Pharmacogenomics最新文献

Systemic lupus erythematosus (SLE) is a complex autoimmune disease requiring immunosuppressive medications to control symptoms and prevent organ damage. This review explores the influence of genetic polymorphisms on the pharmacokinetics and therapeutic responses of immunosuppressants in SLE. A total of 37 studies were reviewed, focusing on mycophenolic acid, tacrolimus, azathioprine, glucocorticoids, and cyclophosphamide. Genetic variants in UGT1A9, UGT2B7, CYP3A5, ABCB1,ABCC2 and TPMT significantly affect drug metabolism, efficacy, and toxicity. For instance, ABCB1 polymorphisms influence drug transport and bioavailability, impacting tacrolimus and glucocorticoid response, while ABCC2 variants alter MPA clearance, potentially affecting therapeutic outcomes, UGT1A9 and UGT2B7 variants influence mycophenolic acid metabolism, CYP3A5 impacts tacrolimus dosing, TPMT determines azathioprine metabolism, and CYP2C19 and CYP2B6 affect cyclophosphamide processing. These genetic differences can alter treatment effectiveness and risk of adverse effects. However, most pharmacogenetic studies focus on organ transplantation, leaving a critical gap in SLE-specific research, particularly among diverse populations. Addressing this gap is essential to optimizing personalized treatment for SLE. Integrating pharmacogenetics into clinical practice holds great potential to enhance the safety, efficacy, and outcomes of immunosuppressive therapy in SLE. This review highlights the urgent need for further studies to advance precision medicine for SLE patients.

As an emerging health technology, pharmacogenetic (PGx) testing has the capacity to improve medication therapy. However, implementation in medically underserved populations (MUPs) remains limited, which has the potential to increase healthcare disparities. While there is no single accepted definition for MUPs, demographic, socioeconomic, cultural, and geographic factors can lead to reduced access to healthcare, which contributes to disparate health outcomes in these populations. In the case of PGx testing, as MUPs have an increased risk of adverse drug events, have lower numbers of healthcare encounters, and are prescribed more medications which can be guided by PGx testing, additional benefits from PGx testing may occur in MUPs. Study of the acceptability and perceptions of PGx testing in MUPs, as reported in literature, provides support for the development of successful PGx testing implementations. Additionally, a few limited pilot PGx testing implementations in MUPs have assessed feasibility. However, further studies establishing the feasibility and effectiveness of PGx testing implementations in MUPs will enable more widespread PGx testing in those who are medically underserved. Thus, this narrative review explores the impact of medical underservice on health, PGx testing's potential impact on MUPs, and the research and early clinical implementations of PGx in MUPs.

Introduction: Genotype-guided tacrolimus management is not routine in clinical practice despite the availability of Clinical Pharmacogenetics Implementation Consortium dosing guidelines. Prior surveys have evaluated patient and provider perspectives of pharmacogenetics (PGx) in transplant, but limited recent data exists on tacrolimus PGx implementation across United States transplant centers.

Methods: An electronic survey was distributed to transplant pharmacists regarding utilization of tacrolimus PGx, methods of implementing PGx, and barriers to clinical implementation. A survey response was requested for each organ program within the transplant center.

Results: A total of 90 programs from 69 transplant centers (28.1% of active U.S. transplant centers) responded to the survey. Tacrolimus PGx was utilized for patient care in 14 programs (15.6%). There was substantial variability in the implementation methods and application of tacrolimus PGx results among transplant programs. In programs that had not implemented tacrolimus PGx, common barriers for implementation included PGx testing cost and availability and lack of evidence for clinical utility.

Conclusion: Implementation of PGx guided tacrolimus in solid organ transplant centers remains limited with heterogeneity in the implementation approach. Additional research is needed to establish the clinical utility of PGx guided tacrolimus and education on reimbursement and testing resources may help to increase uptake.

Aim: The aim of this study is to find out the effect of SOD1 rs36232792 and SOD2 rs5746136 on the risk of opioid use disorder (OUD).

Methods: Individuals with OUD (n = 101) and controls (n = 104) were included. SOD1 rs36232792 was genotyped by PCR. A novel PCR-RFLP method for SOD2 rs5746136 was optimized.

Results: A significant difference was observed between individuals with OUD and controls in view of the frequency of 'Ins/Del+Del/Del' genotypes of the SOD1 rs36232792 (p = 0.049), but not for SOD2 rs5746136 (p = 0.254). The intensity of anxiety and depressive symptoms was significantly higher in individuals with OUD compared to controls (p = 0.001).

Conclusion: The SOD1 rs36232792 polymorphism could contribute to the risk of OUD in a Turkish population. A novel PCR-RFLP method for SOD2 rs5746136 confirmed by sequencing can be used in a research laboratory without advanced equipment.

Pharmacogenomics (PGx) is an evolving field that integrates genetic information into clinical decision-making to optimize drug therapy and minimize adverse drug reactions (ADRs). Its application in rare disease (RD) drug development is promising, given the genetic basis of many RDs and the need for precision medicine approaches. Despite significant advancements, challenges persist in developing effective therapies for RDs due to small patient populations, genetic heterogeneity, and limited surrogate biomarkers. The Orphan Drug Act in the U.S. has incentivized RD drug development. However, the traditional drug approval process is constrained by logistical and economic challenges, necessitating innovative PGx-driven strategies. Identifying genetic biomarkers in the early drug development stages can optimize dose selection, enhance therapeutic efficacy, and reduce ADRs. Case studies such as eliglustat for Gaucher disease and ivacaftor for cystic fibrosis demonstrate the efficacy of PGx-guided treatment strategies. Integrating PGx into global drug development requires the harmonization of regulatory policies and increased diversity in genetic research. Artificial intelligence (AI) tools further enhance genetic analysis, disease prediction, and clinical decision-making. Modernizing drug labeling with PGx information is critical to ensuring safe and effective drug use. Collectively, PGx offers transformative potential in RD therapeutics by facilitating personalized medicine approaches and addressing unmet medical needs.

Aims: To study the availability, perceived necessity, barriers, and preferred formats for pharmacogenomics (PGx) education disseminated to healthcare professionals by professional societies.

Materials & methods: A web-based survey of professional organizations affiliated with the Inter-Society Coordinating Committee for Practitioner Education in Genomics (ISCC-PEG), a U.S.-based initiative coordinated by the National Human Genome Research Institute, targeted representatives who could reflect their organization's educational stance.

Results: Of the 34 unique responses analyzed, most organizations provided general and genomic education (94.1% and 82.4%, respectively), and 70.6% offered PGx-specific education. Most (61.8%) indicated they either needed major additions to the education they provide or had no PGx education resources. Key barriers included a lack of PGx focus within organizations (78.1%) and challenges in maintaining an up-to-date curriculum (75.0%). Preferred educational formats were live webinars (84.4%), hybrid courses (78.1%), and self-study modules (78.1%).

Conclusions: Our study identifies gaps in PGx education across professional organizations and underscores the need for resources to advance clinician competence in PGx. While some PGx education is available, many organizations require additional resources and support. Enhancing PGx education through targeted initiatives by organizations like ISCC-PEG may improve clinician competence and the integration of PGx into clinical practice.

Aim: Providers can use combinatorial pharmacogenomic panels to aid psychiatric medication prescribing. Results are typically documented in static documents which list the genotype and predicted phenotype (interpretation). However, genotype-to-phenotype translations can differ between laboratories and change as scientific consensuses evolves. Here, we describe the implications of reinterpreting phenotype after combinatorial psychiatric pharmacogenomic testing in a real-world setting.

Patients and methods: 143 patients underwent testing from 2014 to 2021. Reported genotypes and phenotypes were compared to 2024 Clinical Pharmacogenetics Implementation Consortium definitions. Chi-square tests and logistic regression were used to examine the differences in phenotype frequencies before and after reinterpretation and examine the association with time since testing.

Results: Eighty-one patients (57%) required at least one updated interpretation. CYP2C19 interpretations changed for 44/143 patients (31%), followed by CYP2D6 (29%), CYP2B6 (3%), and CYP2C9 (1%). Reinterpretation reduced the number of CYP2D6 ultrarapid and poor metabolizers (p = 0.005), which has implications for antidepressant prescribing. Likelihood of a patient having a reinterpreted phenotype was not associated with time since reporting (p = 0.71).

Conclusions: Reported phenotypes from combinatorial PGx testing often do not align with current standardized definitions, even from tests performed recently. Health systems should establish procedures to standardize and periodically update pharmacogenomic interpretations.

Aim: To assess patient perspectives following evaluation in a multidisciplinary pharmacogenomics clinic run by a clinical pharmacist, genetic counselor, and physician.

Methods: A survey was distributed to 187 adults seen in the Brigham and Women's Hospital Pharmacogenomics Clinic. Participants who completed the survey were invited to complete a semi-structured interview. Interview subjects were selected based on order of responses, scheduling availability, and range of participant experiences with testing and the clinic process. Surveys were analyzed with descriptive statistics, and interview transcripts were analyzed with thematic analysis.

Results: Forty-two survey responses were received; 13 participants were interviewed. Quantitative data demonstrated high satisfaction with the multidisciplinary clinic model and belief that pharmacogenomic testing has value. Qualitative analysis identified four themes: 1) Self-Advocacy as a Patient Responsibility in the Utilization of Pharmacogenomic Results, 2) High Satisfaction with Multidisciplinary Pharmacogenomics Clinic Model and Team, 3) Utility of Pharmacogenomics, and 4) Desire for Pharmacogenomics Resources.

Conclusion: Patients value the care provided by a multidisciplinary pharmacogenomics clinic team, but they need to advocate for the use of their results with other healthcare professionals.

Receptor tyrosine kinase pathways are frequently deregulated in cancer. Inhibiting these pathways with small molecule inhibitors or monoclonal antibodies has become a crucial addition to the therapeutic armamentarium in oncology. Since the introduction of drugs that target receptor tyrosine kinase pathways, it has become evident that not all patients respond to treatment. Therefore, biomarkers to predict response and benefit of drugs targeting tyrosine kinases have been sought. Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), one of the four receptors of the EGFR family were among the first targeted therapies used in solid tumors. Two drugs of this class, cetuximab and panitumumab, have been used in patients with metastatic colorectal cancer initially without any biomarker requirement. Soon, it became clear that responses were mostly observed in patients without mutations in KRAS oncogene. Currently, additional mutations of the pathway, including non-exon 2 mutations in KRAS, mutations in the homologous GTPase NRAS, in kinase BRAF and PIK3CA and other pathway proteins, have been added in the evaluation for responsiveness prediction to cetuximab and panitumumab. In this review, the predictive biomarker landscape for anti-EGFR monoclonal antibody inhibitors in metastatic colorectal cancers with no extended RAS and BRAF mutations will be examined.