Anke Hilse Maitland-van der Zee

Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors

Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patients health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subjects genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.

Pharmacogenetic-guided dosing of coumarin anticoagulants : Algorithms for warfarin, acenocoumarol and phenprocoumon

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials.

The interface between pharmacoepidemiology and pharmacogenetics

One of the most challenging areas of research in pharmacoepidemiology is to understand why individuals respond differently to drug therapy, both in terms of beneficial and adverse effects. Pharmacogenetics focuses on the question to what extent variability in genetic make-up is responsible for these observed differences. Pharmacoepidemiologic research can contribute to pharmacogenetics by explaining the observed variability in drug response in real life patient populations with known polymorphisms in their genetic profile. Genetic pharmacoepidemiologists also are interested in the distribution of polymorphisms and correlated frequencies of responders and non-responders in the general population, and in searching for unknown genetic links to variability in drug response. In the future, we will probably have fewer drugs that suit all individuals. Genetic pharmacoepidemiology is going to play a major role in the development and evaluation of the concept of tailor-made pharmacotherapy.

Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI

Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p<0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.

Pharmacogenetics of anti-inflammatory treatment in children with asthma: rationale and design of the PACMAN cohort

AIMSnTo investigate the effects of genetic variation on treatment response to asthma medication in children and to identify (profiles of) SNPs that characterize response phenotypes.nnnMATERIAL & METHODSnThe Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects (PACMAN) study was initiated in April 2009 as an observational retrospective pharmacy-based study, including at least 1000 children with asthma medication (aged 4-12 years). Data on respiratory symptoms and medication use behavior will be collected using a questionnaire; complete medication histories will be extracted from the pharmacy information system; additional health information will be requested from the general practitioner; quality of inhalation technique and lung function measurements will be performed and saliva samples for DNA extraction and genotyping will be collected. Two groups of patients will be defined based on questionnaire data and lung function measurements: responders and nonresponders to anti-inflammatory asthma treatment. These two groups will be compared with respect to genetic variation. Corrections will be made for potential confounding factors.nnnRESULTSnThe main study end point is treatment response, including asthma control, medication use and exhaled nitric oxide as a measure of airway inflammation. Whilst our focus is on genetic factors, this study allows us to also investigate other treatment response determinants, such as inhalation technique and therapy adherence.nnnCONCLUSIONnResults from the PACMAN study could eventually lead to a more individualized therapy approach. PACMAN will focus on pharmacogenetics of asthma medication in children, while knowledge will be gained of relevant interest to the treatment of the asthma population at large.

Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study.

Background High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels. Aim To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of coronary heart disease (CHD) and other cardiovascular outcomes. Methods The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The genotyped population in the Lipid-Lowering Trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata (MTHFR 677 CC, CT, and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I+) by examining an interaction term in a proportional hazards model. Results No evidence existed of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype, a significantly protective effect against CHD [0.71 (95% CI 0.58–0.87)] was shown, although in the CT [1.25 (95% CI 0.97–1.61)] and TT groups [0.80 (95% CI 0.50–1.28)] there were no such effects (interaction hazard ratio P=0.004). The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment [0.58 (95% CI 0.44–0.78)] whereas the DD genotype showed no effect of statin therapy [1.01 (95% CI 0.84–1.20; P=0.002 for interaction]. For the endpoint all-cause mortality, no significant differences in efficacy were noted. Conclusion Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events.

Interaction between the Gly460trp α-adducin gene variant and diuretics on the risk of myocardial infarction

Introduction The Gly460Trp variant of the α-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. Objective The aim of the study was to determine whether the α-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on myocardial infarction (MI). Design, setting and participants In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case–control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis was used to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. Results The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR 0.71, 95% CI 0.55–0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58–1.33), whereas among wild-type carriers this risk was significantly lower (OR 0.62, 95% CI 0.44–0.87). The interaction between current use of diuretics and the α-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91–2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45–2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98–2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30–1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04–3.47). Conclusion This study suggests that the α-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.

Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting β2-agonists: results of the pacman cohort

BACKGROUNDnCurrent evidence suggests that asthma patients with the ADRB2 Arg16 genotype have a poorer response to long-acting β2-agonists (LABA), but the results remain inconsistent.nnnAIMnThis study assessed the association between Arg16 variants and treatment outcome in children treated with inhaled corticosteroids (ICS) and LABA.nnnMATERIALS & METHODSnADRB2 Arg16 was genotyped in 597 children (4-12 years of age) participating in the PACMAN cohort study. A questionnaire was used to assess asthma control, frequency of asthma-related emergency department visits and use of oral corticosteroids in the past year.nnnRESULTSnArg/Arg carriers with a reported use of ICS and LABA had an increased risk of oral corticosteroid use (odds ratio: 14.9; 95% CI: 1.59-140.1) and emergency department visits in the past year (odds ratio: 11.9; 95% CI: 1.22-115.8) compared to Gly/Gly carriers. This effect was not observed in Arg/Arg genotype carriers reporting ICS use only.nnnCONCLUSIONnChildren who are homozygous for ADRB2 Arg16 have an increased risk of exacerbations when treated with combined LABA and ICS.

A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide

Objectives To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide. Methods A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case–control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype. Results Two polymorphisms in the sodium channel &ggr;-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65–16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27–3.77]. Conclusions Two polymorphisms in the sodium channel &ggr;-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.

Cost Effectiveness of New Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation in Two Different European Healthcare Settings

ObjectivesOur objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country without these clinics (the UK).MethodsA decision-analytic Markov model was used to analyse the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives in the Netherlands and the UK over a lifetime horizon.ResultsIn the Netherlands, the use of rivaroxaban, apixaban, or dabigatran increased health by 0.166, 0.365, and 0.374 quality-adjusted life-years (QALYs) compared with coumarin derivatives, but also increased costs by €5,681, €4,754, and €5,465, respectively. The incremental cost-effectiveness ratios (ICERs) were €34,248, €13,024, and €14,626 per QALY gained. In the UK, health was increased by 0.302, 0.455, and 0.461 QALYs, and the incremental costs were similar for all three new oral anticoagulants (€5,118–5,217). The ICERs varied from €11,172 to 16,949 per QALY gained. In the Netherlands, apixaban had the highest chance (37xa0%) of being cost effective at a threshold of €20,000; in the UK, this chance was 41xa0% for dabigatran. The quality of care, reflected in time in therapeutic range, had an important influence on the ICER.ConclusionsApixaban, rivaroxaban, and dabigatran are cost-effective alternatives to coumarin derivatives in the UK, while in the Netherlands, only apixaban and dabigatran could be considered cost effective. The cost effectiveness of the new oral anticoagulants is largely dependent on the setting and quality of local anticoagulant care facilities.