A. H. Maitland-van der Zee

Pharmacogenetics: from bench to byte--an update of guidelines.

Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics‐based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine‐S‐methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA‐B44, HLA‐B*5701, CYP3A5, and factor V Leiden (FVL).

Phenotype Standardization for Statin‐Induced Myotoxicity

Statins are widely used lipid‐lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin‐related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid‐treated asthmatic children

To cite this article: Koster ES, Maitland‐van der Zee A‐H, Tavendale R, Mukhopadhyay S, Vijverberg SJH, Raaijmakers JAM, Palmer CNA. FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid‐treated asthmatic children. Allergy 2011; 66: 1546–1552.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Abstract Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter‐individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti‐inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors.

Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users

Summary.  Background:  The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known.

The effectiveness of hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) in the elderly is not influenced by apolipoprotein E genotype.

We aimed to assess whether the effectiveness of statins in the prevention of myocardial infarction, stroke and total mortality is influenced by apolipoprotein E (apoE) genotype in an elderly population. We used data from the Rotterdam Study, a prospective population-based cohort study in the Netherlands which started in 1990 and included 7983 subjects aged 55 years and older. Subjects who were treated with cholesterol lowering drugs at baseline or with a serum total cholesterol > or = 6.5 mmol/l at baseline were included. We compared the incidence of myocardial infarction, stroke and total mortality in subjects who received > or = 2 years of statin treatment with that in subjects who had been treated for less than 2 years, and in untreated subjects, using a Cox proportional hazard model with cumulative statin use defined as time-dependent covariates. The adjusted relative risk of all-cause mortality was 0.79 [95% confidence interval (CI) 0.51-1.22] and of myocardial infarction and stroke 0.50 (95% CI 0.28-0.91) for subjects treated with statins for > or = 2 years compared to untreated subjects. The adjusted relative risks for subjects with the epsilon4 allele were 0.91 (95% CI 0.45-1.84) for all-cause mortality and 0.63 (95% CI 0.23-1.78) for myocardial infarction and stroke. In subjects without the epsilon4 allele, adjusted relative risks were 0.71 (95% CI 0.41-1.24) for all-cause mortality and 0.46 (95% CI 0.22-0.95) for myocardial infarction and stroke. We found a protective effect of statins on the risk of myocardial infarction and stroke that was independent of apoE genotype. The protective effect of statins on total mortality was not statistically significant, but did not seem to differ between subjects with different apoE genotypes.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2–1.4), P=1.0 × 10−8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01–1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01–1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15–1.32), P=1.9 × 10−9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Patients Benefit From Genetics-Guided Coumarin Anticoagulant Therapy

Observational studies have overwhelmingly shown that variants in the genes CYP2C9 and VKORC1 are significant determinants of individual dose of coumarin anticoagulants needed to maintain a therapeutic international normalized ratio (INR). 1 Until recently, however, few randomized clinical trials had been performed relating to the use of genetic data to predict dosing. Three sucsh clinical trials have now reported their findings.

An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.

Background: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.