Pharmacogenetics and genomics最新文献

Purpose: Valsartan, an angiotensin II receptor blocker, is widely used for hypertension and heart failure. While its cardiovascular benefits are established, its broader pharmacological effects remain incompletely characterized. This study aimed to identify genetic variants associated with valsartan use and to systematically explore its potential effects and adverse events across a wide range of phenotypes.

Methods: Using UK Biobank data, we selected participants of European ancestry prescribed valsartan as cases, compared with controls not prescribed any ARBs. A genome-wide association study (GWAS) was conducted to identify suggestive genetic variants associated with valsartan use. These variants were then used as instruments in a phenome-wide association study (PheWAS) to screen for associated traits. Mendelian randomization analyses, including inverse-variance weighted and pleiotropy-robust methods, were employed to assess potential causal relationships.

Results: The GWAS identified 19 suggestive single nucleotide polymorphisms (P < 1 × 10-5) near genes, including PREP, GCLC, and ZNF133. The PheWAS analysis revealed associations with 14 phenotypes, including lower levels of total cholesterol (β = -0.59) and low-density lipoprotein cholesterol (LDL-C) (β = -0.56), and increased risk of cough (odds ratio = 1.67). Mendelian randomization provided genetic evidence consistent with potential causal effects of valsartan in lowering LDL-C (β = -2.34 × 10-3) and reducing the risk of transient cerebral ischemic attack.

Conclusion: Our genetic-based study suggests valsartan use may be associated with lowered LDL-C and reduced risks of certain ischemic cardiovascular events. These findings generate novel hypotheses regarding the drug's pleiotropic effects and potential applications beyond hypertension management, which warrant further clinical investigation.

Objective: To investigate the distribution of the apolipoprotein E (ApoE) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) polymorphisms in dyslipidemia patients and their impact on statin efficacy and safety.

Methods: A retrospective analysis was conducted on dyslipidemic inpatients (April 2024-March 2025) who received statin therapy and genetic testing for SLCO1B1 (rs4149056) and ApoE (rs429358 and rs7412), to analyze the association of genotypes with lipid levels and safety indicators.

Results: The final analysis included 238 hospitalized patients with dyslipidemia (156 males and 82 females) who met the inclusion criteria. The study population had a mean age of 60.61 ± 0.91 years (mean ± SEM). The allele frequencies for both ApoE and SLCO1B1 polymorphisms were in Hardy-Weinberg equilibrium (P > 0.05). Analysis of statin efficacy revealed a significant association between ApoE genotype and atorvastatin response: E3 carriers demonstrated higher low-density lipoprotein cholesterol levels posttreatment compared to E2 carriers (2.85 ± 1.00 mmol/l vs. 2.28 ± 0.96 mmol/l, P = 0.026). However, no such association was found in patients administered rosuvastatin. For safety outcomes, comparisons of creatine kinase and alanine aminotransferase levels between carriers of the SLCO1B1 TC and TT genotypes showed no statistically significant differences.

Conclusion: APOE polymorphisms influence statin efficacy. The E2 genotype is associated with better atorvastatin efficacy in lipid management. At low-to-moderate doses, the SLCO1B1 TC genotype did not increase safety risk, supporting its clinical safety.

Background: Dehydroepiandrosterone (DHEA) is considered an endogenous steroid hormone precursor, and 17-ß estradiol (E2) is one of the estrogen steroid hormones. Of the 13 known human cytosolic sulfotransferases (SULTs), SULT2B1a has been shown to be expressed in steroid hormone-responsive tissues such as the prostate, ovary, and placenta, as well as the fetal brain. Previous studies have demonstrated that SULT2B1a is capable of sulfating 3β-hydroxysteroids such as DHEA and pregnenolone. The present study aimed to investigate the effects of human SULT2B1 single-nucleotide polymorphisms (SNPs) on the enzymatic characteristics of SULT2B1a allozymes in mediating the sulfation of DHEA and E2.

Methods: To inspect the effects of SNPs of the SULT2B1 gene on the sulfation of DHEA and E2 by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were produced, expressed, and purified using established procedures. Thirteen SULT 2B1a nonsynonymous missense coding SNPs (cSNPs) were selected among numerous identified human SULT 2B1a SNPs by a comprehensive database search. The corresponding cDNAs, packaged in pGEX-2TK expression vector, and encoding the selected 13 SULT2B1a allozymes, have been generated by performing site-directed mutagenesis. These were then bacterially expressed in BL21 E. coli cells and purified using glutathione-Sepharose affinity chromatography. The purified allozymes were tested for their ability to sulfonate DHEA and E2.

Results: In terms of the kinetic parameters, the wild-type SULT2B1a exhibited higher enzyme affinity toward DHEA than with E2. In comparison with the wild-type SULT2B1a, the purified allozymes displayed differential sulfating activities toward DHEA and E2.

Conclusion: Accordingly, these findings indicate an apparent effect of SULT2B1 cSNPs on the sulfating activities of SULT2B1a allozymes toward DHEA and E2, and may provide for a better understanding of the pharmacokinetics of DHEA and E2 in individuals with differing SULT2B1a genotypes.

Objective: The pathogenic mechanisms of antituberculosis drug-induced liver injury (AT-DILI) remain unclear. Isoniazid and rifampicin may lead to hepatic accumulation of protoporphyrin IX in which heme synthesis ferrochelatase (FECH), a key rate-limiting enzyme, potentially plays an important role. This study aimed to investigate the combined effects of FECH gene polymorphisms and promoter methylation on AT-DILI risk in the Eastern Chinese population.

Methods: A 1 : 1 matched case-control study was conducted, detecting one CpG island in the FECH promoter and four single-nucleotide polymorphisms (SNPs). A multivariate conditional logistic regression was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (OR) with 95% confidence intervals (CIs). Additive and multiplicative interactions between methylation status and SNPs were further analyzed: additive interactions via the relative excess risk due to interaction (RERI) with 95% CIs, and multiplicative interactions by incorporating methylation-SNP product terms into regression models.

Results: Overall, 182 cases and 182 controls were included. Neither FECH promoter methylation (adjusted OR: 0.978, 95% CI: 0.408-1.560, P  = 0.509) nor the four SNPs showed individual associations with AT-DILI risk ( P  > 0.05). Crossover analyses revealed no significant genotype-methylation interactions ( P  > 0.05). Both additive (rs17063905 RERI: -0.556, P  = 0.691) and multiplicative interaction models (rs17063905, OR: 0.723, P  = 0.615) demonstrated no synergistic effects between methylation and polymorphisms.

Conclusion: This research finds no significant association between FECH promoter methylation status in the CpG island, polymorphisms, or their interactions and the risk of AT-DILI.

Background: Pharmacogenetic testing plays a key role in personalized pharmacotherapy and improving treatment outcomes; however, its benefit in clinical hyperpolypharmacy (≥ 10 chronic drugs) remains uncertain.

Objective: This study assessed the impact of extensive pharmacogenetic testing in hyperpolypharmacy patients. The primary outcome was the number of actionable drug-gene interactions (DGIs) per patient; secondary outcomes included clinical recommendations, clinician adherence, and DGIs with potential for severe adverse events.

Design: This intervention included 100 hyperpolypharmacy inpatients (≥ 10 drugs) from Maasstad Hospital internal ward and Antes psychiatry ward. Eligible patients (≥ 18 years) underwent a 14-gene pharmacogenetic panel test. A multidisciplinary team reviewed drug-gene interactions (DGIs), evaluated medical records, and implemented monitoring or medication adjustments as needed.

Results: An average of 4.7 (interquartile range: 4.0-5.5) actionable variants in the tested pharmacogenes per patient was identified, resulting in at least one DGI in 46% of the patients, with an average of 0.6 DGI per patient. After evaluation by the multidisciplinary team, 12 out of 64 DGIs (19%) led to recommendations for interventions, with an adherence rate of 67%. In 5% of patients, the identified DGI could potentially be associated with a higher risk of hospitalization or mortality.

Conclusion: Systematic pharmacogenetic panel testing in clinical hyperpolypharmacy patients identified at least one DGI in 46% of the patients. Of these DGIs, 19% led to a recommendation for intervention. This study demonstrates that pharmacogenetic panel testing holds the potential to optimize pharmacotherapy in clinical hyperpolypharmacy patients.

Objective: This study examined the impact of glutathione- S -transferase polymorphisms (GSTA1, GSTM1, GSTP1, and GSTT1) on the area under the curve (AUC), clearance, veno-occlusive disease (VOD), and graft-versus-host disease (GvHD) in hematopoietic stem cell transplant (HSCT) patients treated with intravenous busulfan.

Methods: A systematic review was performed on three electronic databases to identify relevant studies. The relative risk and the 95% confidence interval (CI) of the association of different GST polymorphisms with pharmacokinetic and clinical outcomes were reported using the random and fixed effect models. Quality of the studies was assessed using the Newcastle-Ottawa Scale for cohort studies. Heterogeneity between studies and publication bias were also carried out using R software.

Results: Eighteen studies were included in the meta-analysis. GSTA1*A/*B was significantly associated with lower clearance (95% CI: 0.008-1.223, P = 0.048) and higher AUC (95% CI: -374.960 to -56.661, P = 0.008) than the GSTA1*A/*A genotype. GSTA1*B/*B had a higher busulfan AUC than GSTA1*A/*A (95% CI: -403.531 to -89.454, P = 0.002). None of the other genotypes was significantly associated with busulfan pharmacokinetic parameters or the risk of VOD or GvHD.

Conclusion: GSTA1 should be considered as a guide for intravenous busulfan dosing in allogeneic HSCT patients, where patients with the GSTA1*A/*A genotype require a higher dose than GSTA1*B carriers.

Pharmacogenomics (PGx) is a scientific field that aims to understand how an individual's genetic code regulates drug metabolism and response. The response to many anesthetic drugs varies widely among patients due to many factors including, but not limited to, age, gender, and comorbidities. However, PGx contributes to this variability, particularly regarding adverse drug reactions. This review explores the influence of PGx on five commonly used induction agents in anesthesia: propofol, midazolam, ketamine, etomidate, and thiopental. Propofol metabolism is significantly affected by polymorphisms in CYP2B6, CYP2C9, and UGT1A9, influencing both efficacy and toxicity. Midazolam's PGx is mainly mediated by variations in CYP3A4, CYP3A5, and UDP-glucuronosyltransferase enzymes, with implications for sedation depth and drug clearance. Ketamine response is modulated by polymorphisms in metabolic enzymes (e.g. CYP2B6), as well as neurobiological targets such as brain-derived neurotrophic factor and gamma-aminobutyric acid (GABA) receptors, particularly in psychiatric applications. Etomidate shows less studied but emerging PGx associations, including single-nucleotide polymorphisms in GABA receptor subunits and metabolic enzymes, which may affect both sedative depth and cardiovascular stability. Thiopental is a rapid-acting metabolite whose effect stems from GABA-A receptor potentiation; no studies have yet identified specific genetic polymorphisms influencing its action. Overall, PGx provides a promising avenue for tailoring anesthetic management to improve patient safety and outcomes. However, clinical integration remains limited due to practical and infrastructural barriers. This review highlights the potential and current limitations of pharmacogenomic-guided anesthesia, underscoring its relevance in the era of precision medicine.

Background: Major depressive disorder (MDD) and bipolar disorder (BD) are common, disabling conditions. Despite associated morbidity and premature mortality, current treatments have modest efficacy and response to treatment highly variable. Contributing factors to variability in response include influence of common genetic variations in the pharmacokinetic and/or pharmacodynamic action of medications. As such, attention has turned toward the identification of genetic markers that could assist with determining who will respond or not to psychotropic treatment. Results of studies to date are promising but primarily have been small. This study aims to evaluate the efficacy of a pharmacogenetic (PGx)-based decision support tool among adults with MDD and BD.

Methods: This single-site, single (rater) blinded, randomized controlled trial with two arms evaluates the 24-week efficacy of a PGx-based support tool for adults with MDD or BD. Participants are randomized to receive PGx testing or standard prescribing. Participants provide DNA samples at baseline, but only those (including clinicians) randomized to the former receive the results at the start of their study participation. It is not mandatory for clinicians to follow the test recommendations. Remission rate (primary outcome), change in depression symptoms, drop-out rate, medication adherence, and medication side effects (secondary outcomes) are assessed at 4-, 8-, 12-, and 24-week postbaseline by a blinded rater. Analyses will follow an intention-to-treat approach and use mixed models for repeated measures.

Discussion: Treatment response to medication for severe mood disorders is highly variable and less than optimal. This trial will provide evidence as to whether a PGx-based support tool is an efficacious strategy to inform selection and dosing of pharmacotherapy among adults with severe mood disorders. Importantly, it will do so independently and with a larger sample size than previous studies.

Trial registration: This trial is registered under the number ACTRN12621001374853 (11 Oct 2021).

Objectives: Given the varying frequency and significance of genetic factors associated with severe cutaneous adverse reactions (SCARs) across different ethnicities, this study aimed to identify high-risk priority drug-variant pairs by considering genetic differences between Korea and the USA to inform preventive strategies.

Methods: A list of drug-variant pairs associated with SCARs was identified using the Pharmacogenomics Knowledge Base. Prioritization of drug-variant pairs for preventive strategies was conducted using the risk priority number (RPN) method incorporating expert opinions in the field of drug allergy. The RPN for each drug-variant was calculated based on severity, probability, and detectability, with each parameter derived as an odds ratio of the genetic variant associated with SCARs, the occurrence frequency of drug-associated SCARs, and the variant prevalence in Korean and American populations, respectively. Higher values were evaluated as higher priority.

Results: A total of 80 drug-variant pairs from 16 drugs associated with SCARs were identified in Koreans, and 12 drug-variant pairs from four drugs in Americans. Six drug-variant pairs were included in Korean drug labels, while only two drug-variant pairs were included in US drug labels. In Koreans, the highest priority drug-variant pair was rs3131003 for allopurinol, which is in moderate linkage disequilibrium with HLA-B*58:01, whereas in Americans, HLA-B*58:01 itself for allopurinol was the highest priority variant.

Conclusion: Drug-variant pairs with high RPN scores can be prioritized in clinical strategies to prevent SCARs in Korean and American populations. Incorporating these findings into clinical practices could ultimately contribute to the safe use of drugs.