2011,心衰综述 -药物基因组学的过去、现在和未来
10页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 permission)Curr Cardiol RepTable 1 Summary of heart failure pharmacogenetic associationsSNPReference allele/functionPharmacogenetic associationsADRB1 Arg389GlyReference: Arg389Prognostic indicatorsOutcome
2、sIncreased receptor activation of adenylyl cyclase with Arg389 allele 79Greater LVEF improvement in 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 survival 19No association with LVEF and Arg389Gly in bisoprolol- or carvedilol-treated patients 12N
3、o 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 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:
4、 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 24Ser49Gly + Arg389Arg diplotype: decrease in LVEDD 11Ser49Ser + Arg389Gly diplotype: increase in LVEDD 11ADRB2 Gly16ArgReference: Gly16OutcomesConflicting data regarding agonist- mediated downregulation 15,
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