UNASSIGNED: Pharmacogenomics (PGx) is a well-established concept of how genes impact medication response, with many studies demonstrating reductions in medication side effects, improved efficacy and cost effectiveness. Despite these benefits, implementation of PGx in daily practice remains limited. Studies on the implementation of PGx in clinical practice have previously found that inadequate knowledge is one of the main barriers. Details regarding specifically which educational needs exist among family medicine clinicians requires further study.
UNASSIGNED: The aim of this study was to identify both the perceived role that pharmacogenomics (PGx) could play in primary care practice, the knowledge gaps that family medicine clinicians experience, and the skills they require to use PGx in their daily practice.
UNASSIGNED: To achieve this aim, the attitudes, knowledge, barriers, skills needed, and preferred educational program were explored in a family medicine clinician focus group study via a semi-structured interview and knowledge quiz. Second, multidisciplinary focus groups provided information on the level of knowledge and necessary skills to use PGx in patient care. After gathering key recorded information from both focus groups, the perceived role pharmacogenomics could possibly play in primary care, the predominant knowledge gaps, and the most appropriate educational program was determined by qualitative analysis.
UNASSIGNED: Four themes emerged regarding the PGx educational needs and the role of PGx in family medicine: 1) need for PGx competences, 2) insight into the roles and responsibilities of PGx services, 3) optimization of PGx workflow through artificial intelligence integrated in the electronic health record, and 4) the ethical dilemmas and psychological effects related to PGx. These themes reflect a shift in the role of PGx in family medicine with implications for education.
UNASSIGNED: The results obtained from this study will help improve the implementation of PGx in daily practice, and consequently, may result in increased utilization of PGx, thereby resulting in improved medication efficacy and reduced side effects.

BACKGROUND: Genetic polymorphisms are known to play a crucial role in the development of osteoporosis. Vitamin D3 regulates bone homeostasis through the vitamin D receptor (VDR). Reduced VDR activity increases osteoporosis risk. Study Design: A case-control study.
METHODS: This case-control study investigated the potential association between six single-nucleotide polymorphisms (SNPs) within the VDR gene (rs11568820, rs4516035, rs2228570, rs1544410, rs7975232, and rs731236) and the occurrence of osteoporosis in Kerman province. The genotypes of the SNPs were analyzed using polymerase chain reaction-restriction fragment length polymorphism, tetra primer amplification refractory mutation system-PCR, and sequencing in two groups of osteoporosis patients (n=40) and controls (n=42). Additionally, the levels of calcium and vitamin D3 in the serum of the patients were measured, and the in silico analysis of the VDR structure and interaction was performed using I-TASSER, ProSA, PROCHECK, GeneMANIA, GTEx, and GPS 6.0.
RESULTS: None of the patients exhibited calcium or vitamin D3 deficiencies. Among the six SNPs, only the T allele in rs4516035, which leads to a shorter variant called VDRA, showed a significant association with susceptibility to osteoporosis (odds ratio=3.061, P=0.007). The in silico analysis demonstrated that the 3D structure, expression, and post-transcriptional modification of VDRA are distinct from those of the more extended variant, VDRB1. VDRB1 is upregulated in sun-exposed skin, and its interactions with its partners differ from those of VDRA.
CONCLUSIONS: Despite adequate vitamin D levels, the VDRA variant, which has lower activity, could increase the predisposition to osteoporosis in the studied population. These findings clarify the importance of genetic screening for personalized medicine and the effectiveness of prevention and treatment strategies.

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.

BACKGROUND: Pharmacogenetics can impact patient care and outcomes through personalizing the selection of medicines, resulting in improved efficacy and a reduction in harmful side effects. Despite the existence of compelling clinical evidence and international guidelines highlighting the benefits of pharmacogenetics in clinical practice, implementation within the National Health Service in the United Kingdom is limited. An important barrier to overcome is the development of IT solutions that support the integration of pharmacogenetic data into health care systems. This necessitates a better understanding of the role of electronic health records (EHRs) and the design of clinical decision support systems that are acceptable to clinicians, particularly those in primary care.
OBJECTIVE: Explore the needs and requirements of a pharmacogenetic service from the perspective of primary care clinicians with a view to co-design a prototype solution.
METHODS: We used ethnographic and think-aloud observations, user research workshops, and prototyping. The participants for this study included general practitioners and pharmacists. In total, we undertook 5 sessions of ethnographic observation to understand current practices and workflows. This was followed by 3 user research workshops, each with its own topic guide starting with personas and early ideation, through to exploring the potential of clinical decision support systems and prototype design. We subsequently analyzed workshop data using affinity diagramming and refined the key requirements for the solution collaboratively as a multidisciplinary project team.
RESULTS: User research results identified that pharmacogenetic data must be incorporated within existing EHRs rather than through a stand-alone portal. The information presented through clinical decision support systems must be clear, accessible, and user-friendly as the service will be used by a range of end users. Critically, the information should be displayed within the prescribing workflow, rather than discrete results stored statically in the EHR. Finally, the prescribing recommendations should be authoritative to provide confidence in the validity of the results. Based on these findings we co-designed an interactive prototype, demonstrating pharmacogenetic clinical decision support integrated within the prescribing workflow of an EHR.
CONCLUSIONS: This study marks a significant step forward in the design of systems that support pharmacogenetic-guided prescribing in primary care settings. Clinical decision support systems have the potential to enhance the personalization of medicines, provided they are effectively implemented within EHRs and present pharmacogenetic data in a user-friendly, actionable, and standardized format. Achieving this requires the development of a decoupled, standards-based architecture that allows for the separation of data from application, facilitating integration across various EHRs through the use of application programming interfaces (APIs). More globally, this study demonstrates the role of health informatics and user-centered design in realizing the potential of personalized medicine at scale and ensuring that the benefits of genomic innovation reach patients and populations effectively.

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.

BACKGROUND: Cardiovascular disease induces erectile dysfunction modulated by endothelial nitric oxide synthase enzyme and an impaired ejection fraction that restricts penis vascular congestion. However, the mechanisms regulating endothelial dysfunction are not understood.
OBJECTIVE: Exploring the functional impact of endothelial nitric oxide synthase genetic polymorphisms on erectile dysfunction and drug therapy optimization in high-risk cardiovascular disease patients.
METHODS: Patients with erectile dysfunction symptoms and candidates for andrology therapy were included (n = 112). Clinical data and endothelial nitric oxide synthase rs1799983 (G894T) and rs2070744 (T-786C), genotyped by fluorescence polarization assays, were registered. The 27-bp variable number of the tandem repeat polymorphism in intron 4 (intron4b/a) was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Association analyses were run with the R-3.2.0 software.
RESULTS: A significant association between endothelial nitric oxide synthase 786-TT (p = 0.005) and the aa/ac of intron 4 variable number of the tandem repeat (p = 0.02) with higher erectile dysfunction susceptibility was observed in cardiovascular disease patients (60 ± 9 years, 66% severe erectile dysfunction, 56% ejection fraction). After 3-months of phosphodiesterase type 5 inhibitors, erectile dysfunction (International Index of Erectile Function, 50 ± 16 scores, the International Index of Erectile Function-Erectile Function 21 ± 10 scores, p < 0.001) and sexual quality of life (modified Sexual Life Quality Questionnaire 55 ± 23 scores, p < 0.001) had significantly improved. The cardiovascular ejection fraction was influenced positively with better sexual quality of life (0.1941), and also in the endothelial nitric oxide synthase G894-T allele (p = 0.076) carriers, which could merit future analyses. Erectile dysfunction was present as the primary clinical manifestation in 62% of cases, with cardiovascular disease occurring concurrently. Only former smokers and obese subjects debuted prior to cardiovascular disease than to erectile dysfunction.
CONCLUSIONS: Our study provides comprehensive insights into the functional interaction linking endothelial nitric oxide synthase gene polymorphisms, erectile function, and ejection fraction in high-risk cardiovascular disease patients. Future therapeutic strategies could target endothelial nitric oxide synthase activity by including lifestyle changes and epigenetic modulations.

Next-generation sequencing (NGS) significantly enhances precision medicine (PM) by offering personalized approaches to diagnosis, treatment, and prevention of unmet medical needs. Little is known about the current situation of PM in Asia. Thus, we aimed to conduct an overview of the progress and gaps in PM in Asia and enrich it with in-depth insight into the possibilities of future PM in Thailand. This scoping review focused on Asian countries starting with non-cancer studies, including rare and undiagnosed diseases (RUDs), non-communicable diseases (NCDs), infectious diseases (IDs), and pharmacogenomics, with a focus on NGS. Subsequent in-depth interviews with experts in Thailand were performed, and a thematic analysis served as the main qualitative methodology. Out of 2898 searched articles, 387 studies were included after the review. Although most of the studies focused on cancer, 89 (23.0%) studies were related to RUDs (17.1%), NCDs (2.8%), IDs (1.8%), and pharmacogenomics (1.3%). Apart from medicine and related sciences, the studies were mostly composed of PM (61.8%), followed by genetics medicine and bioinformatics. Interestingly, 28% of articles were conducted exclusively within the fields of medicine and related sciences, emphasizing interdisciplinary integration. The experts emphasized the need for sustainability-driven political will, nurturing collaboration, reinforcing computational infrastructure, and expanding the bioinformatic workforce. In Asia, developments of NGS have made remarkable progress in PM. Thailand has extended PM beyond cancer and focused on clinical implementation. We summarized the PM challenges, including equity and efficiency targeting, guided research funding, sufficient sample size, integrated collaboration, computational infrastructure, and sufficient trained human resources.

BACKGROUND: Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis.
METHODS: DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES.
RESULTS: Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085).
CONCLUSIONS: Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.

BACKGROUND: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.
METHODS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.
BACKGROUND: The ethics approval of the trial has been obtained from the Royal Children\'s Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.
BACKGROUND: NCT05667766.

UNASSIGNED: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications.
UNASSIGNED: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events.
UNASSIGNED: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response.
UNASSIGNED: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.