Cts-Clinical and Translational Science最新文献

{"title":"The Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants","authors":"Jasmine A. Luzum,&nbsp;Shana D. R. Littleton,&nbsp;Ana I. Lopez-Medina,&nbsp;Bin Liu,&nbsp;Ruicong She,&nbsp;David E. Lanfear","doi":"10.1111/cts.70239","DOIUrl":"https://doi.org/10.1111/cts.70239","url":null,"abstract":"<p>Previous pharmacogenetic findings for beta-blocker pharmacodynamic candidate genes (<i>ADRB1</i>, <i>ADRB2</i>, <i>ADRA2C, GRK4,</i> and <i>GRK5)</i> have been inconsistent. Therefore, the purpose of this study was to determine whether interactions of pharmacodynamic variants with beta-blocker exposure significantly associated with survival in patients with heart failure with reduced ejection (HFrEF). The 893 patients were 51% self-reported African American and 49% self-reported White race, 36% female, and 240 died (27%) over a median follow-up of 2.8 years. The primary outcome was all-cause mortality. Using Cox proportional hazards models with time-varying beta-blocker exposure and adjusted for clinical risk factors and ancestry, interactions of <i>ADRB1</i> Arg389Gly, <i>ADRB1</i> Ser49-Arg389Gly haplotype, <i>ADRA2C</i> Del_322-325, and <i>GRK4</i> Ala486Val with beta-blocker exposure were significant before correction for multiple comparisons (<i>p</i> &lt; 0.1), but only <i>GRK4</i> Ala486Val remained significant in African Americans after correction for multiple comparisons using the adaptive Hochberg method (<i>p</i> = 0.022). Beta-blocker exposure only associated with a significant reduction in the risk of mortality in the African American HFrEF patients with the <i>GRK4</i> Ala486/Ala486 genotype (HR = 0.44; 95% CI = 0.20–0.96; <i>p</i> = 0.04). In conclusion, the interaction of <i>GRK4</i> Ala486Val with beta-blocker exposure significantly associated with survival in African American HFrEF patients. Larger sample sizes or meta-analyses are needed to have more statistical power to better assess beta-blocker pharmacogenetic interactions for <i>ADRB1</i> Arg389Gly, <i>ADRB1</i> Ser49-Arg389Gly haplotype, and <i>ADRA2C</i> Del_322-325 in the future.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875621","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}

{"title":"Development of an Ancestrally Inclusive Preemptive Pharmacogenetic Testing Panel","authors":"Christelle Lteif,&nbsp;Brian E. Gawronski,&nbsp;Emily J. Cicali,&nbsp;Katherine A. Martinez,&nbsp;Kimberly J. Newsom,&nbsp;Petr Starostik,&nbsp;Larisa H. Cavallari,&nbsp;Julio D. Duarte","doi":"10.1111/cts.70230","DOIUrl":"https://doi.org/10.1111/cts.70230","url":null,"abstract":"<p>Pharmacogenetic (PGx) testing can individualize pharmacotherapy, but many current panels lack inclusivity for diverse populations and are often cost-prohibitive for medically underserved communities. This study aimed to develop and validate GatorPGx Plus, a low-cost, preemptive PGx panel tailored for diverse patient populations. Pharmacogenes were selected based on the drug/drug classes potentially influenced by their variants, the clinical severity of drug-gene interactions, or the strength of guideline recommendations or emerging evidence. Variants within the pharmacogenes were included if their allele frequencies were approximately 1% or greater in any major ancestral population. The panel was validated for accuracy, precision, and analytical sensitivity and applied to 124 participants from an ongoing pharmacogenetic clinical implementation trial. To reduce costs, a high-throughput platform was chosen, laboratory technician hands-on time was minimized, and result translation and reporting were automated. The panel comprised tests for 62 variants in 14 genes/gene regions, including a <i>CYP2D6</i> copy number assay. It demonstrated 100% concordance with reference methods. The average turnaround time between test order and results was 14.3 (±6.4) days. Among the 124 genotyped trial participants (mean age 60 years, 57.3% female), 99% had at least one non-normal function (less common or higher-risk) phenotype. The most frequently identified non-normal function phenotypes were in <i>CYP2C19</i> (69.4%). <i>CYP2D6 *17</i>, <i>*29</i>, and <i>CYP2C19 *9</i> were captured at higher frequencies than reported in European populations. GatorPGx Plus is a low per-test cost, clinically validated, preemptive PGx panel that effectively captures key variants in a mixed-ancestry population, underscoring its potential clinical utility in diverse, medically underserved populations.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875643","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}

{"title":"Bioequivalence and Food Effect Assessment of Two Fixed-Dose Combination Formulations of Telmisartan-Hydrochlorothiazide Tablets in Chinese Healthy Subjects","authors":"Minwan Hu,&nbsp;Man Yang,&nbsp;Shuyu Zhang,&nbsp;Jiangfan Li,&nbsp;Hongxian Pang,&nbsp;Yingzi Pei,&nbsp;Chao Guo,&nbsp;Xuhong Wang","doi":"10.1111/cts.70228","DOIUrl":"https://doi.org/10.1111/cts.70228","url":null,"abstract":"<p>This study assessed the bioequivalence and food effect of two fixed-dose combination (FDC) formulations of telmisartan-hydrochlorothiazide tablets (telmisartan 40 mg, hydrochlorothiazide 12.5 mg) in healthy Chinese subjects. Seventy-two subjects were enrolled and divided into fasted and fed cohorts in a single-center, randomized, open-label, single-dose, three-period, three-sequence, and crossover study. The pharmacokinetic characteristics of telmisartan and hydrochlorothiazide, including C_max and AUC, were compared after subjects received single oral doses of telmisartan-hydrochlorothiazide tablets using a validated LC–MS/MS method. Safety and tolerability of treatments were monitored. Pharmacokinetic profiles of two FDC telmisartan-hydrochlorothiazide tablets were comparable after single-dose administration. 90% CI of geometric mean ratios (GMRs) of AUC_0-t, AUC_0-∞, and C_max of telmisartan and hydrochlorothiazide of two FDC formulations fell within the predefined bioequivalence range of 80.0%–125.0% under both fasted and fed conditions. Administration with food had significant effects on telmisartan pharmacokinetic parameters but a slight impact on hydrochlorothiazide. Notably, C_max and AUC of telmisartan were significantly decreased by 39.6%–43.7% in the fed versus fasted conditions. Safety assessments revealed all treatments were safe and well tolerated. Two telmisartan-hydrochlorothiazide FDC formulations were bioequivalent in healthy Chinese subjects in both fasted and fed states. All treatments were well tolerated.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875644","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}

{"title":"Ethnic Sensitivity Assessment of Mosunetuzumab Pharmacokinetics and Pharmacodynamics in Chinese Patients With Relapsed or Refractory Follicular Lymphoma","authors":"Junyi Li,&nbsp;Michael Z. Liao,&nbsp;Justin Wilkins,&nbsp;Elicia Penuel,&nbsp;Bei Wang,&nbsp;Shweta Vadhavkar,&nbsp;Kun Peng,&nbsp;Junning Cao,&nbsp;Zhiming Li,&nbsp;Ye Zhang,&nbsp;Wenjin Li,&nbsp;Donghang Li,&nbsp;Mingzhu Zhou,&nbsp;Michael C. Wei,&nbsp;Antonia Kwan,&nbsp;Rong Zhao,&nbsp;Chunze Li,&nbsp;Chi-Chung Li,&nbsp;David C. Turner","doi":"10.1111/cts.70211","DOIUrl":"https://doi.org/10.1111/cts.70211","url":null,"abstract":"<p>Mosunetuzumab, a CD20 × CD3 T-cell-engaging bispecific antibody, redirects T cells to eliminate malignant B cells. The purpose of YO43555 was to assess the pharmacokinetics (PK), safety, tolerability, and efficacy of mosunetuzumab as a single agent in Chinese patients with relapsed/refractory follicular lymphoma (R/R FL). The impact of ethnicity/region on the PK disposition of mosunetuzumab was assessed by non-compartmental analysis (NCA) as well as a population PK (popPK) approach. A previously established popPK model for intravenous mosunetuzumab, built from the global Phase I/II study GO29781, was externally validated with the PK data from study YO43555. Results from the PK analysis showed that the global popPK model adequately captured the individual PK of the Chinese population. The model predicted mosunetuzumab exposure metrics in Chinese patients were similar to those observed in Asian patients in the GO29781 R/R FL subpopulation with the same dose regimen, while the exposure differences between Chinese and Non-Asians from the global population were &lt; 20%. An overlay of the exposure levels for Chinese patients on the established E-R relationship in global patients indicated that the mosunetuzumab exposure of Chinese patients remained within the established bounds for clinical safety and efficacy. The cytokine biomarkers IL-6 and TNF-α showed similar time-course patterns of release as observed in globally enrolled patients. In summary, mosunetuzumab PK disposition did not show significant ethnic sensitivity that would impact patient outcomes. Therefore, dose adjustment of the globally approved mosunetuzumab regimen is not warranted for Chinese patients with R/R FL.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT02500407</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875622","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}

{"title":"Promising New Anti-TIGIT Agents: Stealthy Allies in Cancer Immunotherapy","authors":"Gatadi Srikanth,&nbsp;Durga Prasad Beda,&nbsp;Ashish Ranjan Dwivedi,&nbsp;Nandan Kumar Duddukuri,&nbsp;Srinivas Nanduri,&nbsp;Jitendra Patel","doi":"10.1111/cts.70212","DOIUrl":"https://doi.org/10.1111/cts.70212","url":null,"abstract":"<p>TIGIT (T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain), Vstm3, and VSIG9, are newly recognized immunological checkpoints. They are prominently expressed on CD4+ and CD8+ T cells, tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, and regulatory T cells (Tregs). The TIGIT (TIGIT) protein is crucial for immune modulation since it diminishes NK cell populations and hinders T cell activity in cancer patients and experimental models. CD155, the principal ligand of TIGIT in humans, has been recognized as a pivotal target for immunotherapy owing to its interaction with TIGIT. CD155 is linked to the efficacy of anti-programmed cell death protein 1 (PD-1) therapy, even without TIGIT expression, underscoring its importance in immune checkpoint suppression. Anti-TIGIT medicines, either independently or in conjunction with anti-PD-1 treatments, have demonstrated potential in augmenting immune responses to malignancies. This review examines the structural and functional characteristics of the TIGIT protein, new developments in anti-TIGIT drugs, and their prospective use in cancer immunotherapy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861600","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}

{"title":"Recommended Clinical Context and Patient Context Data Elements for Liquid Biopsy Data Submitted to Data Repositories and Data Commons","authors":"Robert L. Grossman,&nbsp;Jake Vinson,&nbsp;Elizabeth Bain,&nbsp;Karl Bisselou,&nbsp;Sanchi Chandan,&nbsp;Carolyn Compton,&nbsp;John Hu,&nbsp;Donald J. Johann,&nbsp;Frederick Jones,&nbsp;Gregory Jones,&nbsp;Suzanne LeBlang,&nbsp;Jerry S. H. Lee,&nbsp;Tara Lichtenberg,&nbsp;Christina M. Lockwood,&nbsp;John Lyle,&nbsp;Jean-Francois Martini,&nbsp;Jason D. Merker,&nbsp;Lauren Saunders,&nbsp;Howard Scher,&nbsp;Stella Somiari,&nbsp;Jenny You,&nbsp;Lauren C. Leiman","doi":"10.1111/cts.70227","DOIUrl":"https://doi.org/10.1111/cts.70227","url":null,"abstract":"<p>In 2020, BLOODPAC recommended 11 pre-analytical minimal technical data elements for collection and submission of liquid biopsy data to public databases. This article expands on that work by recommending 22 clinical context and 10 patient context data elements. These elements, essential for liquid biopsy data submitted to repositories like the BLOODPAC Data Commons, cover tumor characteristics, disease progression, and patient demographics, supporting biomarker validation, research, and clinical trials.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856896","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}

{"title":"Unlocking the Mysteries of Rare Disease Drug Development: A Beginner's Guide for Clinical Pharmacologists","authors":"Mariam A. Ahmed,&nbsp;Bilal AbuAsal,&nbsp;Jeffrey S. Barrett,&nbsp;Karim Azer,&nbsp;Yuen Yi Hon,&nbsp;Salwa Albusaysi,&nbsp;Elizabeth Shang,&nbsp;Meng Wang,&nbsp;Maria Burian,&nbsp;Noha Rayad","doi":"10.1111/cts.70215","DOIUrl":"https://doi.org/10.1111/cts.70215","url":null,"abstract":"<p>Clinical pharmacologists face unique challenges when developing drugs for rare diseases. These conditions are characterized by small patient populations, diverse disease progression patterns, and a limited understanding of underlying pathophysiology. This tutorial serves as a comprehensive guide, offering practical insights and strategies to navigate its complexities. In this tutorial, we outline global regulatory incentives and resources available to support rare disease research, describe some considerations for designing a clinical development plan for rare diseases, and we highlight the role of biomarkers, real-world data, and modeling and simulations to navigate rare disease challenges. By leveraging these tools and understanding regulatory pathways, clinical pharmacologists can significantly contribute to advancing therapeutic options for rare diseases.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861599","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}

{"title":"Care Team Attributes Predict Likelihood of Utilizing Pharmacogenomic Information During Inpatient Prescribing","authors":"Zhong Huang,&nbsp;Matthew Jack,&nbsp;Kevin J. O'Leary,&nbsp;Edith A. Nutescu,&nbsp;Thomas Chen,&nbsp;Gregory W. Ruhnke,&nbsp;David George,&nbsp;Larry K. House,&nbsp;Randall Knoebel,&nbsp;Seth Hartman,&nbsp;Anish Choksi,&nbsp;Kiang-Teck J. Yeo,&nbsp;Minoli A. Perera,&nbsp;Mark J. Ratain,&nbsp;David O. Meltzer,&nbsp;Peter H. O'Donnell","doi":"10.1111/cts.70193","DOIUrl":"https://doi.org/10.1111/cts.70193","url":null,"abstract":"<p>Medication prescribing is imperfect, and unintended side effects complicate patient care. Pharmacogenomics (PGx) is an emerging solution that associates genotypes with personalized drug-related outcomes, but it has not been widely adopted. We hypothesize that patient and provider attributes may predict and promote PGx utilization. We studied PGx using data from the ACCOuNT study, a multi-institutional prospective trial that implemented broad preemptive PGx result delivery for African American inpatients [Clinicaltrials.gov NCT03225820]. Patients were genotyped, and their PGx information was made available within an integrated informatics portal. Utilization of PGx data (defined as the active choice to review PGx information) was left to the enrolled provider's discretion. Our primary endpoint was to identify patient and care team attributes associated with PGx use. We identified statistically significant univariate predictors and utilized logistic regression to compare relative predictiveness. This study included 187 patients (60.4% female, median age 55, 75.4% treated at the University of Chicago, 17.6% at Northwestern University, and 7.0% at the University of Illinois Chicago) and 188 providers (63.8% MD, 22.3% PharmD, 6.4% PA, and 7.4% APN). In multivariate analysis, we found that the use of PGx information in a prior admission significantly predicted the use in subsequent admissions (OR 7.62, <i>p</i> &lt; 0.05). Similarly, pharmacist participation on care teams significantly predicted PGx use (OR 4.52, <i>p</i> &lt; 0.05). In the first systematic analysis of the impact of patient and care team factors on inpatient PGx clinical decision support (CDS) adoption, we found that actionable care team attributes, such as pharmacist participation or successful initial adoption measures, predict PGx CDS use.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856711","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}

{"title":"Phenoconversion of CYP3A4, CYP2C19 and CYP2D6 in Pediatrics, Adolescents and Young Adults With Lymphoma: Rationale and Design of the PEGASUS Study","authors":"Rachel Conyers,&nbsp;Tayla Stenta,&nbsp;Andrew A. Somogyi,&nbsp;Carl Kirkpatrick,&nbsp;Andreas Halman,&nbsp;Sophie Wang,&nbsp;Claire Moore,&nbsp;Dhrita Khatri,&nbsp;Elizabeth Williams,&nbsp;Roxanne Dyas,&nbsp;Tim Spelman,&nbsp;David A. Elliott,&nbsp;Amanda Gwee,&nbsp;Marliese Alexander","doi":"10.1111/cts.70209","DOIUrl":"https://doi.org/10.1111/cts.70209","url":null,"abstract":"<p>Phenoconversion is the discrepancy between genotype-predicted phenotype and clinical phenotype, due to nongenetic factors. In oncology patients, the impact of phenoconversion on drug selection, efficacy, toxicity, and treatment outcomes is unknown. This study will assess acceptability and feasibility of investigating phenoconversion using probe medications in a pediatric and adolescent and young adult (AYA) oncology population. This prospective, single-arm, single-blind, nonrandomized feasibility study, will enroll individuals aged 6–25 years with a new diagnosis of Hodgkin Lymphoma or Non-Hodgkin Lymphoma. Genotyping will be performed at baseline using whole genome sequencing or targeted panel testing. Longitudinal phenotyping will be conducted throughout the cancer treatment using exogenous oral enzyme-specific probes, specifically subtherapeutic dextromethorphan (CYP2D6) and omeprazole (CYP2C19, CYP3A4) for enzyme activity assessment. The primary outcome measure will be the proportion of patients who consent to the study and successfully complete baseline and at least two longitudinal time points with valid probe drug metabolic ratio measurements. Secondary outcomes include classification of clinical phenotypes based on probe drug metabolic ratios, probe drug safety, barriers to consent, acceptability of pharmacogenomic and phenoconversion testing, longitudinal genotype/phenotype concordance, inflammatory profiles, and patient and disease factors influencing phenoconversion. The trial has received ethics approval (2023/ETH1954) and is registered at ClinicalTrials.gov (NCT06383338). Findings will be disseminated through peer-reviewed publications and professional conferences, providing critical insights to advance the understanding of phenoconversion in oncology from pediatrics to adults. These results will help shape future research and drive the implementation of more personalized precision medicine strategies for all people with cancer.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857137","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}

{"title":"Genome Wide Association Study (GWAS) Identifies Novel Genetic Loci for Second-Generation Antipsychotics (SGA)-Induced Metabolic Syndrome (MetS)","authors":"Nihal El Rouby,&nbsp;Aniwaa Owusu-Obeng,&nbsp;Michael H. Preuss,&nbsp;Simon Lee,&nbsp;Mingjian Shi,&nbsp;Rajiv Nadukuru,&nbsp;Sara L. Van Driest,&nbsp;Jonathan D. Mosley,&nbsp;Melissa DelBello","doi":"10.1111/cts.70216","DOIUrl":"https://doi.org/10.1111/cts.70216","url":null,"abstract":"<p>Second-generation antipsychotics (SGA) are widely used for treating psychiatric disorders; however, their use is associated with an increased risk of metabolic syndrome (MetS). To identify common genetic associations of SGA-induced metabolic syndrome (SGA-MetS), we conducted a genome-wide association study (GWAS) in a diverse patient population within the BioVU and Bio<i>M</i>e electronic health records (EHRs)-linked biobanks. Additionally, we performed Mendelian Randomization (MR) analysis to investigate the association between the individual metabolic parameters comprising MetS (body mass index [BMI], fasting glucose, blood pressure, HDL, and triglycerides) and SGA-MetS. The meta-analysis of European ancestry GWAS from BioVU and Bio<i>M</i>e (<i>N</i> = 9248) identified a genome-wide signal (rs61900075, <i>β</i> = −0.27, SE = 0.05, <i>p</i> = 1.6 × 10⁻⁸) on chromosome 11. Multiple associated variants met the suggestive level of association (<i>p</i> ≤ 10⁻⁵) in the <i>PELO-ITGA1</i> locus on chromosome 5 and were associated among the Hispanic Ancestry within Bio<i>M</i>e. The meta-analysis of the African Ancestry patients of BioVU and Bio<i>M</i>e (<i>N</i> = 2018) identified multiple genome-wide signals that were functionally mapped to <i>NPPC-DIS3L2</i> in chromosome 2. Finally, the inverse-variance weighted average MR (BMI: OR = 1.2, 95% CI: 1.1–1.4, <i>p</i> = 0.002) showed that genetically predicted, higher BMI was associated with an increased risk of SGA-MetS. Similar results were seen in the sensitivity analyses using the weighted median and Egger MR. This study identified novel variants for SGA-MetS and suggested a role of BMI in increasing the risk of SGA-MetS. The findings highlight the value of EHR biobanks for identifying the genetics underlying SGA-MetS. The associations in chromosome 2 and 5 will need further replication.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857138","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}