membrane vesicles from Milan hypertensive rats. Biochem Biophys Res Commun. 1992;183:55–61.
87. − cotransport in resealed ghosts from erythrocytes of the Milan hypertensive rats. Biochim Biophys Acta. 1992;1111:111–9.
88. Salardi S, Modica R, Ferrandi M, et al. Characterization of erythrocyte adducin from the Milan hypertensive strain of rats. J Hypertens. 1988;6:196s–8.
89. Salardi S, Saccardo B, Borsani G, et al. Erythrocyte adducin differential properties in normotensive and hypertensive rats of the Milan strain (characterization of spleen adducin m-RNA). Am J Hypertens. 1989;2:229–37.
90. Salardi S, Hofstede J, Op Den Camp JA. F, Bianchi G. Protein and lipid composition of erythrocytes from the Milan hypertensive strain rat. J Vasc Med Biol. 1989;1:262–8.
91. Tripodi MG, Piscone A, Borsani G, et al. Molecular cloning of an adducin-like protein: evidence of a polymorphism in the normotensive and hypertensive rats of the Milan strain. Biochem Biophys Res Commun. 1991;177:939–47.
92. Bianchi G, Tripodi MG, Casari G, et al. Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci. 1994;91:3999–4003.
93. Casari G, Barlassina C, Cusi D, et al. Association of the α-adducin locus with essential hypertension. Hypertension. 1995;25:320–6.
94. Tripodi MG, Casari G, Tisminetzky S, et al. Characterization and chromosomal localization of the rat α- and β-adducin-encoding genes. Gene. 1995;166:307–11.
95. Tisminetzky S, Devescovi G, Tripodi MG, et al. Genomic organisation and chromosomal localisation of the gene encoding human beta adducin. Gene. 1995;167:313–6.
96. Melzi ML, Bertorello A, Fukuda Y, et al. Na, K-ATPase activity in renal tubule cells from Milan hypertensive rats. Am J Hypertens. 1989;2:563–6.
97. Ferrandi M, Tripodi MG, Salardi S, et al. Renal Na, K-ATPase in genetic hypertension. Hypertension. 1996;28:1018–25.
98. Ferrandi M, Salardi S, Tripodi MG, et al. Evidence for an interaction between adducin and Na, K ATPase: relation to genetic hypertension. Am J Physiol. 1999;277:1338–49.
99. Ferrari P, Bianchi G. Pathophysiology of hypertension. Membrane ion transports in hypertension. Hypertension. 1997;17:935–74.
100. Ferrandi M, Molinari I, Torielli L, et al. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1: experimental studies. Sci Transl Med. 2010;2:59ra86.
101. Tripodi MG, Valtorta F, Torielli L, et al. Hypertension-associated point mutations in the adducin α and β subunits affect actin cytoskeleton and ion transport. J Clin Invest. 1996;97:2815–22.
102. Cusi D, Barlassina C, Azzani T, et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet. 1997;349:1353–7.
103. Citterio L, Lanzani C, Manunta P, Bianchi G. Genetics of primary hypertension: the clinical impact of adducin polymorphisms. Biochim Biophys Acta. 1802;2010:1285–98.
104. Liu K, Liu Y, Liu J, et al. Alpha-adducin Gly460Trp polymorphism and essential hypertension risk in Chinese: a meta-analysis. Hypertens Res. 2011;34:389–9.
105. Li YY. α-Adducin Gly460Trp gene mutation and essential hypertension in a Chinese population: a meta-analysis including 10,960 subjects. PLoS ONE. 2012;7:e30214.
106. Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am J Cardiovasc Drugs. 2007;7:173–89.
107. Manunta P, Maillard M, Tantardini C, et al. Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension. J Hypertens. 2008;26:914–20.
108. Manunta P, Ferrandi M, Bianchi G, Hamlyn JM. Endogenous ouabain in cardiovascular function and disease. J Hypertens. 2009;27:9–18.
109. Ferrandi M, Minotti E, Salardi S, et al. Ouabain-like factor in Milan hypertensive rats. Am J Physiol. 1992;263:F739–48.
110. Ferrandi M, Manunta P, Balzan S, et al. Ouabain-like factor quantification in human tissues and plasma: comparison of two independent assays. Hypertension. 1997;30:886–96.
111. Ferrandi M, Molinari I, Barassi P, et al. Organ hypertrophic signalling within caveolae membrane subdomains triggered by ouabain and antagonized by PST2238. J Biol Chem. 2004;279:33306–14.
112. Ferrari P, Torielli L, Ferrandi M, et al. PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain. J Pharmacol Exp Ther. 1998;285:83–94.
113. Efendiev R, Krmar RT, Ogimoto G, et al. Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na, K-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res. 2004;95:1100–8.
114. + channel (ENaC), hormones, and hypertension. J Biol Chem. 2010;285:23527–31.
115. Manunta P, Hamilton BP, Hamlyn JM. Salt intake and depletion increase circulating levels of endogenous ouabain in normal men. Am J Physiol Regul Integr Comp Physiol. 2006;290:R553–9.
116. Manunta P, Messaggio E, Ballabeni C, et al. Salt sensitivity study group of the Italian Society of Hypertension. Plasma ouabain-like factor during acute and chronic changes in sodium balance in essential hypertension. Hypertension. 2001;38:198–203.
117. Zhang J, Lee MY, Cavalli M, et al. Sodium pump alpha2 subunits control myogenic tone and blood pressure in mice. J Physiol. 2005;569:243–56.
118. Kurtz TW, Dominiczak AF, DiCarlo SE, et al. Molecular-based mechanisms of mendelian forms of salt-dependent hypertension: questioning the prevailing theory. Hypertension. 2015;65:932–41.
119. Warnock DG, Kusche-Vihrog K, Tarjus A, et al. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells. Nat Rev Nephrol. 2014;10:146–57.
120. Liang M, Lee NH, Wang H, et al. Molecular networks in Dahl salt-sensitive hypertension based on transcriptome analysis of a panel of consomicrats. Physiol Genomics. 2008;34:54–64.
121. Davidson EH. Emerging properties of animal gene regulatory networks. Nature. 2010;468:911–20.
122. Erwin DH, Davidson EH. The evolution of hierarchical gene regulatory networks. Nat Rev Genet. 2009;10:141–8.
123. Gu J, Xuan Z. Inferring the perturbed microRNA regulatory networks in cancer using hierarchical gene co-expression signatures. PLoS ONE. 2013;8:e81032.
124. +ATPase alterations in ouabain and adducin-dependent hypertension. Am J Physiol Regul Integr Comp Physiol. 2006;290:R529–35.
125. + ATPase in genetic hypertension. J Pharmacol Exp Ther. 1999;288:1074–83.
126. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600.
127. Muslin J. MAPK signaling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci. 2008;115:203–18.
128. Staessen JA, Kuznetsova T, Acceto R, et al. OASIS-HT: design of a pharmacogenomic dose-finding study. Pharmacogenomics. 2005;6:755–75.
129. Lanzani C, Citterio L, Glorioso N, et al. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci Transl Med. 2010;2:59ra87.
130. Staessen JA, Thijs L, Stolarz-Skrzypek K, et al. Main results of the ouabain and adducin for specific intervention on sodium in hypertension trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin. Trials. 2011;12:13.
131. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290–300.
132. Finucane HK, Bulik-Sullivan B, Gusev A, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015;47:1228–35.
133. Zhao B, Tan PH, Li SS, Pei D. Systematic characterization of the specificity of the SH2 domains of cytoplasmic tyrosine kinases. J Proteomics. 2013;81:56–69.
134. Ferrandi M, Molinari I, Rastaldi MP, et al. Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain. J Pharmacol Exp Ther. 2014;351:278–87.
135. Duboule D, Wilkins AS. The evolution of ‘bricolage’. Trends Genet. 1998;14:54–9.
136. Citterio L, Ferrandi M, Delli Carpini S, et al. cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment. Hypertension. 2013;62:1027–33.
137. Kuznetsova T, Citterio L, Zagato L, et al. Left ventricular radial function associated with genetic variation in the cGMP-dependent protein kinase. Hypertension. 2013;62:1034–9.
138. Kuznetsova T, Citterio L, Herbots L, et al. Effects of genetic variation in adducin on left ventricular diastolic function as assessed by tissue Doppler imaging in a Flemish population. J Hypertens. 2008;26:1229–36.
139. Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet. 2002;3:165–75.
140. Hamlyn JM, Laredo J, Shah JR, et al. 11-hydroxylation in the biosynthesis of endogenous ouabain: multiple implications. Ann N Y Acad Sci. 2003;986:685–93.
141. Pitzalis MV, Hamlyn JM, Messaggio E, et al. Independent and incremental prognostic value of endogenous ouabain in idiopathic dilated cardiomyopathy. Eur J Heart Fail. 2006;8:179–86.
142. Jacobs BE, Liu Y, Pulina MV, et al. Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. Am J Physiol Heart Circ Physiol. 2012;302:H1317–29.
143. Robertson JI. Dietary salt and hypertension: a scientific issue or a matter of faith? J Eval Clin Pract. 2003;9:1–22.
144. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95:144s–50. This is a very thorough discussion on the difficulty to demonstrate causation of a given factor (either genetic or environmental) within the complex interactions among the various modifiers factors (either genetic or environmental).
145. Stolarz-Skrzypek K, Kuznetsova T, Thijs L, et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA. 2011;305:1777–85.
146. Nelson RM, Pettersson ME, Carlborg Ö. A century after fisher: time for a new paradigm in quantitative genetics. Trends Genet. 2013;29:669–76. The present analysis paradigms in genetics are at its limits in regards to unraveling complex traits with GWAS.
147. Mackay TF. Epistatis and quantitative traits: using model organisms to study gene-gene interactions. Nat Rev Genet. 2014;15:22–33. Carrying out tests for about 18 million possible pairwise interactions remains a practical impossibility even in a tractable model system.
148. Wei WH, Hemani G, Haley CS. Detecting epistasis in human complex traits. Nat Rev Genet. 2014;15:722–33. Testing interactions with GWAS data based on SNPs that have been grouped into genes or functional modules can markedly reduce the multiple test burden, particular when one of this functional module has a very strong experimental and clinical support.