Pharmacogenetics and genomics最新文献

{"title":"UGT1A1 polymorphisms and metabolic phenotypes in indigenous peoples from the Brazilian Amazon.","authors":"Jamila A Perini, Alessandra S Dias, Leonor Gusmão, Larissa B Skaf, Anna Beatriz R Elias, Paulo C Basta, Marcelo A Carvalho, Guilherme Suarez-Kurtz","doi":"10.1097/FPC.0000000000000566","DOIUrl":"10.1097/FPC.0000000000000566","url":null,"abstract":"<p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"153-158"},"PeriodicalIF":1.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of the potential impact of polymorphisms in the Foxp3 and CTLA-4 genes in immune balance and disease susceptibility of primary Sjögren's syndrome.","authors":"Min Feng, Fanxing Meng, Yanlin Wang, Yuhan Jia, Guozhen Ji, Yue Jin, Chong Gao, Jing Luo","doi":"10.1097/FPC.0000000000000567","DOIUrl":"10.1097/FPC.0000000000000567","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Method: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"159-169"},"PeriodicalIF":1.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of switching antiplatelet therapy in acute coronary syndrome patients with different CYP2C19 phenotypes: insights from a single-center study.","authors":"Nagendra Boopathy Senguttuvan, Muralidharan Thoddi Ramamurthy, Nithesh Kumar, Pavitraa Saravana Kumar, Yogapriya Chidambaram, Madhesh Kasi, Gautam Ganesan Karthikeyan, Asuwin Anandaram, Bharath Raj Kidambi, Sadhanandham Shanmugasundram, Manokar Panchanatham, Rammurthy Anjanappa, Venu Seenappa, Vettriselvi Venkatesan, Ramesh Sankaran, Thanikachalam Sadagopan","doi":"10.1097/FPC.0000000000000564","DOIUrl":"10.1097/FPC.0000000000000564","url":null,"abstract":"<p><strong>Objective: </strong>Optimizing antiplatelet therapy is crucial in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCIs). This study aimed to assess the prevalence of CYP2C19 loss-of-function (LOF) variants and evaluate the clinical outcome of ticagrelor, clopidogrel, and aspirin in patients with ACS-PCI.</p><p><strong>Methods: </strong>This study included patients from the southern part of India (predominantly Tamil Nadu) with coronary artery disease and PCI. They were categorized based on their CYP2C19 LOF variants. Patients were further divided into group 1 (continued ticagrelor) and group 2 (switched to clopidogrel) and followed up for 40 months. The primary and secondary outcomes were evaluated.</p><p><strong>Results: </strong>A total of 287 patients were genotyped, 36.2% were normal, 46.3% were intermediate, and 17.5% were poor metabolizers, the predominant allele being CYP2C19 *2. After considering only patients who underwent PCI and received ticagrelor, 111 patients were recruited. Ticagrelor was switched to clopidogrel in 45.9% of patients. No statistically significant differences in major adverse cardiovascular events or individual outcomes were observed among different metabolizer groups and patients switched from ticagrelor to clopidogrel. Intermediate metabolizers (IMs) exhibited a trend favoring ticagrelor continuation. Notably, discontinuation of aspirin in IM was linked to increased target vessel reintervention (TVR) in the clopidogrel-only group.</p><p><strong>Conclusion: </strong>Our study provides preliminary evidence on favoring ticagrelor continuation and increased TVR upon aspirin withdrawal in IM.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"145-152"},"PeriodicalIF":1.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating pharmacogenetics in sport medicine: enhancing treatment precision and preventing unintentional doping violation.","authors":"Guillaume Drevin, Marie Briet, Chadi Abbara","doi":"10.1097/FPC.0000000000000565","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000565","url":null,"abstract":"","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"35 5","pages":"170-171"},"PeriodicalIF":1.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of VKORC1 and CYP2C9 gene polymorphisms with warfarin dose requirements in a representative Iranian population with cardiac valve replacement surgery.","authors":"Omid Maleki, Javad Gharechahi","doi":"10.1097/FPC.0000000000000571","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000571","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Materials and methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microsampling with dried blood spots and mass spectrometry enables PK/PD profiling of responses to praziquantel in a Schistosoma haematobium-exposed Zimbabwean population.","authors":"David Twesigomwe, Grace Zdesenko, Takafira Mduluza, Gavin Blackburn, Richard Burchmore, Francisca Mutapi","doi":"10.1097/FPC.0000000000000572","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000572","url":null,"abstract":"<p><strong>Introduction: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cardiomyopathies associated with RASopathies: the role of mitogen-activated protein kinase inhibitors and therapeutic challenges.","authors":"Valentina Botia-Arciniegas, Natalia Jimenez-Cardozo, Juliana Lores","doi":"10.1097/FPC.0000000000000569","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000569","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of estrogen and progesterone receptor polymorphisms with idiopathic thin endometrium.","authors":"Belén Lledo, Mónica Hortal, María Martínez, Jose A Ortiz, Ruth Morales, Andrea Bernabeu","doi":"10.1097/FPC.0000000000000560","DOIUrl":"10.1097/FPC.0000000000000560","url":null,"abstract":"<p><p>The research question is as follows: Are estrogen and progesterone receptor genotypes associated with thin endometrium? We performed a prospective cohort study of 129 patients who underwent preimplantation genetic testing for aneuploidies. These patients were categorized according to endometrial thickness: >7 mm control group ( n  = 94) and ≤7 mm study group ( n  = 35). Polymorphisms in the genes ESR1 (rs9340799 and rs3138774), ESR2 (rs1256049 and rs4986938), and PGR (rs1042838) were analyzed. Regarding genotype distribution, the GA/AA genotype frequency for rs4986938- ESR2 was higher in the thin endometrium group (80% in the study group vs. 50% in the control group; P  = 0.002), as well as the GG genotype of PGR (8.6% in the study group vs. 0% in the control group; P  = 0.002). No differences were observed for the remaining genotypes. In terms of clinical data, the pregnancy rate after euploid embryo transfer was lower in patients with the AA genotype for rs4986938- ESR2 (18.2% AA vs. 40.8% GA vs. 44.0% GG; P  = 0.039). Finally, a predictive pregnancy model was developed using clinical data and ESR2 and PGR genotypes, with an area under the curve of 0.76, sensitivity of 64%, and specificity of 76%. The genetic variants rs4986938 in the ESR2 gene and rs1042838 in the PGR gene seem to correlate with idiopathic thin endometrium. In addition, the rs4986938 polymorphism in the ESR2 gene is associated with pregnancy rate. Finally, a predictive model combining clinical data and patient genetic profiles has been proposed to predict clinical pregnancy outcomes.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"136-139"},"PeriodicalIF":1.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of genetic variations in FPGS , MTHFR , and ATIC on methotrexate response among pediatric patients with acute lymphoblastic leukemia.","authors":"Shu-Mei Wang, Dan-Qi Zhao, Xiao-Yan Kong, Miao Li","doi":"10.1097/FPC.0000000000000563","DOIUrl":"10.1097/FPC.0000000000000563","url":null,"abstract":"<p><strong>Objectives: </strong>Genetic polymorphisms in FPGS , MTHFR , and ATIC have emerged as important modulators of methotrexate (MTX) metabolism and toxicity. We investigated the distribution of FPGS rs10106, MTHFR rs1801131, and ATIC rs2372536 polymorphisms in children with acute lymphoblastic leukemia (ALL) and assessed their influence on MTX concentrations, toxicity profiles, and clinical outcomes.</p><p><strong>Methods: </strong>Genotyping of FPGS rs10106 G > A, MTHFR rs1801131 A > C, and ATIC rs2372536 C > G polymorphisms was conducted using the Sequenom MassARRAY iPLEX platform in 145 pediatric ALL patients.</p><p><strong>Results: </strong>Significant ethnic differences were observed in the allelic and genotypic distributions of the three single nucleotide polymorphisms (SNPs) investigated. None of these three SNPs had a significant effect on MTX levels or toxicities. The frequencies of the ATIC rs2372536 CC genotype and C allele in ALL patients (44.8% and 68.6%, respectively) were significantly lower than those in Han Chinese in Beijing, China (58.3% and 78.2%, respectively; P  = 0.036 and 0.019, respectively). Patients carrying the ATIC rs2372536 GG genotype (36.4%, 4/11) had a significantly higher relapse rate than the CC genotype carriers (6.2%, 4/65, P  = 0.013). There, however, were no significant effects on relapse-free survival in Kaplan-Meier and Cox regression analyses for all three candidate SNPs.</p><p><strong>Conclusion: </strong>Our findings offer valuable insights into the intricate interplay between genetic polymorphisms, MTX exposure, toxicities, and clinical outcomes in patients with ALL and have the potential to inform precision medicine strategies.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"127-135"},"PeriodicalIF":1.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetics of plasma dolutegravir exposure during 1-month rifapentine/isoniazid treatment of latent tuberculosis.","authors":"Nia Covington, Anne F Luetkemeyer, Marjorie Z Imperial, Rodney Dawson, Yoninah Cramer, Sue Rosenkranz, Susan Swindells, Irina Gelmanova, Anchalee Avihingsanon, Roberto C Arduino, Wadzanai Samaneka, Kelly E Dooley, Rada Savic, Anthony T Podany, David W Haas","doi":"10.1097/FPC.0000000000000562","DOIUrl":"10.1097/FPC.0000000000000562","url":null,"abstract":"<p><p>In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (C trough ). Here, we characterize the impact on dolutegravir C trough of UGT1A1 , AADAC , and NAT2 polymorphisms that affect dolutegravir, rifapentine, and isoniazid, respectively. People with HIV receiving dolutegravir-based antiretroviral therapy with an indication to treat latent tuberculosis underwent pharmacokinetic sampling during dolutegravir 50 mg once daily alone, and on day 28 of dolutegravir 50 mg twice daily with rifapentine/isoniazid. Multivariable linear regression models characterized genetic associations with dolutegravir C trough . Among 30 participants evaluable for genetic associations, median (Q1, Q3) day 0 dolutegravir C trough was 1745 (1099, 2694) ng/ml, and day 28 was 2146 (1412, 2484) ng/ml. Day 28 C trough was higher with UGT1A1 rs887829 TT [geometric mean ratio (GMR) = 1.65; 90% confidence interval (CI): 0.97-2.78] and CT (GMR = 1.38; 90% CI: 1.02-1.86) than with CC, and was higher with AADAC rs1803155 GG (GMR = 1.79; 90% CI: 1.09-2.93) and AG (GMR = 1.48; 90% CI: 1.14-1.90) than with AA. Median day 28 C trough ranged from 1205 (1063, 1897) ng/ml with 4 total UGT1A1 and AADAC risk alleles, to 3882 and 3717 ng/ml with only one risk allele. Individuals with concomitant AADAC slow metabolizer and UGT1A1 normal metabolizer genotypes may be at greater risk for clinically significant drug-drug interactions between rifapentine/isoniazid and dolutegravir.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"140-144"},"PeriodicalIF":1.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}