The last decade has seen a dramatic increase in the understanding of the molecular basis of arrhythmias. Much of this new information has been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular electrophysiological or biochemical studies. The marked clinical heterogeneity known from these familial arrhythmia syndromes has led to the development of a multifactorial (multi-hit) concept of arrhythmogenesis in which causal gene mutations have a major effect on disease expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this article is to review common genetic variation in ion channel genes and to compare these recent findings.

Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below.

Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

There is heterogeneity in patient responses to current asthma medications. Significant progress has been made identifying genetic polymorphisms that influence the efficacy and potential for adverse effects to asthma drugs, including; β(2)-adrenergic receptor agonists, corticosteroids and leukotriene modifiers. Pharmacogenetics holds great promise to maximise clinical outcomes and minimize adverse effects. Asthma is heterogeneous with respect to clinical presentation and inflammatory mechanisms underlying the disease, which is likely to contribute to variable results in clinical trials targeting specific inflammatory mediators. Genome-wide association studies have begun to identify genes underlying asthma (e.g., IL1RL1), which represent future therapeutic targets. In this article, we review and update the pharmacogenetics of current asthma therapies and discuss the genetics underlying selected Phase II and future targets.

Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

The cystic fibrosis membrane conductance regulator can be activated through beta2-adrenoceptor (beta2AR) stimulation. We tested the hypothesis that coding sequence polymorphisms in the beta2AR gene contribute to the disease state in patients with cystic fibrosis. The Arg16Gly, Gln27Glu, and Thr164Ile beta2AR polymorphisms were studied by specific polymerase chain reaction and restriction fragment length polymorphism analysis in 126 cystic fibrosis patients. Forced expiratory volume in 1 s was significantly (P < 0.05) reduced in cystic fibrosis patients carrying the Gly16 allele in either homozygous or heterozygous form (Gly16Gly + Arg16Gly) compared to patients homozygous for the Arg16 allele (60.3 +/- 3.5% versus 75.7 +/- 4.9% predicted). Similarly, forced vital capacity and flows at lower lung volumes were significantly (P < 0.05 and P < 0.01) lower in cystic fibrosis patients carrying the Gly16 allele. In addition, the Gly16 allele was associated with a greater 5 year decline in pulmonary function (P < 0.01). Bronchodilator responses to albuterol were not significantly different between the groups. The Thr164Ile variant was found in four patients; these patients had markedly reduced pulmonary function. Isoproterenol-stimulated cyclic AMP formation was significantly blunted in cystic fibrosis patients carrying either the Gly16 allele or Thr164Ile genotype compared to cystic fibrosis patients homozygous for the respective Arg16 alleles. These data provide the first evidence suggesting that polymorphisms of the beta2AR gene contribute to clinical severity and disease progression in cystic fibrosis.

Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

Myocardial β-adrenergic receptors (βARs) are important in altering heart rate, inotropic state, and myocardial relaxation (lusitropy). The β1AR and β2AR stimulation increases cyclic adenosine monophosphate concentration with the net result of myocyte contraction, whereas β3AR stimulation results in decreased inotropy. Downregulation of β1ARs in heart failure, as well as an increased β3AR activity and density, lead to decreased cyclic adenosine monophosphate production and reduced inotropy. The βAR antagonists are commonly used in patients with coronary artery disease and heart failure; however, perioperative use of βAR antagonists is controversial. Individual patient's response to beta-blocker therapy is an area of intensive research, and apart from pharmacokinetics, pharmacodynamics, and ethnic differences, genetic alterations have become more important in the last 20 years. The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). There are 2 clinically relevant SNPs for the β1AR (Ser49Gly, Arg389Gly), 3 for the β2AR (Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the β3AR (Trp64Arg). Although results are somewhat controversial, generally large datasets have the potential to show a relationship between βAR SNPs and outcomes such as development and progression of heart failure, coronary artery disease, vascular reactivity, hypertension, asthma, obesity, and diabetes. Although βAR SNPs may not directly cause disease, they appear to be risk factors for, and modifiers of, disease and the response to stress and drugs. In the perioperative setting, this has specifically been demonstrated for the Arg389Gly β1AR polymorphism with which patients with the Gly variant had a higher incidence of adverse perioperative events. Knowing that genetic variants play an important role, perioperative medicine will likely change from simple therapeutic intervention to a more personalized way of adrenergic receptor modulation.

Stroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.