Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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190 Applying Pharmacogenomics in TherapeuticsANGIOTENSIN-CONVERTING ENZYME INHIBITORSThe renin–angiotensin–aldosterone system (RAAS) is important for the developmentof hypertension, and several antihypertensive drugs target this system.ACEIs block the conversion of angiotensin I to angiotensin II through competitiveinhibition of the angiotensin-converting enzyme (ACE). Angiotensin is formed viathe RAAS, an enzymatic cascade that leads to the proteolytic cleavage of angiotensinI by ACEs to angiotensin II. RAAS impacts cardiovascular, renal, and adrenalfunctions via the regulation of systemic blood pressure (BP) and electrolyte and fluidbalance. Reduction in plasma levels of angiotensin II, a potent vasoconstrictor andnegative feedback mediator for renin activity, by ACEIs leads to increased plasmarenin activity and decreased BP, vasopressin secretion, sympathetic activation, andcell growth. Decreases in plasma angiotensin II levels also results in a reduction inaldosterone secretion, with a subsequent decrease in sodium and water retention. 30ACEIs also inhibit the breakdown of bradykinin, a potent vasodilator, by kininaseII, an enzyme identical to ACE, which may increase levels of nitric oxide.Bradykinin-induced vasodilation is thought to be of secondary importance in the BPlowering effect of ACEIs.Most data regarding genomic modulators of response refer to a common insertion/deletion (I/D) polymorphism in the ACE gene that is strongly correlated with plasmaenzyme levels. 40,41 In an observational study, carriers of the DD genotype were foundto have significantly higher mortality than those with the I/I genotype, with therisk for heterozygotes being intermediate. 42 However, prospective trials have failedto validate these findings, 43,44 and, at present, there is no strong evidence that thisvariant influences response to ACEIs. A number of other candidates in the renin–angiotensin–aldosterone pathway have been analyzed, including angiotensinogen(AGT) and angiotensin II receptor types I and II (AGTR1 and AGTR2). Signals forhigher risk of adverse cardiovascular outcomes while taking ACEIs have emergedwith variants in AGT 45 ; however, the data are not conclusive.Recently, the Perindopril Genetic Association study (PERGENE) 46 evaluated12 genes from the pharmacodynamic pathway of ACEIs in 8907 patients with stableCAD treated with perindopril or placebo. Two polymorphisms in AGTR1 and athird in the bradykinin type I receptor were significantly associated with the combinedprimary outcome of cardiovascular mortality, nonfatal myocardial infarction,and resuscitated cardiac arrest during 4.2 years of follow-up. A pharmacogenetic scorecombining these SNPs demonstrated a stepwise decrease in treatment benefit of perindoprilwith an increasing score and identified a subgroup of 26.5% of the populationthat did not benefit from therapy. 46 This finding requires independent replication butrepresents a potential advance toward understanding variable response to ACEIs.Clinical ApplicationAlthough currently there are no treatment guidelines for the RAAS-acting drugs basedon genomics, large multigene haplotype and genome-wide pharmacogenomic studiessuch as PERGENE may provide clearer evidence to improve therapeutic choices,reduce side effects, improve BP control, and prevent organ damage.
Drug Therapy of Cardiovascular Diseases191ANGIOTENSIN II RECEPTOR BLOCKERSARBs inhibit activation of the AT1 (Angiotensin I) receptor. The role of ARBs inpharmacogenomics still appears to be inconclusive. The Swedish Irbesartan LeftVentricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial found thatthe ACE I/D6 and CYP11B2 C-344T polymorphisms were associated with modifiedBP response. This study consisted of 50 subjects who took irbesartan. 7 Subjects carryingthe ACE I/I genotype and those carrying the CYP11B2-344 T/T variant hadgreater BP response to irbesartan. However, Redon et al. 47 conducted a similar studywith 206 subjects treated with telmisartan and found no significant association withthe RAAS gene polymorphisms. 8 Ortlepp et al. had results that differed from theSILVHIA trial. These results concluded that the C allele of the CYP11B2 C-344Tpolymorphism is associated with a better response to candesartan. 48Clinical ApplicationGenetic determinants of BP and long-term outcomes in hypertensive patients arebeing identified. Although the results to date are promising, broader studies wouldhelp clarify the role of the RAAS polymorphisms in the use of ARBs.THIAZIDE DIURETICSVaried BP response to diuretics is observed in hypertensive patients. It has beenproposed that genetic polymorphisms in several candidate genes such as the ACE,alpha-adducin (ADD1), G protein b3- subunit (GNB3) gene, angiotensinogen (AGT),and angiotensin II receptor 1 (AGTR1) may influence BP response to diuretictherapy. 49 ACE insertion/deletion (ACE I/D) polymorphism has been extensivelystudied for association with BP lowering response to diuretics 50 ; however contradictoryresults have been reported in different studies. Both association and lackof association of ACE genotypes with BP lowering response to diuretics have beenreported in different studies.Carriers of polymorphisms in the ADD1 alpha-adducin Trp460Trp (homozygouspatients for the Trp460Trp allele) gene have shown a reduction in the effective renalplasma flow, effective renal blood flow, and glomerular filtration rate compared tononcarriers of the Trp460 allele patients with the Gly460Gly gene. 51The GenHAT multicenter randomized clinical trial studied the pharmacogeneticassociation of the atrial natriuretic precursor A (NPPA) T2238C genetic variant withCVD outcomes in patients with hypertension. The study concluded that (NPPA)2238 T>C polymorphism was associated with better cardiovascular outcomes inpatients taking chlorthalidone compared to amlodipine. Carriers of the T/T allelecarriers on amlodipine had better outcomes when taking amlodipine. 52CALCIUM CHANNEL BLOCKERSDrugs in this class block voltage-gated calcium channels in the heart and vascularsmooth muscle, thereby reducing intracellular calcium. 53 Very few studies havedescribed the pharmacogenomic associations of calcium channel blockers (CCBs).
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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11 PharmacoeconogenomicsA Good Marr
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Pharmacoeconomics of Pharmacogenomi
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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