Showing papers in "Pharmacogenomics in 2018"

Deep learning in pharmacogenomics: from gene regulation to patient stratification.

Abstract: This Perspective provides examples of current and future applications of deep learning in pharmacogenomics, including: identification of novel regulatory variants located in noncoding domains of the genome and their function as applied to pharmacoepigenomics; patient stratification from medical records; and the mechanistic prediction of drug response, targets and their interactions. Deep learning encapsulates a family of machine learning algorithms that has transformed many important subfields of artificial intelligence over the last decade, and has demonstrated breakthrough performance improvements on a wide range of tasks in biomedicine. We anticipate that in the future, deep learning will be widely used to predict personalized drug response and optimize medication selection and dosing, using knowledge extracted from large and complex molecular, epidemiological, clinical and demographic datasets.

Standardization can accelerate the adoption of pharmacogenomics: current status and the path forward.

Abstract: Successfully implementing pharmacogenomics into routine clinical practice requires an efficient process to order genetic tests and report the results to clinicians and patients. Lack of standardized approaches and terminology in clinical laboratory processes, ordering of the test and reporting of test results all impede this workflow. Expert groups such as the Association for Molecular Pathology and the Clinical Pharmacogenetics Implementation Consortium have published recommendations for standardizing laboratory genetic testing, reporting and terminology. Other resources such as PharmGKB, ClinVar, ClinGen and PharmVar have established databases of nomenclature for pharmacogenetic alleles and variants. Opportunities remain to develop new standards and further disseminate existing standards which will accelerate the implementation of pharmacogenomics.

Patient perspectives following pharmacogenomics results disclosure in an integrated health system.

Abstract: AIM To assess patient perceptions and utilization of pharmacogenomics (PGx) testing in an integrated community health system. METHODS Fifty-seven patients completed an online survey assessing their experiences with PGx testing offered through two methods: a designated PGx clinic or direct access in-home testing. RESULTS The majority of participants perceived PGx testing as helpful in their healthcare and reported understanding their results. Some had concerns about privacy and discrimination; most lacked familiarity with the Genetic Information Nondiscrimination Act. There were no significant differences in views between participants tested through either model. CONCLUSION Participants reported value in both methods of PGx testing. Patient experiences, understanding and result utilization will play an important role in informing future development and implementation of PGx programs.

Genotype-guided warfarin therapy: current status.

Abstract: Warfarin pharmacogenomics has been an extensively studied field in the last decades as it is focused on personalized therapy to overcome the wide interpatient warfarin response variability and decrease the risk of side effects. In this expert review, besides briefly summarizing the current knowledge about warfarin pharmacogenetics, we also present an overview of recent studies that aimed to assess the efficacy, safety and economic issues related to genotype-based dosing algorithms used to guide warfarin therapy, including randomized and controlled clinical trials, meta-analyses and cost-effectiveness studies. To date, the findings still present disparities, mostly because of standard limitations. Thus, further studies should be encouraged to try to demonstrate the benefits of the application of warfarin pharmacogenomic dosing algorithms in clinical practice.

Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients.

Abstract: BACKGROUND Genetic variants of TPMT and NUDT15 have been reported to predict the inter-patient variability in response and toxicity profiles of patients receiving thiopurine therapy. However, the clinical utility of TPMT genotyping in guiding thiopurine doses has been questionable, in part due to underlying differences in the prevalence of TPMT variants in both Caucasian and Asian populations. Several NUDT15 variants have been associated with thiopurine-induced leukopenia, particularly in Asian cohorts. So far, none have been reported in a multiethnic Asian population. AIM To investigate the associations between TPMT and NUDT15 variants with thiopurine-induced myelotoxicity in 129 Asian inflammatory bowel disease patients. MATERIALS & METHODS Pyrosequencing was performed to screen for TPMT and NUDT15 variants. Intracellular steady-state metabolite concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS Significant declines in nadir white blood cell, absolute neutrophil count and platelet counts were observed with increasing copy numbers of the risk T allele at NUDT15 c.415C>T locus (overall p < 0.05) within 4, 8 and 12 weeks and 6 months after thiopurine initiation. Patients with low and intermediate NUDT15 activity, as inferred from haplotype pairs, had significantly higher risks of leukopenia (p = 0.000253) and neutropenia (p = 0.002) compared with patients with normal NUDT15 activity. CONCLUSION These findings highlight the critical relevance of NUDT15 pharmacogenetics in predicting for thiopurine-induced myelotoxicity and confirm the lack of significance of TPMT variants in Asian inflammatory bowel disease patients.

Genetic variations of the xenoreceptors NR1I2 and NR1I3 and their effect on drug disposition and response variability.

Abstract: NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir. This review provides an overview of NR1I2 and NR1I3 pharmacogenetic studies in various therapeutic fields (oncology, immunomodulation and infectiology) and discusses the implementation of NR1I2 and NR1I3 genetic polymorphism testing in the clinical routine.

Pharmacogenetics of Warfarin Dosing in Patients of African and European Ancestry

Abstract: Despite the introduction of direct acting oral anticoagulants, warfarin remains the most commonly prescribed oral anticoagulant. However, warfarin therapy is plagued by the large inter- and intrapatient variability. The variability in dosing fueled research to identify clinical and genetic predictors and develop more accurate dosing algorithms. Observational studies have demonstrated the significant impact of single nucleotide polymorphisms in CYP2C9 and VKORC1 on warfarin dose in patients of European ancestry and African-Americans. This evidence supported the design and conduct of clinical trials to assess whether genotype-guided dosing results in improved anticoagulation control and outcomes. The trial results have shown discordance by race, with pharmacogenetic algorithms improving dose and anticoagulation control among European ancestry patients compared with African-American patients. Herein, we review the evidence from observational and interventional studies, highlight the need for inclusion of minority race groups and propose the need to develop race specific dosing algorithms.

Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing.

Abstract: Aim To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia Patients & methods Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405) Results Minor alleles of rs2781377/SYNE2 (p = 001) and rs10513762/MRPL47 (p = 001) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0007) Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0003) The addition of rs1135989/ACTG1 further enhanced model performance (p = 00001) Conclusion Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

Abstract: It is well established that the CYP2C19 nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.

Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease.

Abstract: Aim Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. Methods Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. Results & conclusion We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.

Attempted validation of 44 reported SNPs associated with tacrolimus troughs in a cohort of kidney allograft recipients.

Abstract: AIM Multiple genetic variants have been associated with variation in tacrolimus (TAC) trough concentrations. Unfortunately, additional studies do not confirm these associations, leading one to question if a reported association is accurate and reliable. We attempted to validate 44 published variants associated with TAC trough concentrations. MATERIALS & METHODS Genotypes of the variants in our cohort of 1923 kidney allograft recipients were associated with TAC trough concentrations. RESULTS Only variants in CYP3A4 and CYP3A5 were significantly associated with variation in TAC trough concentrations in our validation. CONCLUSION There is no evidence that common variants outside the CYP3A4 and CYP3A5 loci are associated with variation in TAC trough concentrations. In the future rare variants may be important and identified using DNA sequencing.

EGFR-TKIs in non-small-cell lung cancer: focus on clinical pharmacology and mechanisms of resistance.

Abstract: The clinical introduction of EGFR-TKIs within the oncologic armamentarium has changed the therapeutic landscape of non-small-cell lung cancer (NSCLC) creating widespread expectations both in patients and clinicians. However, several gaps in current understanding leave open important questions regarding the use of these drugs in clinical practice. For instance, there is uncertainty in regard to which EGFR-TKI should be given first in naive patients with EGFR-driven malignancies since different generations of drugs are available with different pharmacological profiles. Furthermore, acquired drug resistance may limit the therapeutic potential of EGFR-TKIs and the choice of the best treatment strategy after first-line treatment failure is still debated. This review article is aimed at describing the pharmacological properties of EGFR-TKIs and the current treatment options for NSCLC patients who develop acquired resistance. This information might be useful to design new rational and more effective pharmacological strategies in patients with EGFR-mutant NSCLC.

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis.

Abstract: AIM This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. MATERIALS & METHODS Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (n = 95) and 6 months of treatment (n = 90). Significant SNPs for univariate analysis were subjected to multivariate analysis. RESULTS Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. CONCLUSION Nevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice.

RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms.

Abstract: AIM To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls. MATERIALS & METHODS Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls. RESULTS 12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over variants found in statin-tolerant controls. Subjects with probably pathogenic RYR1 or CACNA1S variants had plasma CK 5X to more than 400X the upper limit of normal in addition to having muscle symptoms. CONCLUSIONS Genetic variants within the RYR1 and CACNA1S genes are likely to be a major contributor to the susceptibility to statin-associated muscle symptoms.

Computational functional genomics-based approaches in analgesic drug discovery and repurposing.

Abstract: Persistent pain is a major healthcare problem affecting a fifth of adults worldwide with still limited treatment options. The search for new analgesics increasingly includes the novel research area of functional genomics, which combines data derived from various processes related to DNA sequence, gene expression or protein function and uses advanced methods of data mining and knowledge discovery with the goal of understanding the relationship between the genome and the phenotype. Its use in drug discovery and repurposing for analgesic indications has so far been performed using knowledge discovery in gene function and drug target-related databases; next-generation sequencing; and functional proteomics-based approaches. Here, we discuss recent efforts in functional genomics-based approaches to analgesic drug discovery and repurposing and highlight the potential of computational functional genomics in this field including a demonstration of the workflow using a novel R library 'dbtORA'.

A nationwide cross-sectional survey of pharmacy students on pharmacogenetic testing in The Netherlands.

Abstract: AIM To benchmark knowledge and attitude of pharmacy students toward pharmacogenetics (PGx) and PGx testing and compare the results with practicing colleagues. METHODS All pharmacy students in The Netherlands were invited to participate in a web-based survey consisting of 28 questions. Out of the 824 invited students, 148 individuals (18.0%) completed the questionnaire. All responders believed in the concept of PGx and had high expectations toward PGx. The majority (96.6%) had received some form of education on PGx, but only 12.8% felt adequately informed. RESULTS When compared with practicing pharmacists, differences were observed in the use of information and feeling qualified to recommend PGx testing. CONCLUSION More education on PGx is required in the curriculum to fill the perceived knowledge gap among future pharmacists.

Pharmacogenetic of voriconazole antifungal agent in pediatric patients

Abstract: AIM We explored the role of SNPs within the SLCO1B3, SLCO1B1, SLC22A6, ABCB1, ABCG2, SLCO3A1, CYP2C19, ABCC2, SLC22A1, ABCB11 and NR1I2 genes on voriconazole pharmacokinetics. PATIENTS & METHODS 233 pediatric patients were enrolled. Drug plasma Ctrough was measured by a HPLC-MS method. Allelic discrimination was performed by qualitative real-time PCR. RESULTS SLCO1B3 rs4149117 c.334 GT/TT (p = 0.046), ABCG2 rs13120400 c.1194 + 928 CC (p = 0.029) and ABCC2 rs717620 c.-24 GA/AA (p = 0.025) genotype groups significantly influenced Ctrough. ethnicity (p = 0.042), sex (p = 0.033), SLCO1B3 rs4149117 c.334 GT/TT (p = 0.041) and ABCB1 rs1045642 c.3435 TT (p = 0.016) have been retained in linear regression model as voriconazole predictor factors. CONCLUSION Understanding how some gene polymorphisms affect the voriconazole pharmacokinetic is essential to optimally dose this agent.

CYP3A pharmacogenetic association with tacrolimus pharmacokinetics differs based on route of drug administration.

Abstract: Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post-transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship. In addition to CYP3A5, other pharmacogenes associated with CYP3A activity, including CYP3A4, CYP3A7 and POR have also been identified as predictors of tacrolimus exposure. This review will describe the current understanding of the relationship between these pharmacogenes and tacrolimus pharmacokinetics after oral and nonoral administration.

Dopamine gene variants in opioid addiction: comparison of dependent patients, nondependent users and healthy controls

Abstract: Aim To determine whether specific dopaminergic system gene variants are associated with opioid dependence. Patients & methods Subjects included 153 healthy controls, 163 opioid exposed, but not dependent and 281 opioid dependent. Genotypes of 90 variants in 13 genes were examined. Results The most significant results were obtained for DA β-hydroxylase variants, rs2073837 and rs1611131, which were associated with protection from addiction (q = 0.0172, 0.0415, respectively) and the functional TH variant, rs2070762, was associated with more risk (q = 0.0387). The three variants also showed a combined effect that remained significant after correction for multiple testing (pfinal = 0.0039). Conclusion These data offer support that dopaminergic gene variants have a role in opioid dependence and warrant further study.

Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data.

Abstract: Aim Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations. Materials & methods Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Independent evaluation was performed in a small cohort of patients. Results Our analysis revealed significant differences in the the allelic distribution of variants in different ethnicities. Conclusions This is the first and largest genetic map the DPYD variants associated with adverse drug reaction to 5-FU in south Asian population. Our study highlights ethnic differences in allelic frequencies.

From genes to treatments: a systematic review of the pharmacogenetics in smoking cessation.

Abstract: Smoking cessation treatment outcomes may be heavily influenced by genetic variations among smokers. Therefore, identifying specific variants that affect response to different pharmacotherapies is of major interest to the field. In the current study, we systematically review all studies published in or after the year 1990 which examined one or more gene-drug interactions for smoking cessation treatment. Out of 644 citations, 46 articles met the inclusion criteria for the systematic review. We summarize evidence on several genetic polymorphisms (CHRNA5-A3-B4, CYP2A6, DBH, CHRNA4, COMT, DRD2, DRD4 and CYP2B6) and their potential moderating pharamacotherarpy effects on patient cessation efficacy rates. These findings are promising and call for further research to demonstrate the effectiveness of genetic testing in personalizing treatment decision-making and improving outcome.

Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy.

Abstract: Aim A tailored antiplatelet strategy based on CYP2C19 genotype may reduce atherothrombotic and bleeding events. We describe our experience with CYP2C19 genotyping, using on-site TaqMan or Spartan genotyping or shipment to a central laboratory. Methodology Data from two ongoing projects were used: Popular Risk Score project (non-urgent percutaneous coronary intervention patients) and the Popular Genetics study (ST-segment elevation myocardial infarction patients). For both projects, the time to genotyping result was calculated. Results In the Popular Risk Score project (n = 2556), median time from blood collection to genotyping result was 4:04 h. In the Popular Genetics study (n = 1038), median time from randomization to genotyping result was 2:24 h. Conclusion CYP2C19 genotyping is feasible in everyday clinical practice, both in the acute and non-acute settings.

Precision medicine for HIV: where are we?

Abstract: To date, antiretroviral therapy is highly effective in HIV-affected patients, but the individualization of such a life-long therapy may be advised. This review briefly summarizes the main factors involved in the potential personalization of antiretroviral treatment. Relevant articles in English were identified by PubMed and recent congresses' abstracts. Foremost influences concerning pharmacodynamics, therapeutic drug monitoring, pharmacogenetics, comorbidities, immune recovery and viral characteristics affecting the healthcare of HIV-positive patients are listed here. Furthermore, pharmacoeconomic aspects are mentioned. Applying pharmacokinetic and pharmacogenetic knowledge may be informative and guide the better choice of treatment in order to achieve long-term efficacy and avoid adverse events. Randomized investigations of the clinical relevance of tailored antiretroviral regimens are needed in order to obtain a better management of HIV/AIDS-affected patients.

RICTOR gene amplification is correlated with metastasis and therapeutic resistance in triple-negative breast cancer.

Abstract: Triple-negative breast cancer (TNBC) is characterized by its aggressive behavior, metastasis and lack of targeted therapies. Herein, we discuss the clinical, histopathological and genetic profile of a woman diagnosed with TNBC. Since the patient had no durable response to chemotherapy, a genetic profiling was carried out. Next-generation sequencing analysis of 592 genes showed a missense mutation, p.E545A in PIK3CA, thus the patient was started on the mTOR inhibitor everolimus, in combination with exemestane, which controlled her pain; however, the disease progressed aggressively. More importantly, next-generation sequencing analysis showed a RICTOR gene amplification (eight copies) suggesting that RICTOR promotes the genesis of TNBC. We conclude that determining regulators of RICTOR and furthermore, their inhibitors might decrease cancer cells proliferation rate in patients with TNBC.

Use of polygenic risk scores of nicotine metabolism in predicting smoking behaviors

Abstract: Aim This study tests whether polygenic risk scores (PRSs) for nicotine metabolism predict smoking behaviors in independent data. Materials & methods Linear regression, logistic regression and survival analyses were used to analyze nicotine metabolism PRSs and nicotine metabolism, smoking quantity and smoking cessation. Results Nicotine metabolism PRSs based on two genome wide association studies (GWAS) meta-analyses significantly predicted nicotine metabolism biomarkers (R2 range: 9.2-16%; minimum p = 7.6 × 10-8). The GWAS top hit variant rs56113850 significantly predicted nicotine metabolism biomarkers (R2 range: 14-17%; minimum p = 4.4 × 10-8). There was insufficient evidence for these PRSs predicting smoking quantity and smoking cessation. Conclusion Results suggest that nicotine metabolism PRSs based on GWAS meta-analyses predict an individual's nicotine metabolism, so does use of the top hit variant. We anticipate that PRSs will enter clinical medicine, but additional research is needed to develop a more comprehensive genetic score to predict smoking behaviors.

Tacrolimus population pharmacokinetic models according to CYP3A5/CYP3A4/POR genotypes in Chinese Han renal transplant patients.

Abstract: Aim To develop a population pharmacokinetic (PK) model of tacrolimus in Chinese Han renal transplant population and establish the influence of different covariates (especially different CYP3A5/3A4/POR genotype) on PK properties. Materials & methods Trough tacrolimus concentrations, clinical characteristics and CYP3A5/CYP3A4/POR genotypes were collected from 141 adult renal transplant recipients after transplantation. The population PK analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 3.4.2. Results Tacrolimus PK profiles exhibited high interpatient variability. A two compartment model with first-order input and elimination described the tacrolimus PK profiles in the studied population. Among the genotypes, only CYP3A5 genotype was confirmed to have clinical significance. Conclusion Our final model confirmed that CYP3A5*3 plays a more significant role in tacrolimus PK and could affect the blood concentrations and CL/F (clearance rate/bioavailbility). This model is expected to help to improve individualized tacrolimus dosing.

Pharmacogenetic impact of docetaxel on neoadjuvant treatment of breast cancer patients.

Abstract: AIM This study aimed to investigate the effect of CYP3A4 and CYP3A5 genotypes on clinical outcomes of docetaxel treatment PATIENTS & METHODS In the PROMIX trial, 150 breast cancer patients received docetaxel preoperatively CYP3A4 and CYP3A5 genotype combinations were transformed into total CYP 3A phenotypes RESULTS Seven patients were characterized as poor metabolizer (PM), 22 patients as extensive metabolizer and 121 patients as intermediate metabolizer The frequency of grade 3/grade 4 adverse events was higher in the PM group (p = 0002) One PM subject who basically lacked enzyme activity died from typhlitis Total 45 recurrences were reported after a median of 5-year follow-up; none of these was PM CONCLUSION The allelic variants CYP3A4*22 and CYP3A5*3 contribute to the interpatient variations of docetaxel

Role of miRNAs in treatment response and toxicity of childhood acute lymphoblastic leukemia.

Abstract: Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.

Pharmacogenetic guidelines and decision support tools for depression treatment: application to late-life.

Abstract: Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines.