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International Journal of Oral and... Mar 2020Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication that can develop in patients treated with anti-resorptive drugs. Although the pathogenesis... (Meta-Analysis)
Meta-Analysis
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication that can develop in patients treated with anti-resorptive drugs. Although the pathogenesis of MRONJ is still unclear, genetic factors have a demonstrated important role. Thus, the aim of this study was to perform a systematic review on the pharmacogenetics of MRONJ. Studies published until March 2019 were retrieved from eight databases and were selected by two independent reviewers. Evidence on several genetic polymorphisms was summarized and a meta-analysis was conducted when possible. Fourteen studies involving 1515 participants were eligible for systematic review. For CYP2C8 rs1934951, no significant difference was observed between the MRONJ and non-MRONJ groups (odds ratio (OR) 2.04, 95% confidence interval (CI) 0.88-4.73, P=0.09). However, a subgroup analysis based on only multiple myeloma status showed a positive association (OR 3.64, 95% CI 1.29-10.30, P=0.01). PPARG rs1152003 was not differently distributed between groups (OR 0.25, 95% CI 0.01-9.92, P=0.46). Also, VEGF rs3025039 was found to be correlated with the occurrence of MRONJ (OR 0.35, 95% CI 0.15-0.82, P=0.02). CYP2C8 rs1934951 (in multiple myeloma patients) and VEGF rs3025039 are associated with the development of MRONJ in patients treated with bisphosphonates. The results are promising and call for new trials with a larger sample to further explore this growing field.
Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Diphosphonates; Humans; Multiple Myeloma; Osteonecrosis; Pharmacogenetics
PubMed: 31445964
DOI: 10.1016/j.ijom.2019.07.016 -
Clinical and Experimental Allergy :... Feb 2017Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited.
OBJECTIVE
To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in patients with asthma.
METHODS
Articles published between 1999 and June 2015 were searched using PubMed and EMBASE. Pharmacogenomics/genetics studies of patients with asthma using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of Single Nucleotide Polymorphisms (SNPs) that had been replicated at least once were assessed in more detail.
RESULTS
In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two genomewide Genome-Wide association studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This SNP was associated with all three outcomes of poor response, and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64-9.51).
CONCLUSION AND CLINICAL RELEVANCE
There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene [encoding for a low-affinity IgE receptor (CD23)] and poor ICS response. Larger studies with well-phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics.
Topics: Adrenal Cortex Hormones; Alleles; Animals; Anti-Asthmatic Agents; Asthma; Genetic Variation; Humans; Leukotriene Antagonists; Pharmacogenetics; Pharmacogenomic Variants; Treatment Outcome
PubMed: 27790783
DOI: 10.1111/cea.12844 -
British Journal of Clinical Pharmacology Aug 2022To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing... (Meta-Analysis)
Meta-Analysis Review
AIMS
To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs).
METHODS
More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness.
RESULTS
After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial).
CONCLUSION
Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.
Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Humans; Observational Studies as Topic; Randomized Controlled Trials as Topic; COVID-19 Drug Treatment
PubMed: 35322889
DOI: 10.1111/bcp.15331 -
Pharmacogenomics Oct 2016The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean. (Review)
Review
AIM
The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean.
MATERIALS & METHODS
A literature search for pharmacogenetic studies in each country of the region was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers including 'phenotyping probe drugs' for major drug metabolizing enzymes. The review included 132 papers involving 47 biomarkers and 35,079 subjects (11,129 healthy volunteers and 23,950 patients).
RESULTS
The country with the most intensive pharmacogenetic research was Costa Rica. The most studied medical therapeutic area was oncology, and the most investigated biomarkers were CYP2D6 and HLA-A/B. Conclusion: Research activity on pharmacogenetics in Central American and the Caribbean populations is limited or absent. Therefore, strategies to promote effective collaborations, and foster interregional initiatives and research efforts among countries from the region could help for the rational clinical implementation of pharmacogenetics and personalized medicine.
Topics: Biomedical Research; Caribbean Region; Central America; Cytochrome P-450 CYP2D6; HLA-A Antigens; HLA-B Antigens; Humans; Pharmacogenetics
PubMed: 27633613
DOI: 10.2217/pgs-2016-0053 -
Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system.Psychiatric Genetics Oct 2015Substance use disorders have significant personal, familial, and societal consequences. Despite the serious consequences of substance use, only a few therapies are... (Review)
Review
Substance use disorders have significant personal, familial, and societal consequences. Despite the serious consequences of substance use, only a few therapies are effective in treating substance use disorders, thus highlighting a need for improved treatment practices. Substance use treatment response depends on multiple factors such as genetic, biological, and social factors. It is essential that each component is represented in treatment plans. The dopaminergic system plays a critical role in the pharmacotherapy for addictions, and an understanding of the role of variation of genes involved in this system is essential for its success. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement guidelines. A computerized literature search was conducted using PubMed and Scopus (all databases). Articles published up to April 2015 that examined the role of dopaminergic gene variation in the pharmacotherapy of alcohol, opioid, and cocaine use disorders were reviewed. Search terms were dopamine, gene, polymorphism, substance abuse, treatment, and response. Polymorphisms of the DRD2, ANKK1, DAT1, DBH, and DRD4 genes have been found to moderate the effects of pharmacotherapy of alcohol, opioid, and cocaine use disorders. The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapeutic intervention for substance use disorders. More studies are needed to confirm and extend these findings.
Topics: Dopamine; Genetic Predisposition to Disease; Humans; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine; Substance-Related Disorders
PubMed: 26146874
DOI: 10.1097/YPG.0000000000000095 -
International Journal of Cardiology Aug 2014
Meta-Analysis Review
Topics: Anticoagulants; Humans; International Normalized Ratio; Pharmacogenetics; Randomized Controlled Trials as Topic; Treatment Outcome; Warfarin
PubMed: 25005340
DOI: 10.1016/j.ijcard.2014.06.031 -
Epidemiologia E Prevenzione 2015To identify those studies in which economic analysis of predictive genetic and pharmacogenetic testing programs have been carried out. Since the Italian National... (Review)
Review
OBJECTIVES
To identify those studies in which economic analysis of predictive genetic and pharmacogenetic testing programs have been carried out. Since the Italian National Prevention Plan 2014-2018 foresees the implementation of genetic testing for inherited breast cancer, special attention was given to the cost-effectiveness of BRCA1/2 testing programs.
METHODS
A systematic review of primary economic evaluations (EEs) of predictive genetic and pharmacogenetic testing programs and an overview of previously published systematic reviews of economic evaluations (ERs) was performed.
RESULTS
Overall 128 EEs and 11 ERs were identified. The methodological quality of both EEs and ERs was good on average. Both predictive genetic and pharmacogenetic testing programs were mainly concerned with oncological diseases. Seventeen percent of genetic testing programs are cost-saving, while a further 44% of cost/QALY ratios fall under the commonly used threshold of €37,000 per QALY. For BRCA1/2 testing, only cascade genetic screening programs, targeted to close relatives of carriers, show clear evidence of cost-effectiveness.
CONCLUSION
Despite some limitations, EEs and ERs are powerful tools that provide indications to policy-makers on which genetic testing programs might be introduced into health care systems and public health practice.
Topics: Breast Neoplasms; Cost-Benefit Analysis; Delivery of Health Care; Early Detection of Cancer; Female; Genes, BRCA1; Genes, BRCA2; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Testing; Global Health; Health Care Costs; Humans; Insurance, Health, Reimbursement; Life Expectancy; Ovarian Neoplasms; Pharmacogenomic Testing; Quality-Adjusted Life Years
PubMed: 26499415
DOI: No ID Found -
Cancers Jul 2019A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression.... (Review)
Review
A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14-1.93, = 0.003 and HR: 1.90, 95% CI: 1.43-2.54, < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.
PubMed: 31336701
DOI: 10.3390/cancers11070970 -
American Journal of Medical Genetics.... Jun 2014Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder, affecting individuals across the life cycle. Although its etiology is not yet... (Meta-Analysis)
Meta-Analysis Review
Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder, affecting individuals across the life cycle. Although its etiology is not yet completely understood, genetics plays a substantial role. Pharmacological treatment is considered effective and safe for children and adults, but there is considerable inter-individual variability among patients regarding response to medication, required doses, and adverse events. We present here a systematic review of the literature on ADHD pharmacogenetics to provide a critical discussion of the existent findings, new approaches, limitations, and recommendations for future research. Our main findings are: first, the number of studies continues to grow, making ADHD one of the mental health areas with more pharmacogenetic studies. Second, there has been a focus shift on ADHD pharmacogenetic studies in the last years. There is an increasing number of studies assessing gene-gene and gene-environment interactions, using genome-wide association approaches, neuroimaging, and assessing pharmacokinetic properties. Third and most importantly, the heterogeneity in methodological strategies employed by different studies remains impressive. The question whether pharmacogenetics studies of ADHD will improve clinical management by shifting from trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains unanswered. © 2014 Wiley Periodicals, Inc.
Topics: Attention Deficit Disorder with Hyperactivity; Epistasis, Genetic; Gene-Environment Interaction; Genome-Wide Association Study; Humans; Neuroimaging; Pharmacogenetics
PubMed: 24804845
DOI: 10.1002/ajmg.b.32240 -
BMC Cancer Dec 2022Osteosarcoma is the most common bone tumor in children and adolescents. Despite multiagent chemotherapy, only 71% of patients survives and these survivors often...
BACKGROUND
Osteosarcoma is the most common bone tumor in children and adolescents. Despite multiagent chemotherapy, only 71% of patients survives and these survivors often experience long-term toxicities. The main objective of this systematic review is to provide an overview of the discovery of novel associations of germline polymorphisms with treatment response and/or chemotherapy-induced toxicities in osteosarcoma. METHODS: MEDLINE and Embase were systematically searched (2010-July 2022). Genetic association studies were included if they assessed > 10 germline genetic variants in > 5 genes in relevant drug pathways or if they used a genotyping array or other large-scale genetic analysis. Quality was assessed using adjusted STrengthening the REporting of Genetic Association studies (STREGA)-guidelines. To find additional evidence for the identified associations, literature was searched to identify replication studies.
RESULTS
After screening 1999 articles, twenty articles met our inclusion criteria. These range from studies focusing on genes in relevant pharmacokinetic pathways to whole genome sequencing. Eleven articles reported on doxorubicin-induced cardiomyopathy. For seven genetic variants in CELF4, GPR35, HAS3, RARG, SLC22A17, SLC22A7 and SLC28A3, replication studies were performed, however without consistent results. Ototoxicity was investigated in one study. Five small studies reported on mucosistis or bone marrow, nephro- and/or hepatotoxicity. Six studies included analysis for treatment efficacy. Genetic variants in ABCC3, ABCC5, FasL, GLDC, GSTP1 were replicated in studies using heterogeneous efficacy outcomes.
CONCLUSIONS
Despite that results are promising, the majority of associations were poorly reproducible due to small patient cohorts. For the future, hypothesis-generating studies in large patient cohorts will be necessary, especially for cisplatin-induced ototoxicity as these are largely lacking. In order to form large patient cohorts, national and international collaboration will be essential.
Topics: Child; Adolescent; Humans; Pharmacogenetics; Ototoxicity; Osteosarcoma; Cisplatin; Bone Neoplasms
PubMed: 36536332
DOI: 10.1186/s12885-022-10434-5