Pharmacogenetics and genomics最新文献

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, shaped by both environmental and genetic factors. While genome-wide association studies have identified several IPF risk loci, the genetic basis remains incomplete, especially in non-European populations.

Methods: We performed an exome-wide association study in 186 Korean IPF patients and 262 healthy controls using the Illumina HumanExome v1.1 BeadChip to discover novel exonic variants linked to IPF susceptibility. Logistic regression was used to test associations, adjusting for age, sex, and smoking history. Functional implications were evaluated through structural modeling and protein stability predictions.

Results: After quality control, 23 737 single-nucleotide polymorphisms (SNPs) were analyzed. The variant rs1047406 (T>C) in the PEBP4 gene was significantly associated with IPF under a codominant model (odds ratio = 1.94, 95% confidence interval = 1.42-2.65, P < 0.05 after correction). Haplotype analysis, including three nearby SNPs, further supported this association. In-silico analyses predicted that the E11G substitution caused by rs1047406 reduces protein stability and may disrupt proper folding. GTEx eQTL data showed that the minor allele is linked to altered PEBP4 expression in several tissues. PEBP4 is known to regulate phosphoinositide 3-kinase/protein kinase B and nuclear factor kappa B pathways, both implicated in fibrotic remodeling.

Conclusion: A novel PEBP4 variant associated with IPF was identified in a Korean population, likely affecting protein function and expression. These findings underscore the importance of ethnic-specific studies and support PEBP4 as a candidate gene in IPF, meriting further validation.

It is unknown how many people in the US have had pharmacogenetic (PGx) testing and whether people want to be tested. We conducted a nationally representative survey of the general US adult population to determine the prevalence of adults that have had PGx testing using a validated confidential online survey, the Non-Medical Use of Prescription Drugs Program. A weighted logistic regression was used to test health characteristics associated with PGx testing and determine those who desire to be tested. The analysis included 29 146 individuals who completed the survey, which represents approximately 260 000 000 adults in the US. The prevalence of US adults who have been PGx tested is 6.6% [95% confidence interval (CI): 6.2-7.0]. Only 32.2% (95% CI: 31.5-32.9), an estimated 79 million individuals, desired PGx testing. Adults who had or want PGx testing were more likely to be female, have higher education, be students, current or former members of the military, use medications, and have a mental health disorder. The prevalence of adults who have been PGx tested remains low in the US. There are knowledge gaps about the benefits of PGx testing that must be bridged to increase implementation.

Irinotecan treatment is often complicated by gastrointestinal, hematological, and infusion-related toxicities, the latter of which typically presents as acute cholinergic syndrome (ACS). While genetic variation in UGT1A1 increases toxicity risk, fewer studies have investigated variation in other genes. This study aimed to assess the impact of variation in other genes involved in irinotecan pharmacokinetics with irinotecan-related toxicity. This was a retrospective study of patients receiving standard irinotecan doses (180 mg/m2) with available genetic and clinical data. The primary analysis was to investigate the impact of carboxylesterase (CES) genetic variation on irinotecan infusion-related ACS. Exploratory secondary analyses evaluated variation in CES1, CES2, UGT1A7, UGT1A9, ABCB1, ABCG2, ABCC2, and SLCO1B1 with severe toxicity, treatment modification, diarrhea, and neutropenia. Univariate associations with P less than 0.05 were adjusted for UGT1A1*28 and UGT1A1*6 genotype. A total of 93 patients were included in this analysis. CES1 variants were not associated with infusion-related ACS. In the exploratory analysis, CES1 rs3785161 AA was associated with an increased likelihood of severe irinotecan toxicity (37 vs. 16%; P = 0.034), and ABCG2 rs2231142 AA/AC was associated with an increased likelihood of severe neutropenia (33 vs. 8%; P = 0.017). CES1 and ABCG2 variants may increase the risk of irinotecan toxicity. Further studies are needed to validate these associations to justify prospective studies investigating the clinical benefits of genetics-guided irinotecan dosing.

Background: Warfarin is a commonly used oral anticoagulant for managing thromboembolic events after cardiac valve surgery. However, its optimal dose varies between individuals, often requiring trial and error to determine. This study aimed to investigate the association of polymorphisms in the CYP2C9 and VKORC1 genes with warfarin dose requirements in an Iranian population undergoing cardiac valve replacement.

Materials and methods: A total of 140 patients recieving warfarin after cardiac valve replacement surgery were enrolled. Patients were monitored for their daily warfarin dose and international normalized ratio for at least 3 months post-surgery. Genotyping of CYP2C9 rs1057910 and VKORC1 rs2884737 was conducted using the tetra-primer amplification refractory mutation system -PCR method. Associations between genotypes and warfarin dose were analyzed using linear regression. A P value < 0.05 was considered statistically significant.

Results: Patients with the heterozygous AC genotype of CYP2C9 rs1057910 required a significantly lower warfarin dose than those with the wild-type genotype ( P < 0.05). Although variation in warfarin dose was observed among patients with different VKORC1 rs2884737 genotypes, the association was not statistically significant. Including patients' demographic covariates in the regression model did not alter the observed genotype-dose associations.

Conclusion: The CYP2C9 rs1057910 variant was significantly associated with daily warfarin dose requirements, suggesting its potential role in guiding idividualized dosing. In contrast, VKORC1 rs2884737 showed no significant association in this population, despite previous findings in other ethnic groups.

Introduction: Praziquantel (PZQ) is commonly used to treat schistosomiasis; however, there is considerable interindividual variability in its efficacy, partly because of genetic variation. Data on this relationship is scarce across Africa - where schistosomiasis is prevalent. This study aimed to investigate the pharmacokinetic/pharmacodynamic and pharmacogenetic relationship between PZQ and its metabolites in a Zimbabwean population infected with Schistosoma haematobium by leveraging dried blood spots (DBS) and mass spectrometry (MS).

Methods: DBS were obtained from 38 Zimbabwean participants on PZQ treatment at four-time points (0.5, 1.5, 2.5, and 4 h). We compared two extraction methods for recovering PZQ and its metabolites from the DBS cards and performed MS analysis to determine the concentrations. A random forest model was used to determine whether CYP1A2 , CYP2C9 , CYP2C19 , CYP2D6 , CYP3A4 , and CYP3A5 known variants were predictive of PZQ efficacy. The relationships between PZQ/metabolite concentration, metabolite ratio, and drug exposure with genotype were determined using a one-way analysis of variance.

Results: An acetonitrile and water (4 : 1) mixture was determined to be optimal for recovering PZQ and its metabolites from the DBS cards. Subsequent MS analysis identified PZQ and six metabolite compounds - including phase 1 metabolites (-2H)-O-PZQ, O2-PZQ, and 4-OH-PZQ. Pooled MS sampling was comparable to individual MS sampling for determining pharmacokinetic profiles at the 2.5 and 4-h time points. The (-2H)-O-PZQ and O2-PZQ metabolites had significantly higher concentrations in participants with CYP2C9*1/*9 and *9/*9 versus those with CYP2C9*1/*1. CYP1A2 rs2069514-A (formerly *1C ) and rs762551-A ( CYP1A2*30 ; formerly *1F ) were observed to alter PZQ pharmacokinetic profiles; however, differences in analyte concentrations across the corresponding genotypes were NS.

Conclusion: We show that low-cost microsampling using DBS and MS is feasible for detecting and quantifying PZQ and its metabolites. Furthermore, our pharmacogenetics analysis elucidates the impact of known cytochrome P450 variants on PZQ drug response in an African setting.

Propofol is commonly used to sedate patients, but variations in how individuals metabolize the drug may affect dosing requirements. The objective of this study was to explore how genetic variations in CYP450 enzymes, particularly CYP2B6 , influence propofol metabolism in ICU patients receiving mechanical ventilation. Genetic variants of CYP2B6 , CYP2C9 , CYP2C19 , and CYP3A5 were collected from an institutional genetic data repository. Patients were dichotomized into low and high metabolic activity for each enzyme, and the mean weight- and time-normalized propofol dose administered was compared between groups via t test. There was no significant difference in average daily propofol dose between patients with low and high CYP2B6 activity (11 vs. 11 mg/kg/h, P  = 0.78), or any of the other CYP enzymes analyzed (all P  > 0.05). This study could not replicate previous studies indicating that patients carrying genetic variants with diminished CYP2B6 activity required lower propofol doses. Future studies with prospectively collected dosing and outcomes data, and measurement of plasma drug concentrations, may provide insights into personalized propofol dosing strategies.

RASopathies are rare genetic disorders caused by germline mutations in genes that regulate the RAS-mitogen-activated protein kinase (MAPK) pathway, a critical pathway involved in various cellular processes. Disruption of this pathway leads to multisystemic manifestations, including cardiomyopathies, a cause of high morbi-mortality. In response to the urgent need to improve survival in patients with RASopathies, alternative therapies, such as MAPK inhibitors traditionally used in cancer treatment, have been explored. This article reviews the current evidence on the use of these medications in treating cardiomyopathies associated with RASopathies. The search was conducted in the PubMed, Scopus, and Embase databases identifying nine studies reporting a total of 14 cases (nine with Noonan syndrome and five with Costello syndrome) where patients were successfully treated with trametinib, a MEK inhibitor. This therapeutic alternative broadens the horizons of opportunity for patients who often face limited options for enhancing their quality of life. Therefore, it is important to prioritize ongoing research in this field, focusing not only on further investigation on trametinib, but also exploring other potential therapeutic approaches.

Objectives: Evaluate the feasibility of implementing a multigene pharmacogenetic (PGx) test and genotype-guided pharmacist recommendations into gynecologic perioperative workflows and fidelity to pharmacist genotype-guided postoperative analgesic recommendations.

Methods: A randomized, prospective, open-label pilot study was conducted in gynecologic patients undergoing abdominal surgery. Participants received multigene PGx testing and were randomized to the PGx-guided group where results were returned to the electronic health record with pharmacist genotype-guided postoperative analgesic recommendations or usual care. Primary outcomes included the proportion of PGx results and pharmacist recommendations completed before surgery, the number of prescriptions in alignment with pharmacist recommendations, and the proportion of analgesics prescribed differing from usual care.

Results: Of the 101 participants analyzed, all were female, 50 ± 14 years old, 49% were Black, 48% were White, 60% were treated by gynecologic oncology, and 76% underwent minimally invasive surgery. PGx results were returned to the genomics results portal a median of 7 (interquartile range: 6-9) business days after ordering the test. A majority (85%) of results were returned before the participant's surgery. Pharmacist genotype-guided analgesic recommendations were completed for 35 (73%) of the 48 participants in the PGx-guided group. And, 32 (91%) of the prescribed nonsteroidal anti-inflammatory drugs and 23 (66%) of the prescribed opioids matched the pharmacist's recommendations. Barriers included missed pharmacist notes when surgery dates were moved and low use of study-specific order set.

Conclusion: PGx test results were available before most surgeries, but the pharmacist recommendations were not always followed. Enhanced implementation strategies will need to be developed in future genotype-guided protocols.

Objectives: To explore the distribution of clinically relevant UGT1A1 polymorphisms and inferred UGT1A1 phenotypes in two Indigenous groups (Paiter-Suruí and Yanomami) from reservation areas in the Brazilian Amazon.

Methods: Ninety-two Yanomami and 88 Paiter-Suruí were genotyped with a validated panel of ancestry informative markers. Individuals with >90% Native ancestry were genotyped for the promoter TA repeat (rs8175347) polymorphism and UGT1A1*6 (rs4148323) by direct sequencing, and for UGT1A1*80 (rs887829) by TaqMan allele discrimination. The UGT1A1 metabolic phenotypes were inferred from UGT1A1 diplotypes.

Results: All Yanomami and 85 (96.6%) Paiter-Suruí had >92% Native ancestry. UGT1A1 genotype data from these individuals revealed: (i) the absence of both alleles with five and eight TA repeats [TA(5) and TA(8)]; (ii) TA(7) allele frequency of 0.470 in Yanomami and 0.441 in Paiter-Suruí; (iii) rs4148323 was absent in Paiter-Suruí and detected in two Yanomami (frequency 0.012); (iv) a perfect linkage disequilibrium (LD) between rs887829C>T and the promoter repeat polymorphisms in both cohorts: C allele with TA(6) and T allele with TA(7). The distribution of the inferred UGT1A1 metabolizer phenotypes did not differ between cohorts (Paiter-Suruí and Yanomami): the intermediate metabolizer was the most common (50.6-55.4%), followed by the normal (30.6-24.1%) and the slow (18.8-20.5%) phenotypes.

Conclusion: This is the first report on the frequency distribution of clinically relevant UGT1A1 variants and inferred UGT1A1 metabolic phenotypes in two major Native populations from indigenous reservation areas in the Brazilian Amazon, namely the Paiter-Suruí and Yanomami. The TA(5) and TA(8) repeats were absent, whereas TA(7) was common (frequency >0.50) in both cohorts. The intronic rs887829 variant ( UGT1A1 * 80 ) single nucleotide variant was found in perfect LD with the promoter TA repeats. The rs4148323 SNP was absent (Paiter-Suruí) or rare (Yanomami). The frequency of high-risk UGT1A1 poor metabolizer phenotype was 1.6- to 2-fold higher in the indigenous cohorts compared to nonindigenous Brazilians.

Background: Regulatory T (Treg) cell depletion-associated immune tolerance deficiency have been shown to play a key role in the pathogenesis of primary Sjögren's syndrome (pSS). Treg cells mainly express the transcriptional regulator Foxp3 and are characterized by constitutively high expression of inhibitory coreceptor CTLA-4 . Herein, the aim of this study was to investigate the potential association of single nucleotide polymorphisms (SNPs) in Foxp3 and CTLA-4 genes with the susceptibility to pSS.

Method: Ninety-nine pSS patients and 93 healthy controls were recruited into the retrospective study. Nuclear DNA was extracted from peripheral blood leukocytes, and SNP alleles were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Results: For the Foxp3 gene, the T allele, the TT and GT genotype in rs3761548G/T, the A allele and AA genotype in rs3761549G/A, as well as the C allele and the TC genotype in rs2280883T/C, were preponderant in pSS. Polymorphisms of rs3761548G/T and rs3761549G/A were found to be associated with anemia or leukopenia, while rs2232365T/C was associated with neutropenia, and rs2280883T/C was demonstrated to have a correlation with anti-SSA(+). For the CTLA-4 gene, the C allele and the CC genotype in rs733618T/C were significantly more prevalent in pSS. rs733618T/C polymorphisms varied significantly in anti-SSA(+), anti-SSB(+) and leukopenia, and rs16840252T/C was associated with ANA(+). Patients with at least six risk alleles had higher Th17 cells and decreased Treg cell counts, accompanied by elevated Th1/Treg, Th2/Treg, and Th17/Treg ratios. And the phenomenon was also observed in patients with four or more variant genotypes.

Conclusion: Polymorphisms in Foxp3 and CTLA-4 genes were associated with the susceptibility to pSS. The greater number of mutant sites and variant genotypes an individual possessed, the more susceptible they became to immune dysregulation.