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Clinical and Translational Science Jun 2024For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This...
For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.
Topics: Adolescent; Child; Female; Humans; Male; Young Adult; Antineoplastic Agents; Cancer Survivors; Fertility; Infertility; Neoplasms; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 38924306
DOI: 10.1111/cts.13827 -
International Journal of Molecular... May 2024Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid... (Meta-Analysis)
Meta-Analysis Review
The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.
Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.
Topics: Humans; Inflammatory Bowel Diseases; Psoriasis; Polymorphism, Single Nucleotide; Biological Products; Arthritis, Rheumatoid; Arthritis, Psoriatic; NLR Family, Pyrin Domain-Containing 3 Protein; Myeloid Differentiation Factor 88
PubMed: 38891983
DOI: 10.3390/ijms25115793 -
Translational Psychiatry Jun 2024Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood...
Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.
Topics: Child; Female; Humans; Male; Aggression; Catechol O-Methyltransferase; Gene-Environment Interaction; Genome-Wide Association Study; Monoamine Oxidase; Receptors, Dopamine D4
PubMed: 38862490
DOI: 10.1038/s41398-024-02870-7 -
CNS & Neurological Disorders Drug... Jun 2024The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480,...
BACKGROUND AND OBJECTIVE
The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. We conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance.
METHODS
Identifying relevant studies, was carried out bay searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance.
RESULTS
This review included a total of 23 studies and more than 2177 epilepsy patients. As a result the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, where the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It's been found also that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ.
CONCLUSION
Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.
PubMed: 38859787
DOI: 10.2174/0118715273298953240529100325 -
Farmacia Hospitalaria : Organo Oficial... Jun 2024Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is... (Review)
Review
INTRODUCTION
Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine.
MATERIALS AND METHODS
A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualized dosing", "clinical routine" and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis.
RESULTS
49 articles were included for the final analysis following review by two investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNF-α agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found.
CONCLUSION
The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.
PubMed: 38851909
DOI: 10.1016/j.farma.2024.03.010 -
Therapie May 2024The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study...
AIM OF THE STUDY
The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase.
METHODS
We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018.
RESULTS
A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%).
CONCLUSION
The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.
PubMed: 38834394
DOI: 10.1016/j.therap.2024.05.003 -
Ophthalmic Research 2024Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to... (Meta-Analysis)
Meta-Analysis Review
Association of the Complement Factor H Y402H Polymorphism and Response to Anti-Vascular Endothelial Growth Factor Treatment in Age-Related Macular Degeneration: An Updated Meta-Analysis.
INTRODUCTION
Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to several causes, including genetic factors. We evaluated the effects of Complement Factor H (CFH) rs1061170/Y402H polymorphism on the response to anti-VEGF therapy among AMD patients.
METHODS
PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were used for a literature search. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated to assess the effects of CFH Y402H polymorphism on the response to anti-VEGF therapy in AMD. I2 was used to present the amount of heterogeneity. We used STATA version 14.0 software.
RESULTS
Twenty-five papers reporting data for 4,681 patients were included in this study. Better response to anti-VEGF therapy was seen in T over C (OR = 1.25, 95% CI = 1.04-1.50), TT over CC (OR = 1.60, 95% CI = 1.06-2.4), and TT + TC over CC (OR = 1.68, 95% CI = 1.23-2.28) genotypes. There was no significant difference in the three other genetic models (TT vs. TC, TT vs. TC + CC, TC vs. TT + CC). In Asians, no significant difference was observed in all six genetic models. Ranibizumab and bevacizumab had similar efficacy; however, conbercept was more effective in homozygous genotypes. The literature indicated that TT and TC genotypes and T allele were associated with a better functional response, while the CC genotype and C alleles had a better anatomical response. The combination of risk alleles in ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents.
CONCLUSION
In patients with AMD, the CFH Y402H is a predictor of the response to anti-VEGF agents and should be considered in the treatment plan.
Topics: Humans; Complement Factor H; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Polymorphism, Single Nucleotide; Macular Degeneration; Genotype
PubMed: 38754401
DOI: 10.1159/000539377 -
Nature. Mental Health 2024Pharmacogenomics could optimize antipsychotic treatment by preventing adverse drug reactions, improving treatment efficacy or relieving the cost burden on the healthcare...
Pharmacogenomics could optimize antipsychotic treatment by preventing adverse drug reactions, improving treatment efficacy or relieving the cost burden on the healthcare system. Here we conducted a systematic review to investigate whether pharmacogenetic testing in individuals undergoing antipsychotic treatment influences clinical or economic outcomes. On 12 January 2024, we searched MEDLINE, EMBASE, PsycINFO and Cochrane Centrale Register of Controlled Trials. The results were summarized using a narrative approach and summary tables. In total, 13 studies were eligible for inclusion in the systematic review. The current evidence base is either in favor of pharmacogenetics-guided prescribing or showed no difference between pharmacogenetics and treatment as usual for clinical and economic outcomes. In the future, we require randomized controlled trials with sufficient sample sizes that provide recommendations for patients who take antipsychotics based on a broad, multigene panel, with consistent and comparable clinical outcomes.
PubMed: 38746691
DOI: 10.1038/s44220-024-00240-2 -
Clinical and Translational Science May 2024The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and... (Meta-Analysis)
Meta-Analysis Review
The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.
Topics: Humans; Neoplasms; Pharmacogenetics; Pharmacogenomic Variants; Antineoplastic Agents; Adult; Germ-Line Mutation; Pharmacogenomic Testing; Symptom Burden
PubMed: 38700261
DOI: 10.1111/cts.13781 -
Journal of Psychiatric Research Jun 2024Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and... (Review)
Review
Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.
Topics: Humans; Aripiprazole; Cytochrome P-450 CYP2D6; Risperidone; Cytochrome P-450 CYP2C19; Antipsychotic Agents
PubMed: 38631139
DOI: 10.1016/j.jpsychires.2024.04.001