clinical decision support; electronic medical record; genetic counseling; genomic counseling; pharmacogenomics
Second-generation antipsychotics can greatly improve symptoms of psychosis-spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient’s risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical factors. In addition, genetic variations in pathways associated with satiety are increasingly recognized as potential contributors to antipsychotic-associated weight gain. Polymorphisms in the leptin gene, as well as the leptin receptor gene, are potential pharmacogenetic markers associated with these outcomes. This article summarizes evidence for the associations of the leptin gene and the leptin receptor gene polymorphisms with antipsychotic-induced weight gain, potential mechanisms underlying these relationships, and discusses areas for future pharmacogenetic investigation.
antipsychotic; leptin; leptin receptor; obesity; polymorphism; weight gain
The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors.
Patients & methods
The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes.
Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors.
In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans.
CYP2C9; CYP4F2; genotype; NQO1; VKORC1; warfarin
Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of drugs approved for RA and the wide variations in cost and treatment response, markers of efficacy would be very useful. Several candidate genes, including HLA-DRB1 alleles and those encoding TNF, TNF receptors, and Fc receptors, have been examined for a role in the response to treatment with etanercept. In this review, we discuss pharmacogenetic studies of etanercept in RA and other diseases, and comment on the future of such analyses to advance the goal of personalized medicine in RA.
The aim was to determine if the University of Minnesota (MN, USA) healthcare students’ perceived value of pharmacogenomics matches their self-observed comfort and education in pharmacogenomics.
Materials & methods
A 24-question, anonymous, online survey was distributed to all pharmacy, nursing and medical students enrolled at the University of Minnesota.
Among healthcare students, 70.6% agreed or strongly agreed that pharmacogenomics should be an important part of their curriculum; however, only 11.1% agreed or strongly agreed that it actually is. Only 29.7% of students reported taking a genetics course that specifically addressed the applications of genetics in pharmacy, and those students were more likely to feel comfortable interpreting information from a pharmacogenetics test, answering questions on pharmacogenomics, educating patients on risks and benefits of testing, and were comfortable that they knew which medications required pharmacogenomics testing.
Healthcare students consider pharmacogenomics to be an important area of clinical practice; yet generally express it has not been an important part of their curriculum. Education emphasizing medical applications of pharmacogenomics can increase student comfort level in pharmacogenomics practice.
curriculum; education; healthcare; pharmacogenetics; pharmacogenomics; pharmacy; student; survey
A key function of BRCA1 and BRCA2 is the participation in dsDNAbreak repair via homologous recombination. BRCA1 and BRCA2 mutations, which occur in most hereditary ovarian cancers (OCs) and approximately 10% of all OC cases, are associated with defects in homologous recombination and genomic instability, a phenotype termed ‘BRCAness’. The clinical effects of BRCA1 and BRCA2 mutations have commonly been analyzed together; however, it is becoming increasingly apparent that these mutations do not have the same effects in OC. Recently, three major reports highlighted the unequal clinical characteristics of OCs with BRCA1 and BRCA2 mutations. All studies demonstrated that BRCA2-mutated patients are associated with better survival and therapeutic response than BRCA1-mutated and wild-type patients with serous OC. The differing prognostic effects of the BRCA2 and BRCA1 mutations is likely due to differing roles of BRCA1 and BRCA2 in homologous recombination repair and a stronger association between the BRCA2 mutation and a hypermutator phenotype. These new findings have potentially important implications for clinical management of patients with serous OC.
BRCA mutation; drug response; homologous recombination; ovarian cancer; PARP inhibitor; survival
We genotyped 326 “frequently medicated” individuals of European-descent in Vanderbilt’s biorepository linked to de-identified electronic medical records, BioVU, on the ADME Core Panel to assess quality and performance of the assay. We compared quality control metrics and determined the extent of direct and indirect marker overlap between the ADME Core Panel and the Illumina Omni1-Quad. We found the quality of the ADME Core Panel data to be high, with exceptions in select copy number variants (CNVs) and markers in certain genes (notably CYP2D6). Most of the common variants on the ADME panel are genotyped by the Omni1, but absent rare variants and CNVs could not be accurately tagged by single markers. Finally, our frequently medicated study population did not convincingly differ in allele frequency from reference populations, suggesting that heterogeneous clinical samples (with respect to medications) follow similar allele frequency distributions in pharmacogenetics genes as their appropriate reference populations.
ADME; pharmacogenomics; pharmacogenetics; BioVU; biorepository; CYP2D6; personalized medicine; precision medicine
drug; genetics; GWAS; health disparities; heritability; pharmacoethnicity; pharmacogenomics
In order to improve therapeutic outcomes, there is a tremendous need to identify patients who are likely to respond to a given asthma treatment. Pharmacogenomic studies have explained a portion of the variability in drug response and provided an increasing list of candidate genes and SNPs. However, as phenotypic variation arises from a network of complex interactions among genetic and environmental factors, rather than individual genes or SNPs, a multidisciplinary, systems-level approach is required in order to understand the inter-relationships among these factors. Systems biology, which seeks to capture interactions between genetic factors and other variables, offers a promising approach to improved therapeutic outcomes in asthma. This aritcle will review and update progress in the pharmacogenomics of asthma and then discuss the application of systems biology approaches to asthma pharmacogenomics.
asthma; genes; GWAS; network medicine; pharmacogenomics; SNP; systems biology
This study evaluated the impact of 6789 SNPs on treatment response to antipsychotics in Caucasian patients from the CATIE study.
Materials & methods
An Illumina (CA, USA) BeadChip was designed that targeted genes potentially impacting disease risk, disease presentation or antipsychotic response. SNPs tagged regions of linkage disequilibrium or functional variants not detectable using previous genotypes for CATIE. Change in Positive and Negative Syndrome scale total score was modeled using a mixed model repeated measures method that assumed a 30-day lag period. Genetic association analysis was performed using linear regression.
Association analysis identified 20 SNPs with p-values of ≤5 × 10−4. Many of these are in genes previously implicated in schizophrenia and other neuropsychiatric diseases.
The targeted approach identified SNPs possibly influencing response to antipsychotic drugs in Caucasian patients suffering from schizophrenia. The findings support a biological link between disease risk and presentation and antipsychotic response.
neuropsychiatric genes; olanzapine; perphenazine; quetiapine; risperidone; ziprasidone
Acute myelogenous leukemia (AML) is an extremely heterogeneous neoplasm with several clinical, pathological, genetic and molecular subtypes. Combinations of various doses and schedules of cytarabine and different anthracyclines have been the mainstay of treatment for all forms of AMLs in adult patients. Although this combination, with the addition of an occasional third agent, remains effective for treatment of some young-adult patients with de novo AML, the prognosis of AML secondary to myelodysplastic syndromes or myeloproliferative neoplasms, treatment-related AML, relapsed or refractory AML, and AML that occurs in older populations remains grim. Taken into account the heterogeneity of AML, one size does not and should not be tried to fit all. In this article, the authors review currently understood, applicable and relevant findings related to cytarabine and anthracycline drug-metabolizing enzymes and drug transporters in adult patients with AML. To provide a prime-time example of clinical applicability of pharmacogenomics in distinguishing a subset of patients with AML who might be better responders to farnesyltransferase inhibitors, the authors also reviewed findings related to a two-gene transcript signature consisting of high RASGRP1 and low APTX, the ratio of which appears to positively predict clinical response in AML patients treated with farnesyltransferase inhibitors.
acute myelogenous leukemia; AML; anthracycline; APTX; ara-C; cytarabine; farnesyltransferase; pharmacogenomic; RASGRP1
Established in 2002, the Ohio State University Medical Center Program in Pharmacogenomics, lead by Wolfgang Sadee, is comprised of nearly 50 members dedicated to the discovery, investigation and translation of genetic biomarkers with the primary goal of advancing personalized healthcare. This article describes the research teams, bioinformatics infrastructure, supporting laboratories and Centers for Personalized Healthcare and for Clinical and Translational Science, current molecular genetic studies, translational and clinical pharmacogenomic studies, examples of biomarkers under development, and the future directions of the program.
Drug addiction continues to be a serious medical and social problem. Vulnerability to develop an addiction to drugs is dependent on genetic, environmental, social and biological factors. In particular, the interactions of environmental and genetic factors indicate the significance of epigenetic mechanisms, which have been found to occur in response to illicit drug use or as underlying factors in chronic substance abuse and relapse. Epigenetics is defined as the heritable and possibly reversible modifications in gene expression that do not involve alterations in the DNA sequence. This review discusses the various types of epigenetic modifications and their relevance to drug addiction to elucidate whether epigenetics is a predisposing factor, or a response to, developing an addiction to drugs of abuse.
alcohol; azacitidine; cocaine; Depakote; dependence; epigenetic; gene; histone; methylation; opioid; SAHA; sodium butyrate; suberoylanilide; hydroxamic acid; trichostatin A; valproic acid
Tacrolimus is an immunosuppressant used in transplantation. This article reports the validation of the authors’ recently developed genetics-based tacrolimus equation that predicts troughs.
Validation was performed in an independent cohort of 795 kidney transplant recipients receiving tacrolimus. The performance of the equation to predict initial troughs was assessed by calculating the bias and precision of the equation. For all troughs in the first 6 months post-transplant, a comparison was made between the troughs predicted using the equation versus those predicted using a basic apparent clearance model with no covariates.
For initial troughs, the equation had a low bias (0.2 ng/ml) and high precision (1.8 ng/ml). For all troughs, the equation predicted troughs significantly better than the basic apparent clearance model.
The tacrolimus equation had good bias and precision in predicting initial troughs and performed better than a basic apparent clearance model for all the troughs.
clearance equation; CYP3A5; kidney transplant; pharmacogenetics; pharmacokinetics; polymorphism; tacrolimus; trough; validation
Skeletal muscle toxicity is the primary adverse effect for statins. In this review, we summarize current knowledge regarding the genetic and non-genetic determinants of risk for statin induced myopathy. Many genetic factors were initially identified through candidate-gene association studies (CGAS) limited to pharmacokinetic (PK) targets. Through genome-wide association studies (GWAS), it has become clear that SLCO1B1 is among the strongest PK predictors of myopathy risk. GWAS have also expanded our understanding of pharmacodynamic (PD) candidate genes, including RYR2. It is anticipated that deep re-sequencing efforts will define new loci with rare variants that contribute as well, and sophisticated computational approaches will be needed to characterize gene-gene (GxG) and gene-environment (GxE) interactions. Beyond environment, race is a critical covariate, and its influence is only partly explained by geographic differences in the frequency of known PD and PK variants. As such, admixture analyses will be essential to a full understanding of statin-induced myopathy.
statin; myopathy; pharmacokinetic; pharmacodynamics; candidate gene studies; genome-wide studies; ancestry; admixture; covariate; gene-gene interactions
computational biology; drug–drug networks; systems biology
In the past decade, significant strides have been made in the area of cardiovascular pharmacogenomic research, with the discovery of associations between certain genotypes and drug-response phenotypes. While the motivations for personalized and predictive medicine are promising for patient care and support a model of health system efficiency, the implementation of pharmacogenomics for cardiovascular therapeutics on a population scale faces substantial challenges. The greatest obstacle to clinical implementation of cardiovascular pharmacogenetics may be the lack of both reproducibility and agreement about the validity and utility of the findings. In this review, we present the scientific evidence in the literature for diagnostic variants for the US FDA-labeled cardiovascular therapies, namely CYP2C19 and clopidogrel, CYP2C9/VKORC1 and warfarin, and CYP2D6/ADRB1 and β-blockers. We also discuss the effect of HMGCR/LDLR in decreasing the effectiveness of low-density lipoprotein cholesterol with statin therapy, the SLCO1B1 genotype and simvastatin myotoxicity, and ADRB1/ADD1 for antihypertensive response.
biomarker; cardiovascular; clinical utility; clopidogrel; drug label; genetics; personalized medicine; pharmacogenetics; predictive medicine; warfarin
To extend to biomarker studies the consensus clinical significance criterion of a three-point difference in Hamilton Rating Scale for Depression.
Materials & methods
We simulated datasets modeled on large clinical trials.
In a typical clinical trial comparing active treatment and placebo, a difference of three Hamilton Rating Scale for Depression (HRSD) points at the end of treatment corresponds to 6.3% of variance in outcome explained. To achieve a similar explanatory power, genotypes with minor allele frequencies of 5, 10, 20, 30 and 50% need to attain a per allele difference of 4.7, 3.6, 2.8, 2.4 and 2.2 HRSD points, respectively. A normally distributed continuous biomarker will need an effect size of 1.5 HRSD points per standard deviation. A number needed to assess of three suggests that with this effect size, a biomarker will significantly improve the prediction of outcome in one out of every three patients assessed.
This report provides guidance on assessing clinical significance of biomarkers predictive of outcome in depression treatment.
antidepressant medication; biomarkers; clinical significance; major depressive disorder; number needed to assess
Hepatic enzymes, CYP2B6 and UGT2B7 play a major role in the metabolism of the widely used antiretroviral drugs efavirenz, nevirapine and zidovudine. In the present study, we provide a view of UGT2B7 haplotype structure, and quantify the genetic diversity and differentiation at both CYP2B6 and UGT2B7 genes on a worldwide scale.
Materials & methods
We genotyped one intronic and three promoter SNPs, and together with three nonsynonymous SNPs, inferred UGT2B7 alleles in north American (n = 326), west African (n = 133) and Papua New Guinean (n = 142) populations. We also included genotype data for five CYP2B6 and six UGT2B7 SNPs from an additional 12 worldwide populations (n = 629) analyzed in the 1000 Genomes Project.
We observed significant differences in certain SNP and allele frequencies of CYP2B6 and UGT2B7 among worldwide populations. Diversity values were higher for UGT2B7 than for CYP2B6, although there was more diversity between populations for CYP2B6. For both genes, most of the genetic variation was observed among individuals within populations, with the Papua New Guinean population showing the highest pairwise differentiation values for CYP2B6, and the Asian and European populations showing higher pairwise differentiation values for UGT2B7.
These new genetic distinctions provide additional insights for investigating differences in antiretroviral pharmacokinetics and therapy outcomes among ethnically and geographically diverse populations.
1000 Genomes Project; CYP2B6; efavirenz; HIV/AIDS; nevirapine; Papua New Guinea; UGT2B7; zidovudine
This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy.
Patients & methods
A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors.
The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose’ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R2 = 51%).
Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.
algorithm; CYP2C9; genotyping; personalized medicine; pharmacogenetics; VKORC1; warfarin
Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European–Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose.
Patients & methods
We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European–Americans (n = 1022) and African–Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose.
Associations between variants in VKORC1, CYP2C9 and CYP4F2 with weekly dose were observed in European–Americans as well as additional variants in CYP2C9 and CALU in African–Americans. Compared with traditional 5 mg/day dosing, implementing the US FDA recommendations or the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm reduced error in weekly dose in European–Americans (13.5–12.4 and 9.5 mg/week, respectively) but less so in African–Americans (15.2–15.0 and 13.8 mg/week, respectively). By further incorporating associated variants specific for European–Americans and African–Americans in an expanded algorithm, dose-prediction error reduced to 9.1 mg/week (95% CI: 8.4–9.6) in European–Americans and 12.4 mg/week (95% CI: 10.0–13.2) in African–Americans. The expanded algorithm explained 41 and 53% of dose variation in African–Americans and European–Americans, respectively, compared with 29 and 50%, respectively, for the IWPC algorithm. Implementing these predictions via dispensable pill regimens similarly reduced dosing error.
These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.
anticoagulants; bioinformatics; electronic health record; genes; pharmacogenomics; warfarin
B-RAF; melanoma; N-RAS; targeted therapy; vemurafenib; whole-exome sequencing