Search

Aim: Drug-induced long QT syndrome (diLQTS), an adverse effect of many drugs, can lead to sudden cardiac death. Candidate genetic variants in cardiac ion channels have been associated with diLQTS, but several limitations of previous studies hamper clinical utility. Materials & methods: Thus, the purpose of this study was to assess the associations of KCNE1 -D85N, KCNE2 -I57T and SCN5A -G615E with diLQTS in a large observational case-control study (6,083 self-reported white patients treated with 27 different high-risk QT-prolonging medications; 12.0% with diLQTS). Results: KCNE1 -D85N significantly associated with diLQTS (adjusted odds ratio: 2.24 [95% CI: 1.35-3.58]; p = 0.001). Given low minor allele frequencies, the study had insufficient power to analyze KCNE2 -I57T and SCN5A -G615E. Conclusion: KCNE1 -D85N is a risk factor for diLQTS that should be considered in future clinical practice guidelines.

Drug-induced long QT syndrome (diLQTS) is an adverse effect of many commonly prescribed drugs, and it can increase the risk for lethal ventricular arrhythmias. Genetic variants in pharmacodynamic genes have been associated with diLQTS, but the strength of the evidence for each of those variants has not yet been evaluated. Therefore, the purpose of this review was to evaluate the strength of the evidence for pharmacodynamic genetic variants associated with diLQTS using a novel, semiquantitative scoring system modified from the approach used for congenital LQTS. KCNE1- D85N and KCNE2 -T8A had definitive and strong evidence for diLQTS, respectively. The high level of evidence for these variants supports current consideration as risk factors for patients that will be prescribed a QT-prolonging drug.

Aim: To determine the association of coenzyme Q10 (CoQ10) use with the resolution of statin-associated muscle symptoms (SAMS). Patients & methods: Retrospective analysis of a large, multicenter survey study of SAMS (total n = 511; n = 64 CoQ10 users). Univariate and multivariate logistic regression models assessed the association between CoQ10 use and the resolution of SAMS. Results: The frequency of SAMS resolution was similar between CoQ10 users and non-users (25% vs 31%, respectively; unadjusted odds ratio [OR]: 0.75 [95% CI: 0.41-1.38]; p = 0.357). Similarly, CoQ10 use was not significantly associated with the resolution of SAMS in multivariable models adjusted for SAMS risk factors (OR: 0.84 [95% CI: 0.45-1.55]; p = 0.568) or adjusted for significant differences among CoQ10 users and non-users (OR: 0.82 [95% CI: 0.45-1.51]; p = 0.522). Conclusion: CoQ10 was not significantly associated with the resolution of SAMS.

The primary research approach in pharmacogenetics has been candidate gene association studies (CGAS), but pharmacogenomic genome-wide association studies (GWAS) are becoming more common. We are now at a critical juncture when the results of those two research approaches, CGAS and GWAS, can be compared in pharmacogenetics. We analyzed publicly available databases of pharmacogenetic CGAS and GWAS (i.e., the Pharmacogenomics Knowledgebase [PharmGKB ® ] and the NHGRI-EBI GWAS catalog) and the vast majority of variants (98%) and genes (94%) discovered in pharmacogenomic GWAS were novel (i.e., not previously studied CGAS). Therefore, pharmacogenetic researchers are not selecting the right candidate genes in the vast majority of CGAS, highlighting a need to shift pharmacogenetic research efforts from CGAS to GWAS.

Current guideline recommendations for pharmacogenetic testing for clopidogrel by the American Heart Association/American College of Cardiology (AHA/ACC) contradict the Clinical Pharmacogenetics Implementation Consortium and the US FDA. The AHA/ACC recommends against routine pharmacogenetic testing for clopidogrel because no randomized controlled trials have demonstrated that testing improves patients' outcomes. However the AHA/ACC and the National Comprehensive Cancer Network (NCCN) recommend other pharmacogenetic tests in the absence of randomized controlled trials evidence. Using clopidogrel as a case example, we compared the evidence for other pharmacogenetic tests recommended by the AHA/ACC and NCCN. In patients that received percutaneous coronary intervention, the evidence supporting pharmacogenetic testing for clopidogrel is stronger than other pharmacogenetic tests recommended by the AHA/ACC and NCCN.

Aim: 'Pharmacoepigenomics' methods informed by omics datasets and pre-existing knowledge have yielded discoveries in neuropsychiatric pharmacogenomics. Now we evaluate the generality of these methods by discovering an extended warfarin pharmacogenomics pathway., Materials & Methods: We developed the pharmacoepigenomics informatics pipeline, a scalable multi-omics variant screening pipeline for pharmacogenomics, and conducted an experiment in the genomics of warfarin., Results: We discovered known and novel pharmacogenomics variants and genes, both coding and regulatory, for warfarin response, including adverse events. Such genes and variants cluster in a warfarin response pathway consolidating known and novel warfarin response variants and genes., Conclusion: These results can inform a new warfarin test. The pharmacoepigenomics informatics pipeline may be able to discover new pharmacogenomics markers in other drug-disease systems.

Aim: This study aimed to examine pharmacogenomic test results and patient perspectives at an academic cardiovascular medicine clinic., Patients & Methods: Test results for three common cardiovascular drug-gene tests (warfarin- CYP2C9-VKORC1 , clopidogrel- CYP2C19 and simvastatin- SLCO1B1 ) of 208 patients in the Ohio State University-Coriell Personalized Medicine Collaborative were examined to determine the incidence of potentially actionable test results. A post-hoc, anonymous, patient survey was also conducted., Results: Potentially actionable test results for at least one of the three drug-gene tests were determined in 170 (82%) patients. Survey responses (n = 134) suggested that patients generally considered their test results to be important (median of 7.5 on a 10-point scale of importance) and were interested (median of 7.3 on a 10-point scale of interest) in a Clinical Pharmacogenomic Service., Conclusion: Attitudes toward pharmacogenomic testing were generally favorable, and potentially actionable test results were not uncommon in this cardiovascular medicine cohort., Competing Interests: Financial & competing interests disclosure The Coriell Personalized Medicine Collaborative was funded by the William G. Rohrer Foundation, the RNR Foundation and a grant from the endowment of the Coriell Institute for Medical Research. This work was supported by the NIH (grant awards R21HG006575, K23GM100372, L32MD006365, L30HL110279, UL1TR001070) and the American Heart Association (grant award 14POST20100054). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the American Heart Association. This work was also supported in part by the Ohio State University Comprehensive Cancer Center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

The University of Michigan College of Pharmacy has made substantial investment in the area of pharmacogenomics to further bolster its activity in pharmacogenomics research, implementation and education. Four tenure-track faculty members have active research programs that focus primarily on the discovery of functional polymorphisms (HJ Zhu), and genetic associations with treatment outcomes in patients with cancer (DL Hertz), cardiovascular disease (JA Luzum) and psychiatric conditions (VL Ellingrod). Recent investments from the University and the College have accelerated the implementation of pharmacogenetics broadly across the institution and in targeted therapeutic areas. Students within the PharmD and other health science professions receive substantial instruction in pharmacogenomics, in preparation for careers in biomedical health in which they can contribute to the generation, dissemination and utilization of pharmacogenomics knowledge to improve patient care.

Aim: Our aim was to evaluate physicians' attitudes toward pharmacogenetic testing before and after pharmacogenetic education., Methods: In total, 12 physicians (˜40% response rate) completed a survey with eight questions on 10-point scales on their attitudes toward pharmacogenetic testing before and after a 1-h grand rounds presentation on pharmacogenetics. Differences in question scores overall, among training levels (resident/fellow/attending), and specific drugs (clopidogrel/simvastatin/warfarin) were assessed using Wilcoxon signed-rank and exact Kruskal-Wallis tests., Results & Conclusion: The scores for all eight questions increased, with statistically significant (p < 0.05) increases for four out of eight questions. The scores were similar among training levels, but the postscores for clopidogrel were significantly higher than for simvastatin and warfarin. In conclusion, brief pharmacogenetic education can significantly affect physicians' attitudes toward pharmacogenetic testing.

Introduction: Buprenorphine is a lipid-soluble pharmaceutic used in the management of chronic pain. It is a partial agonist at μ-opioid receptors, an antagonist at κ-opioid receptors, an agonist at δ-opioid receptors and a partial agonist at ORL-1 (nociceptin) receptors., Methods: An extensive literature search, including Google Scholar and Pubmed database, was conducted. Terms including and associated to 'efficacy of transdermal buprenorphine' were utilized to procure contemporary research articles in order to evaluate and compare the transdermal buprenorphine patch to commonly used traditional pain management medications., Results: Transdermal buprenorphine has demonstrated better efficacy than conventional pain management pharmacotherapies. Side effects were similar to those associated with other opioids and included headache, dizziness, somnolence, constipation, dry mouth, nausea, vomiting, pruritus and erythema. Similar to transdermal delivery systems used with other medication, transdermal buprenorphine was associated with application-site pruritus and application-site reactions., Conclusion: Transdermal buprenorphine has significant potential for managing chronic pain. In addition to increased convenience and efficacy, advantages of transdermal buprenorphine include decreased tolerance and decreased withdrawal.