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1、Heart Failure Pharmacogenetics: Past, Present, and FutureHeather M. Davis cAMPcyclic adenosine monophosphate; DAG diacylglycerol; EPIepinephrine; GRKG-protein-coupled receptor kinase; IP3inositol triphosphate; NEnorepinephrine; PLCphos- pholipase C. (From Johnson and Liggett 45; reproduced with perm
2、ission)Curr Cardiol RepTable 1 Summary of heart failure pharmacogenetic associationsSNPReference allele/functionPharmacogenetic associationsADRB1 Arg389GlyReference: Arg389Prognostic indicatorsOutcomesIncreased receptor activation of adenylyl cyclase with Arg389 allele 79Greater LVEF improvement in
3、Arg389Arg homozygotes among carvedilol- and metoprolol-treated subjects 911Arg389Arg: reduced mortality with bucindolol compared with placebo, no clinical response among Gly389 carriers 14Trend toward increase in LVEF with carvedilol-treated Arg389 carriers 13Gly389: decreased risk of NSVT, improved
4、 survival 19No association with LVEF and Arg389Gly in bisoprolol- or carvedilol-treated patients 12No association with outcome among subjects receiving blocker 20No changes in LVEF by codon 389 among bucindolol-treated patients 14No effect on transplant-free survival for polymorphisms of adrenergic
5、receptors 21No association with outcomes for metoprolol CR/XL or placebo randomized patients 22Gly389: increased mortality risk inCaucasians not receiving blocker 20Gly389 carriers: higher 5-year mortality risk compared with Arg389Arg in subjects receiving low-dose blocker 24ADRB1 Ser49GlyReference:
6、 Ser49Prognostic indicatorsOutcomesGly49: increased agonist-promoted downregulation and adrenergic coupling, more sensitive to inhibition 23Decreased LVEDD in Gly49 carriers 11Gly49: carriers on low-dose blocker, lower 5-year mortality, no association among those receiving high-dose blocker 24Ser49G
7、ly + Arg389Arg diplotype: decrease in LVEDD 11Ser49Ser + Arg389Gly diplotype: increase in LVEDD 11ADRB2 Gly16ArgReference: Gly16OutcomesConflicting data regarding agonist- mediated downregulation 15, 16, 42, 43Two copies of Arg16Gln27 haplotype associated with increased risk for death or heart trans
8、plantation 44ADRB2 Gln27GluReference: Gln27Prognostic indicatorsGlu27: resistance to downregulation in vitro 15, 16Glu27Glu: greater increase in LVEF compared with Gln27 carriers in response to carvedilol 13Glu27Glu: enhanced vasodilation in response to agonist in vivo 42Glu27 carriers: improvement
9、in LVEF, not seen in Gln27 14Glu27: allele prevalence greater among “good responders” to carvedilol 18ADRA2C Del322- 325Reference: Ins322-325Prognostic indicatorsOutcomesLoss of 2c receptor autoinhibition of norepinephrine release 25, 26Del322-325 carriers: threefold greater decrease in norepinephri
10、ne 28Del322-325 carriers: no survival benefit with bucindolol therapy, wild-type had 30% reduced incidence of mortality 28Del322-325 carriers: greater negative chronotropic response to metoprolol CR/XL 29Synergistic effect between Arg389Arg/ Del322-325 carrier genotypes had largest increase in LVEF
11、29GRK5 Gln41LeuReference: Gln41OutcomesLeu41: gain-of-function, greater agonist-promoted desensitization of -adrenergic receptors 30Leu41 -blocker nave: longer transplantation-free survival in African Americans, no difference in treated subjects 30Leu41: longer survival in -blocker untreated African
12、 Americans 20ACE I/DReference: DPrognostic indicatorsOutcomesIncreased plasma levels of ACE associated with the D allele 33, 34D/D: greater prevalence among subjects with “aldosterone escape” 36D allele associated with poorer transplant-free survival, exaggerated with low-dose ACE inhibitor and no b
13、locker 35D/D: nonsignificant change in LVEF after spironolactone treatment 37ACE angiotensin-converting enzyme, CR/XL controlled release/extended release, I/D insertion/deletion, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, NSVT nonsustained ventricular tac
14、hycardia, SNP single nucleotide polymorphismCurr Cardiol Repcompared with subjects homozygous for the Gly389Gly genotype (8.7%1.1% vs 7.0%1.5% vs 0.93%1.7%, respectively; P 50% of full dose), the 5-year mortality risk was not different by codon 49 genotype (RR, 0.27; 95% CI, 0.042.04; P=0.20), sugge
15、sting great benefit among Ser49Ser with high- versus low-/no-dose blocker 24. Although the data on Arg389Gly may seem conflicting, they may not be as conflicting as they appear. Specifically, BEST and the Brazilian cohort showed significant differ- ences in outcomes when patients with a single genot
16、ype were compared relative to treatment versus placebo (or no-/ low-dose blocker). These analysis approaches allowed for the assessment of treatment benefit by genotype, and both suggested that the Arg389 genotypes accrued signif- icant benefits from -blocker therapy whereas Gly389Gly did not. In contrast, the other two cohort studies compared outcomes across genotype a
