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Journal of Personalized Medicine Sep 2022Vitamin K antagonists (VKAs) are used in the prophylaxis and treatment of thromboembolic disorders. Despite a high efficacy, their narrow therapeutic window and high... (Review)
Review
Vitamin K antagonists (VKAs) are used in the prophylaxis and treatment of thromboembolic disorders. Despite a high efficacy, their narrow therapeutic window and high response variability hamper their management. Several patients experience fluctuations in dose−response and are at increased risk of over- or under-anticoagulation. Therefore, it is essential to monitor the prothrombin time/international normalized ratio to determine the so-called stable dose and to adjust the dosage accordingly. Three polymorphisms, CYP2C9∗2, CYP2C9∗3 and VKORC1-1639G>A, are associated with increased sensitivity to VKAs. Other polymorphisms are associated with a request for a higher dose and VKA resistance. We described the clinical cases of two patients who were referred to the Clinical Pharmacology and Pharmacogenetics Unit of the University Hospital of Salerno for pharmacological counseling. One of them showed hypersensitivity and the other one was resistant to VKAs. A systematic review was performed to identify randomized clinical trials investigating the impact of pharmacogenetic testing on increased sensitivity and resistance to VKAs. Although international guidelines are available and information on the genotype-guided dosing approach has been included in VKA drug labels, VKA pharmacogenetic testing is not commonly required. The clinical cases and the results of the systematically reviewed RCTs demonstrate that the pharmacogenetic-based VKA dosing model represents a valuable resource for reducing VKA-associated adverse events.
PubMed: 36294717
DOI: 10.3390/jpm12101578 -
Critical Reviews in Oncology/hematology Dec 2017Chemotherapy-induced peripheral neuropathy (CIPN) can adversely affect completion of systemic anti-cancer treatment and cause long-term morbidity. Increasingly... (Meta-Analysis)
Meta-Analysis Review
Chemotherapy-induced peripheral neuropathy (CIPN) can adversely affect completion of systemic anti-cancer treatment and cause long-term morbidity. Increasingly pharmacogenetic studies have been performed to explore susceptibility to this important adverse effect. A systematic review was conducted to identify pharmacogenetic studies, assess their quality and findings and undertake meta-analysis where possible. 93 studies were included. Notable methodological issues included lack of standardisation and detail in phenotype definition and acknowledgement of potential confounding factors. Insufficient data was presented in many studies meaning only a minority could be included in meta-analysis showing mainly non-significant effects. Nonetheless, SNPs in CYP2C8, CYP3A4, ARHGEF10, EPHA and TUBB2A genes (taxanes), FARS2, ACYP2 and TAC1 (oxaliplatin), and CEP75 and CYP3A5 (vincristine) are of potential interest. These require exploration in large cohort studies with robust methodology and well-defined phenotypes. Seeking standardisation of phenotype, collaboration and subsequently, individual-patient-data meta-analysis may facilitate identifying contributory SNPs which could be combined in a polygenic risk score to predict those most at risk of CIPN.
Topics: Antineoplastic Agents; Cohort Studies; Genetic Predisposition to Disease; Humans; Neoplasms; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide
PubMed: 29198326
DOI: 10.1016/j.critrevonc.2017.09.009 -
The Pharmacogenomics Journal Jul 2022Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the... (Meta-Analysis)
Meta-Analysis
Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, p = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.
Topics: Agranulocytosis; Alleles; Antipsychotic Agents; Clozapine; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 35710824
DOI: 10.1038/s41397-022-00281-9 -
Genetics Research 2023Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance.
METHODS
We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's value was higher than 0.1. We used random models when the value was less than 0.1.
RESULTS
Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations.
CONCLUSION
This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.
Topics: Humans; Rivaroxaban; Pharmacogenetics; Homozygote; Heterozygote; Drug-Related Side Effects and Adverse Reactions
PubMed: 37942082
DOI: 10.1155/2023/6105320 -
Clinical Pharmacokinetics Oct 2021Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug response are observed among individuals receiving the same dosage of the drug. Identification of candidate genes whose polymorphisms could be used to predict MPA exposure and clinical outcome is of clinical value.
OBJECTIVES
This study aimed to determine the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of MPA in humans by means of a systematic review and meta-analysis.
METHODS
A systematic search was conducted on PubMed, EMBASE, Web of Sciences, Scopus, and the Cochrane Library databases. A meta-analysis was conducted to determine any associations between genetic polymorphisms and pharmacokinetic or pharmacodynamic parameters of MPA. Pooled-effect estimates were calculated by means of the random-effects model.
RESULTS
A total of 37 studies involving 3844 individuals were included in the meta-analysis. Heterozygous carriers of the UGT1A9 -275T>A polymorphism were observed to have a significantly lower MPA exposure than wild-type individuals. Four single nucleotide polymorphisms (SNPs), namely UGT1A9 -2152C>T, UGT1A8 518C>G, UGT2B7 211G>T, and SLCO1B1 521T>C, were also significantly associated with altered MPA pharmacokinetics. However, none of the investigated SNPs, including SNPs in the IMPDH gene, were found to be associated with the clinical efficacy of MPA. The only SNP that was associated with adverse outcomes was SLCO1B3 344T>G.
CONCLUSIONS
The present systematic review and meta-analysis identified six SNPs that were significantly associated with pharmacokinetic variability or adverse effects of MPA. Our findings represent the basis for future research and clinical implications with regard to the role of pharmacogenetics in MPA pharmacokinetics and drug response.
Topics: Area Under Curve; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver-Specific Organic Anion Transporter 1; Mycophenolic Acid; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 34105062
DOI: 10.1007/s40262-021-01037-7 -
Pharmacogenomics May 2021Teaching of genetics and pharmacogenetics with personal genotyping (PGT) is becoming commonplace. We aimed to perform a systematic review and meta-analysis to... (Meta-Analysis)
Meta-Analysis
Teaching of genetics and pharmacogenetics with personal genotyping (PGT) is becoming commonplace. We aimed to perform a systematic review and meta-analysis to understand the effects of PGT on student outcomes. A systematic review was performed on studies that reported the effects of PGT on student attitudes, perceptions or knowledge. Extracted data were summarized qualitatively and when possible, quantitatively. Student PGT has a positive effect on student attitude and perceptions survey responses in studies without a control group (p = 0.009) and in studies with a control group (p = 0.025). Knowledge increased after the use of PGT (p < 0.001) in studies without a control group. The findings here suggest that perceptions, attitudes and knowledge increase with PGT in the classroom.
Topics: Genetics, Medical; Genotyping Techniques; Humans; Pharmacogenetics; Students
PubMed: 33858193
DOI: 10.2217/pgs-2021-0004 -
The Patient Jan 2022Although genetic testing has the potential to offer promising medical benefits, concerns regarding its potential negative impacts may influence its acceptance. Users and...
BACKGROUND
Although genetic testing has the potential to offer promising medical benefits, concerns regarding its potential negative impacts may influence its acceptance. Users and providers need to weigh the benefits, costs and potential harms before deciding whether to take up or recommend genetic testing. Attribute-based stated-preference methods, such as discrete choice experiment (DCE) or conjoint analysis, can help to quantify how individuals value different features of genetic testing.
OBJECTIVES
The aim of this paper was to conduct a systematic review of DCE and conjoint analysis studies on genetic testing, including genomic tests.
METHODS
A systematic search was conducted in seven databases: Web of Science, CINAHL Plus with Full Text (EBSCO), PsycINFO, PubMed, Embase, The Cochrane Library and SCOPUS. The search was conducted in February 2021 and was limited to English peer-reviewed articles published until the search date. The search keywords included relevant keywords such as 'genetic testing', 'genomic testing', 'pharmacogenetic testing', 'discrete choice experiment' and 'conjoint analysis'. Narrative synthesis of the studies was conducted on survey population, testing type, recruitment and data collection, survey development, questionnaire content, survey validity, analysis, outcomes and other design features.
RESULTS
Of the 292 articles retrieved, 38 full-text articles were included in this review. Nearly two-thirds of the studies were published since 2015 and all were conducted in high-income countries. Survey samples included patients, parents, general population and healthcare providers. The articles assessed preferences for pharmacogenetic testing (28.9%), predictive testing and diagnostic testing (18.4%), while only one (2.6%) study investigated preferences for carrier testing. The most common sampling method was convenience sampling (57.9%) and the majority recruited participants via web-enabled surveys (60.5%). Review of literature (84.6%), discussions with healthcare professionals (71.8%) and cognitive interviews (53.8%) were commonly used for attribute identification. A survey validity test was included in only one-quarter of the studies (28.2%). Cost attributes were the most studied attribute type (76.9%), followed by risk attributes (61.5%). Among those that reported relative attribute importance, attributes related to benefits were the most commonly reported attributes with the highest relative attribute importance. Preference heterogeneity was investigated in most studies by modelling, such as via mixed logit analysis (82.1%) and/or by using interaction effects with respondent characteristics (74.4%). Willingness to pay was the most commonly estimated outcome and was presented in about two-thirds (n = 25; 64.1%) of the studies.
CONCLUSION
With the continuous advancement in genetic technology resulting in expanding options for genetic testing and improvements in delivery methods, the application of genetic testing in clinical care is expected to rise. DCEs and conjoint analysis remain robust and useful methods to elicit preferences of potential stakeholders. This review serves as a summary for future researchers when designing similar studies.
Topics: Choice Behavior; Genetic Testing; Humans; Parents; Patient Preference; Research Design; Surveys and Questionnaires
PubMed: 34085205
DOI: 10.1007/s40271-021-00531-1 -
Pharmacogenomics Aug 2008Pharmacological treatment of colorectal cancer has improved survival rates in recent years. Individual genetic variation in genes associated with metabolism and targets... (Review)
Review
Pharmacological treatment of colorectal cancer has improved survival rates in recent years. Individual genetic variation in genes associated with metabolism and targets of commonly used drugs can be responsible for variability in treatment outcome and toxicity. Diverse study designs have been used and heterogeneous end points evaluated by studies assessing the association of genetic markers with treatment outcome. We conducted this systematic review, including 51 studies, to present a comprehensive overview and draw further conclusions. To facilitate comparison of reported study results, risk estimates for observed genetic variants in 33 key genes are presented using defined reference categories and recalculated risk estimates based on data provided in original publications, where necessary. Overall, evidence indicates associations of the UGT1A1(*) 28 variant genotype with toxicity after irinotecan treatment, mutations in GSTP1-105 with improved treatment outcome and the XPD-751 variant genotype with poor treatment outcome after oxaliplatin treatment, and amplification of the EGFR gene with improved treatment outcome after therapy with monoclonal antibodies. Adequately powered prospective investigations designed specifically for pharmacogenetics are needed.
Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Humans; Pharmacogenetics
PubMed: 18681783
DOI: 10.2217/14622416.9.8.1079 -
Journal of Crohn's & Colitis Dec 2023Nudix hydrolase 15 [NUDT15] genetic variants confer an increased risk of thiopurine-induced leukopenia [TIL]; however, their global prevalence in inflammatory bowel... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Nudix hydrolase 15 [NUDT15] genetic variants confer an increased risk of thiopurine-induced leukopenia [TIL]; however, their global prevalence in inflammatory bowel disease [IBD] patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients.
METHODS
Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early [≤8 weeks] and late [>8 weeks] leukopenia, and relative risk of developing leukopenia.
RESULTS
Twenty studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C > T C/T diplotype was 13% (95% confidence interval [CI]: 10-18%), *3/*3 c.415C > T T/T diplotype was 2% [95% CI: 1-2%], *1/*5 c.52G > A G/A diplotype was 2% [95% CI: 1-3%], and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% [95% CI: 4-12%]. The pooled prevalence of *1/*3 was high in Japanese [20%, 95% CI: 16-24%] and Chinese patients [18%, 95% CI: 12-27%]. The incidence of early leukopenia was 20% [95% CI: 16-26%] in *1/*3 patients, 99% [95% CI: 7-100%] in *3/*3 patients, and 49% [95% CI: 29-69%] in *1/*6 patients. The incidence of late leukopenia was 36% [95% CI: 26-49%] in *1/*3 patients.
CONCLUSIONS
NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations, to guide thiopurine dosing and prevent myelotoxicity.
Topics: Adult; Humans; Mercaptopurine; Incidence; Prevalence; Genetic Predisposition to Disease; Risk Factors; Pyrophosphatases; Inflammatory Bowel Diseases; Leukopenia; Purines; Sulfhydryl Compounds
PubMed: 37346013
DOI: 10.1093/ecco-jcc/jjad107 -
Cells Oct 2022Major Depressive Disorder (MDD) is a highly prevalent multifactorial psychopathology affected by neurotransmitter levels. Monoamine Oxidase A (MAOA) influences several...
Major Depressive Disorder (MDD) is a highly prevalent multifactorial psychopathology affected by neurotransmitter levels. Monoamine Oxidase A (MAOA) influences several neural pathways by modulating these levels. This systematic review (per PRISMA protocol and PECOS strategy) endeavors to understand the polymorphism influence on MDD and evaluate its 3R/3R and 3R* genotypic frequencies fluctuation in MDD patients from different populations. We searched the Web of Science, PubMed, Virtual Health Library, and EMBASE databases for eligible original articles that brought data on genotypic frequencies related to the variant in patients with MDD. We excluded studies with incomplete data (including statistical data), reviews, meta-analyses, and abstracts. Initially, we found 43 articles. After removing duplicates and applying the inclusion/exclusion criteria, seven articles remained. The population samples studied were predominantly Asians, with high 3R and 4R allele frequencies. Notably, we observed higher 3R/3R (female) and 3R* (male) genotype frequencies in the healthy control groups and higher 4R/4R (female) and 4R* (male) genotype frequencies in the MDD groups in the majority of different populations. Despite some similarities in the articles analyzed, there is still no consensus on the variant's role in MDD pathogenesis.
Topics: Female; Humans; Male; Depressive Disorder, Major; Gene Frequency; Minisatellite Repeats; Monoamine Oxidase; Polymorphism, Genetic
PubMed: 36291132
DOI: 10.3390/cells11203267