Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Current status of the analytical validation of next generation sequencing applications for pharmacogenetic profiling.

BACKGROUND: Analytical validity is a prerequisite to use a next generation sequencing (NGS)-based application as an in vitro diagnostic test or a companion diagnostic in clinical practice. Currently, in the United States and the European Union, the intended use of such NGS-based tests does not refer to guided drug therapy on the basis of pharmacogenetic profiling of drug metabolizing enzymes, although the value of pharmacogenetic testing has been reported. However, in research, a large variety of NGS-based tests are used and have been confirmed to be at least comparable to array-based testing. METHODS AND RESULTS: A systematic evaluation was performed screening and assessing published literature on analytical validation of NGS applications for pharmacogenetic profiling of CYP2C9, CYP2C19, CYP2D6, VKORC1 and/or UGT1A1. Although NGS applications are also increasingly used for implementation assessments in clinical practice, we show in the present systematic literature evaluation that published information on the current status of analytical validation of NGS applications targeting drug metabolizing enzymes is scarce. Furthermore, a comprehensive performance evaluation of whole exome and whole genome sequencing with the intended use for pharmacogenetic profiling has not been published so far. CONCLUSIONS: A standard in reporting on analytical validation of NGS-based tests is not in place yet. Therefore, many relevant performance criteria are not addressed in published literature. For an appropriate analytical validation of an NGS-based qualitative test for pharmacogenetic profiling at least accuracy, precision, limit of detection and specificity should be addressed to facilitate the implementation of such tests in clinical use.

Evaluation of the EMPAR study population on the basis of metabolic phenotypes of selected pharmacogenes.

The impact of genetic variability of pharmacogenes as a possible risk factor for adverse drug reactions is elucidated in the EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung/English: influence of metabolic profiles on the safety of drug therapy in routine care) study. EMPAR evaluates possible associations of pharmacogenetically predicted metabolic profiles relevant for the metabolism of frequently prescribed cardiovascular drugs. Based on a German study population of 10,748 participants providing access to healthcare claims data and DNA samples for pharmacogenetic assessment, first analyses were performed and evaluated. The aim of this first evaluation was the characterization of the study population with regard to general parameters such as age, gender, comorbidity, and polypharmacy at baseline (baseline year) as well as important combinations of cardiovascular drugs with relevant genetic variants and predicted metabolic phenotypes. The study was registered in the German Clinical Trials Register (DRKS) on July 6, 2018 (DRKS00013909).

The phenotype of adverse drug effects: Do emergency visits due to adverse drug reactions look different in older people? Results from the ADRED study.

AIMS: Older patients in particular suffer from adverse drug reactions (ADR) when presenting in the emergency department. We aimed to characterise the phenotype of those ADRs, to be able to recognise an ADR in older patients. METHODS: Cases of ADRs in emergency departments collected within the multicentre prospective observational study (ADRED) were analysed (n = 2215). We analysed ADR-associated diagnoses, symptoms and their risk profiles. We present frequencies and odds ratios (OR) with 95% confidence intervals for adults (18-64 years) compared to older adults (≥65 years; young-old 65-79, old-old ≥80 years) and regression coefficients (B) for each year of age. RESULTS: Most prominent differences were seen for drug-associated confusion, dehydration, and bradycardia (OR 6.70 [1.59-28.27], B .054; OR 6.02 [2.41-15.03], B .081, and 4.82 [2.21-10.54], B .040), more likely seen in older adults. Bleedings were reported in all age groups, but gastrointestinal bleedings occurred with more than doubled chance in older adults (OR 2.46 [1.77-3.41], B .030), likewise did other bleedings such as haemorrhage from respiratory passages (OR 2.89 [1.37-6.11], B.036). Falls were more likely in older adults (OR 2.84 [1.77-4.53], B .030), while dizziness was frequent in both age groups. CONCLUSION: Our data point to differences in symptoms of ADRs between adults and older individuals, with dangerous drug-associated phenomena in the older adult such as bleedings or falls. Physicians should consider drug-associated origins of symptoms in older adults with an increased risk for serious health problems.

Personalising drug safety-results from the multi-centre prospective observational study on Adverse Drug Reactions in Emergency Departments (ADRED).

PURPOSE: Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits. METHODS: We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment. RESULTS: A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54-28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49-3.47), antibiotics (OR 2.65, 95% CI 1.78-3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54-3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46-3.81), antidepressants (OR 2.10, 95% CI 1.57-2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15-3.84), opioids (OR 1.79, 95% CI 1.26-2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01-1.72). CONCLUSIONS: Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs. TRIAL REGISTRATION: DRKS-ID: DRKS00008979.

Prevalence of Psychotropic Drugs in Cases of Severe Adverse Drug Reactions Leading to Unplanned Emergency Visits in General Hospitals.

INTRODUCTION: The prevalence of psychotropic drug use in our society is increasing especially in older adults, thereby provoking severe adverse drug reactions (ADR). To identify specific patient risk profiles associated with psychotropic drug use in the situation of polymedication. METHODS: Cases of ADRs in general emergency departments (ED) collected within the multi-center prospective observational study (ADRED) were analyzed (n=2215). We compared cases with use of psychotropic drugs and without concerning their clinical presentation at the ED. RESULTS: A third of patients (n=731, 33%) presenting to the ED with an ADR took at least 1 psychotropic drug. Patients with psychotropic drug use tended to be older, more often female, and took a higher number of drugs (all p<0.001). The frequency of falls was almost 3 times higher than compared to the non-psychotropic drug group (10.5 vs. 3.9%, p<0.001), and similar syncope was also more often seen in the psychotropic drug users (8.8 vs. 5.5%, p=0.004). The use of psychotropic drugs increased the risk for falls by a factor of 2.82 (OR, 95% CI (1.90-4.18)), when adjusting for gender, age, numbers of pre-existing diseases, and drugs, respectively. DISCUSSION: The association of psychotropic drug use with fall and syncope in combination with polymedication and older age leads to the suspicion that psychotropic drugs might be potentially harmful in specific risk populations such as older adults. It may lead us to thoroughly weigh the benefit against risk in a patient-oriented way, leading to an integrative personalized therapy approach.

A serotonin transporter polymorphism is associated with postoperative nausea and vomiting: An observational study in two different patient cohorts.

BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are well described, whereas genetic findings are conflicting. OBJECTIVE: The aim of this study was to investigate a possible association of genetic variants and nongenetic variables with the incidence and severity of PONV. DESIGN: A prospective observational study in two independent and different patient cohorts. SETTING: Two independent patient cohorts differing in surgical procedures were enrolled in two tertiary care hospitals between 2008 and 2016. PATIENTS: Consecutive patients of European origin undergoing elective surgery in two university hospitals. Clinical data were collected up to 24 h after surgery, and blood was drawn for genotyping. Of 2773 patients enrolled, 918 (Cohort A) and 1663 (Cohort B) with complete data sets were analysed. MAIN OUTCOME MEASURE: Patients were allocated to one of three groups (No PONV, Intermediate PONV or Severe PONV) depending on the frequency of vomiting, the severity of nausea and the need for antiemetics. Clinical variables and 13 genetic variants of seven candidate genes were evaluated for association with these three phenotypes. The cohorts were analysed separately by ordinal logistic regression analysis, treating PONV as a dependent ordinal three-stage variable. Odds ratios (ORs) with 95% confidence intervals were calculated. RESULTS: In Cohort A, the main predictors for PONV were female sex [OR (95% CI): 3.6 (2.7 to 4.8), P < 0.0001], nonsmoking status 1.8 (1.3 to 2.5), P < 0.001, the SS genotype (5-HTTLPR, rs4795541) of the promoter polymorphism in the serotonin transporter 1.5 (1.1 to 2.1), P = 0.019, and patient age 0.99 (0.98 to 0.99), P = 0.013. Analysis of Cohort B was consistent with these findings [5-HTTLPR: 1.8 (1.4 to 2.3), P < 0.00001]. Sex-specific regression models confirmed this 5-HTTLPR association in women and men. CONCLUSION: In two independent cohorts, in addition to the well known clinical factors, a polymorphism of 5-HTTLPR in the serotonin transporter was independently associated with PONV. A possible evaluation of this biomarker to improve risk prediction within the scope of precision medicine should be considered. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT03490175.

Medical education in pharmacogenomics-results from a survey on pharmacogenetic knowledge in healthcare professionals within the European pharmacogenomics clinical implementation project Ubiquitous Pharmacogenomics (U-PGx).

PURPOSE: Due to the diversity within Europe, the implementation of pharmacogenomic testing in clinical practice faces specific challenges. In the context of the European pharmacogenomics implementation project "Ubiquitous Pharmacogenomics" (U-PGx; funded by the European Commission), we studied the current educational background. METHODS: We developed a questionnaire including 29 questions. It was spread out to healthcare professionals working at the future implementation sites (in Austria, Greece, Italy, Netherlands, Slovenia, Spain and Great Britain) of the U-PGx project in preparation of an educational programme. Aim of the survey was to analyse the current educational situation at the implementation sites. RESULTS: In total, 70 healthcare professionals participated in the survey. Of participants, 84.3% found pharmacogenomics relevant to their current practice, but experience was still rare. More than two-thirds (65.7%) did not order nor recommend a pharmacogenomic test in the past year. This was mainly attributed to not having enough knowledge on pharmacogenomics (40.0%). Needs were identified in application of pharmacogenomics (identifying drugs 41.4%, interpreting test results 37.2%) as well as in underlining mechanisms (better knowledge on drug metabolism 67.1%, better knowledge on basic principles of pharmacogenomics 60.0%). CONCLUSIONS: This study analysed the specific attitudes, experience and education on pharmacogenomics of future users. There was a general positive attitude and interest towards pharmacogenomic testing. However, the grade of own experience, and knowledge about application and interpretation of pharmacogenomics caused uncertainty. Thus, education and training programmes may be helpful for implementation of pharmacogenomics at a homogenous level within Europe.

Individualized versus standardized risk assessment in patients at high risk for adverse drug reactions (IDrug) - study protocol for a pragmatic randomized controlled trial.

BACKGROUND: Elderly patients are particularly vulnerable to adverse drug reactions, especially if they are affected by additional risk factors such as multimorbidity, polypharmacy, impaired renal function and intake of drugs with high risk potential. Apart from these clinical parameters, drug safety and efficacy can be influenced by pharmacogenetic factors. Evidence-based recommendations concerning drug-gene-combinations have been issued by international consortia and in drug labels. However, clinical benefit of providing information on individual patient factors in a comprehensive risk assessment aiming to reduce the occurrence and severity of adverse drug reactions is not evident. Purpose of this randomized controlled trial is to compare the effect of a concise individual risk information leaflet with standard information on risk factors for side effects. METHODS/DESIGN: The trial was designed as a prospective, two-arm, randomized, controlled, multicenter, pragmatic study. 960 elderly, multimorbid outpatients in general medicine are included if they take at least one high risk and one other long-term drug (polymedication). As high risk "index drugs" oral anticoagulants and antiplatelets were chosen because of their specific, objectively assessable side effects. Following randomization, test group patients receive an individualized risk assessment leaflet evaluating their personal data concerning bleeding- and thromboembolic-risk-scores, potential drug-drug-interactions, age, renal function and pharmacogenetic factors. Control group patients obtain a standardized leaflet only containing general information on these criteria. Follow-up period is 9 months for each patient. Primary endpoint is the occurrence of a thromboembolic/bleeding event or death. Secondary endpoints are other adverse drug reactions, hospital admissions, specialist referrals and medication changes due to adverse drug reactions, the patients' adherence to medication regimen as well as health related quality of life, mortality and resulting costs. DISCUSSION: Despite extensive evidence of risk factors for adverse drug reactions, there are few prospective trial data about an individualized risk assessment including pharmacogenetic information to increase patient safety. By conducting a health economic analysis, we will evaluate if the application of an individualized drug therapy in daily routine is cost-effective. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00006256 , date of registration 09/01/15.

Gene regulatory biomarker identification for skin toxicities induced by EGFR inhibitor treatment.

1 Federal Institute for Drugs and Medical Devices (BfArM), Research Division, Bonn, 2 Institute of Pharmacology of Natural Products and Clinical Pharmacology, 3 Department of Internal Medicine II, University of Ulm, Ulm, 4 Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care Medicine, Clinics Kempten-Oberallgäu, Kempten, and 5 Department of Internal Medicine I, University of Ulm, Ulm, and 4 Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Germany.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

The influence of age, gender and pharmacogenetic profiles on the perspective on medicines in the German EMPAR study.

BACKGROUND: Pharmacogenetic testing in routine care could provide benefits for patients, doctors and statutory health insurances. Therefore, the aim of the retrospective, observational study Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung (EMPAR) was to analyze the relationship between pharmacogenetic profiles, the risk of adverse drug reactions, and patients' perceptions of drug therapy in 10748 adult (≥18 years) participants in Germany. METHODS: A questionnaire was used to assess views and beliefs about medicines and participants individual perception of sensitivity to drug therapies. The questionnaire consisted of the Beliefs about Medicines Questionnaire (BMQ)-General scales (Overuse, Harm, Benefit), the Perceived Sensitivity to Medicines (PSM), Natural Remedy, and Gene Testing scales. The influence of gender, age, study collective, genotype and phenotype of relevant pharmacogenes on participant's perception were evaluated. RESULTS: Overuse, PSM and Benefit scores were significantly higher among patients of the collective International Classification of Diseases and Health Related Disorders (ICD)-10 Y57.9! diagnosis, which indicates complications related to drugs, compared to the anticoagulant/antiplatelet and cholesterol-lowering drug collective. Age and gender also played a significant role in patients' perceptions, with younger patients and female participants more likely to believe in medication overuse according to the Overuse scale score compared to older and male participants. Female participants compared to male participants and the old age group compared to the young and/or middle-age subgroup, scored higher in PSM and/or Harm scales, respectively. Only a tendency of increased Harm, Overuse and PSM scores was observed in the participant group with five or more relevant actionable variants compared to subgroups with 0 up to 4 variants. CONCLUSIONS: In conclusion, patients' beliefs about medicines and their drug sensitivity perceptions are influenced by various factors including age, gender, previous complications with medicines, and with some tendency also pharmacogenetic profiles. The higher association with more negative views related to treatment indicates that there is a need to target the underlying issues in affected patient groups in order to improve compliance to treatment and outcomes in routine care. Trial registration: EMPAR was registered in the German Clinical Trials Register (DRKS) on 06 July 2018 (DRKS00013909).

Association of Polymorphic Cytochrome P450 Enzyme Pathways with Falls in Multimedicated Older Adults.

OBJECTIVES: Dose exposure is considered relevant for drug-associated falls in older adults, pointing to an importance of drug metabolism. Aim was to analyze individual factors altering drug metabolism such as enzyme saturation by drug exposure and pharmacogenetics in the context of drug-associated falls. DESIGN: Prospective population-based study (ActiFE-Ulm study). SETTING AND PARTICIPANTS: Community-dwelling older adults. METHODS: Focus was laid on the metabolism by polymorphic cytochrome P450 (CYP) enzymes CYP2C19, 2C9, and 2D6. Relevant variants of pharmacogenes were analyzed. Logistic binary regression analysis was used to calculate odds ratios (ORs) and 95% CIs for falls observed prospectively over a 1-year period with drug metabolism characteristics. RESULTS: In total, 1377 participants were included in the analysis. Although the phenotype predicted by the genotype was not, the use of drugs metabolized by CYP2C19 was associated with falls. Drugs not known as fall risk-increasing drugs (FRIDs; ie, non-FRIDs), but metabolized by CYP2C19, showed an OR of 1.46 (1.11-1.93) in adjusted analysis. Significant effect modification was observed for a reduced CYP2C19 activity phenotype with non-FRIDs metabolized by CYP2C19. CONCLUSIONS AND IMPLICATIONS: This study suggests an association between the occurrence of falls in older adults and the metabolic capacity of CYP2C19. Thus, an important step toward prevention of falls might be to personalize dosage and treatment length of the main drug classes known to be CYP2C19 substrates, such as many antidepressants, opioids, and sedatives, but also proton pump inhibitors in particular in poor and intermediate metabolizers.

Cluster-localized sparse logistic regression for SNP data.

The task of analyzing high-dimensional single nucleotide polymorphism (SNP) data in a case-control design using multivariable techniques has only recently been tackled. While many available approaches investigate only main effects in a high-dimensional setting, we propose a more flexible technique, cluster-localized regression (CLR), based on localized logistic regression models, that allows different SNPs to have an effect for different groups of individuals. Separate multivariable regression models are fitted for the different groups of individuals by incorporating weights into componentwise boosting, which provides simultaneous variable selection, hence sparse fits. For model fitting, these groups of individuals are identified using a clustering approach, where each group may be defined via different SNPs. This allows for representing complex interaction patterns, such as compositional epistasis, that might not be detected by a single main effects model. In a simulation study, the CLR approach results in improved prediction performance, compared to the main effects approach, and identification of important SNPs in several scenarios. Improved prediction performance is also obtained for an application example considering urinary bladder cancer. Some of the identified SNPs are predictive for all individuals, while others are only relevant for a specific group. Together with the sets of SNPs that define the groups, potential interaction patterns are uncovered.

Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.

Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.

IT behind a platform for Translational Cancer Research - concept and objectives.

The German Consortium for Translational Cancer Research (DKTK) and the Rhine-Main Translational Cancer Research Network (RM-TCRN) are designed to exploit large population cohorts of cancer patients for the purpose of bio-banking, clinical trials, and clinical cancer registration. Hence, the success of these platforms is heavily dependent on the close interlinking of clinical data from cancer patients, information from study registries, and data from bio-banking systems of different laboratories and scientific institutions. This article referring to the poster discusses the main challenges of the platforms from an information technology point of view, legal and data security issues, and outlines an integrative IT-concept concerning a decentralized, distributed search approach where data management and search is in compliance with existing legislative rules.

Molecular Genetic Techniques in Biomarker Analysis Relevant for Drugs Centrally Approved in Europe.

On the basis of scientific evidence, information on the option, recommendation or requirement to test for pharmacogenetic or pharmacogenomic biomarkers is incorporated in the Summary of Product Characteristics of an increasing number of drugs in Europe. A screening of the Genetic Testing Registry (GTR) showed that a variety of molecular genetic testing methods is currently offered worldwide in testing services with regard to according drugs and biomarkers. Thereby, among the methodology indicated in the screened GTR category 'Molecular Genetics', next-generation sequencing is applied for identification of the largest proportion of evaluated biomarkers that are relevant for therapeutic management of centrally approved drugs in Europe. However, sufficient information on regulatory clearances, clinical utility, analytical and clinical validity of applied methods is rarely provided.

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes.

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equivalent to the conventional 7-SNP NAT2 genotype.

Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P<0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity.