Current Pharmacogenomics and Personalized Medicine - Volume 6, Issue 3, 2008

The candidate gene approach to pharmacogenetics is hypothesis driven, and anchored in biological plausibility. Whole genome scanning is hypothesis generating, and it may lead to new biology. While both approaches are important, the scientific community is rapidly reallocating resources toward the latter. We propose a step-wise approach to largescale pharmacogenetic association studies that begins with candidate genes, then uses a pathway-based intermediate step, to inform subsequent analyses of data generated through whole genome scanning. Novel computational strategies are explored in the context of two clinically relevant examples, cholesterol synthesis and lipid signaling.

Genetic variation in drug targets (e.g. receptors) can have pronounced effects on clinical responses to endogenous and exogenous agonists. Polymorphisms in the gene encoding the β2-adrenergic receptor (β2-AR) have been associated with altered expression, down-regulation, and altered cell signaling in vitro. Because β2-ARs play a crucial role in the regulation of the cardiovascular system, the functional importance of genetic variation in the β2-AR on cardiovascular responses to physiological or pharmacological stimuli has gained widespread attention. The objective of this review is to characterize these intermediate cardiovascular phenotypes and their influence on cardiovascular disease and adrenergic drug responses. Two common single nucleotide polymorphisms, encoded at codon 46 (Gly16Arg) and 79 (Gln27Glu) of the β2-AR gene, have been studied intensively. They have been shown to be associated with altered vasodilator responses to regional and systemic administration of β2-agonists, altered cardiovascular responses to sympathoexcitatory maneuvers, and altered myocardial function. Importantly, these intermediate physiological patterns may influence the development of and the outcomes associated with hypertension and other cardiovascular diseases. As recently reported, β2-AR gene variation can risk-stratify patients receiving β-blocker therapy and may predict β-blocker efficacy in patients post acute coronary syndrome or in patients with heart failure. Further studies will advance our understanding of the link between β2-AR genotypes, intermediate cardiovascular phenotypes, and clinical phenotypes. In the long term, reassessment of the benefits of β-blocker-therapy within genotype groups should be carried out with the ultimate goal to design the optimal therapeutic regimen for the individual patient.

Blood platelets are the primary defence mechanism involved in physiological haemostasis. Their disorders constitute a crucial risk factor in arterial thrombosis. As arterial thrombi are predominantly composed of platelet aggregates formed under conditions of elevated shear stress at sites of atherosclerotic vascular injury, prevention of arterial thrombosis can be considered the main target of antiplatelet therapy. However, a large interindividual variability in the clinical response to aspirin, clopidogrel and GpIIb/IIIa inhibitors is widely acknowledged by physicians as a barrier for rational pharmacotherapy. Several case-control studies have indicated that various polymorphisms of different platelet glycoprotein and receptors might contribute to arterial thrombosis. Moreover, polymorphisms of hepatic cytocrome P450, which generate the active metabolites of clopidogrel, are likely to play a considerable role in determining the in vivo response to this prodrug. Functional studies have revealed widespread gene-gene interactions, as well as modulation by non-genetic factors. Thus, the response to anti-platelet drugs is a classic “complex” trait, and the available data require a great deal of caution to avoid misinterpretation. In this article, we review the role of these polymorphisms in modulating platelet function and platelet response to inhibitors.

The sudden unexplained death syndrome, a tragic and devastating event, is often the result of cardiac arrhythmias associated with defects in ion channels. Autopsies are unrevealing due to the absence of an obvious cardiac pathology in these disorders. Substantial efforts have been devoted to identify genetic variations known to cause long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia, all of which have been wellrecognized for their risk of sudden death. Genetic polymorphisms in the ion channel genes under study have also been known to modulate the response to drugs and predispose susceptible individuals to life-threatening arrhythmias. Cardiotoxicity is a serious adverse effect which limits the therapeutic potential of a vast number of clinically available drugs. The awareness of putative drug-gene interactions may lead to the tailoring of therapy for the individual patient based on genetic make-up, as well as the molecular design of drug molecules with reduced cardiac side effects. These efforts aim to prevent the occurrence of sudden unexpected deaths, or adverse complications from drugs. This expert review outlines the emerging strategies to move beyond the idiopathic occurrence of the sudden death syndrome, through a consideration of the molecular genetic pathogenesis of non-ischaemic cardiac conditions underpinning sudden death. Additionally, we discuss the results of our ongoing original research and mutation screening efforts to identify genetic biomarkers for the sudden unexplained death syndrome.

The inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are common causes of significant morbidity, especially in young people. Current knowledge of aetiology is incomplete, but increasingly the evidence points towards a combination of appropriate environmental triggers in a genetically susceptible individual. Therapeutic options include 5-aminosalicylates, corticosteroids and immunosuppressants such as azathioprine and 6-mercaptopurine. These treatments have widely accepted limitations, thus catalyzing the development of the newer biological agents, such as infliximab, which now has an established role in the induction and maintenance of remission of Crohn's disease and in the induction of remission of acute severe ulcerative colitis. Of the pharmacogenetic studies to date in inflammatory bowel disease, it is only the measurement of thiopurine methyltransferase (TPMT) levels before the induction of thiopurine treatment that has had any clinical impact. Although TPMT screening has relatively low sensitivity for identifying patients at risk of complications, it is clear that patients who are homozygous for TPMT alleles are at higher risk of myelosuppression when treated with thiopurines. In this article we review the current understanding of genetic polymorphisms associated with an increased risk of developing inflammatory bowel disease, genetic determinants of metabolism of the drugs used in the management of inflammatory bowel disease and discuss their influence on drug efficacy and the risk of developing side effects.

An abdominal aortic aneurysm (AAA) is usually asymptomatic until the catastrophic event of rupture. Ruptured aneurysms cause ∼5000 deaths each year in the UK. A recent randomized control led trial showed the efficacy of screening for AAA. If a screening programme is implemented, there will be an increase in the detection of small AAAs. AAAs are normally not surgically repaired until their diameter exceeds 5.5cm. A policy of ‘watchful waiting’ is however not risk free as 10% of asymptomatic AAA that rupture are less than 5 cm in diameter. An effective pharmacological treatment to limit aneurysm growth and the risk of rupture would justify screening programmes. The use of agents such as MMP inhibitors, HMG CoA inhibitors and anti-infective agents has yielded disappointing results in clinical trials so far. Adoption of a targeted or personalized treatment strategy may conceivably refine the ongoing efforts to develop efficacious and safe novel treatments for AAA. The cause of AAAs is multifactorial, but 15-20% of patients inherit this condition. There is an approximately 7-fold increase in the prevalence of aortic aneurysms in the male siblings of affected individuals. A monogenic disorder resulting in AAA has not been found, but it is plausible that an inherited predisposition to “sporadic” AAAs may also exist. Over the past decade, there have been an increased interest in identifying specific genes that could be responsible in AAA expansion and progression. This manuscript provides an integrated overview of (1) linkage studies, (2) association studies and (3) micro array analysis aimed at identifying the genes responsible for the development and continued expansion of AAA, and the implications for discovery of novel drug targets and personalized therapy.