The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and response in the Emirati population.

BACKGROUND: Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel. METHODS: Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes. RESULTS: Our data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel's transport, enzymatic clearance, and receptor performance. CONCLUSIONS: Recognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles.

Pharmacogenomics implementation in cardiovascular disease in a highly diverse population: initial findings and lessons learned from a pilot study in United Arab Emirates.

BACKGROUND: Pharmacogenomic (PGx) testing has proved its utility and cost-effectiveness for some commonly prescribed cardiovascular disease (CVD) medications. In addition, PGx-guided dosing guidelines are now available for multiple CVD drugs, including clopidogrel, warfarin, and statins. The United Arab Emirates (UAE) population is diverse and multiethnic, with over 150 nationalities residing in the country. PGx-testing is not part of the standard of care in most global healthcare settings, including the UAE healthcare system. The first pharmacogenomic implementation clinical study in CVD has been approved recently, but multiple considerations needed evaluation before commencing. The current report appraises the PGx-clinical implementation procedure and the potential benefits of pursuing PGx-implementation initiatives in the UAE with global implications. METHODS: Patients prescribed one or more of the following drugs: clopidogrel, atorvastatin, rosuvastatin, and warfarin, were recruited. Genotyping selected genetic variants at genes interacting with the study drugs was performed by real-time PCR. RESULTS: For the current pilot study, 160 patients were recruited. The genotypes and inferred haplotypes, diplotypes, and predicted phenotypes revealed that 11.9% of the participants were poor CYP2C19 metabolizers, 35% intermediate metabolizers, 28.1% normal metabolizers, and 25% rapid or ultrarapid metabolizers. Notably, 46.9% of our cohort should receive a recommendation to avoid using clopidogrel or consider an alternative medication. Regarding warfarin, only 20% of the participants exhibited reference alleles at VKORC1-1639G > A, CYP2C9*2, and CYP2C9*3, leaving 80% with alternative genotypes at any of the two genes that can be integrated into the warfarin dosing algorithms and can be used whenever the patient receives a warfarin prescription. For statins, 31.5% of patients carried at least one allele at the genotyped SLCO1B1 variant (rs4149056), increasing their risk of developing myopathy. 96% of our cohort received at least one PGx-generated clinical recommendation for the studied drugs. CONCLUSION: The current pilot analysis verified the feasibility of PGx-testing and the unforeseen high frequencies of patients currently treated with suboptimal drug regimens, which may potentially benefit from PGx testing.

Mendelian randomization in pharmacogenomics: The unforeseen potentials.

Mendelian randomization (MR) is an epidemiological method that uses genetic variants to proxy an exposure predicting its causal association with an outcome. It occupies a valuable niche between observational studies and randomized trials. MR applications expanded lately, facilitated by the availability of big data, to include disease risk causation prediction, supporting evidence of prior observational data, identifying new drug targets, and drug repurposing. Concurrently, the last decade witnessed the growth of pharmacogenomics (PGx) research as a cornerstone in precision medicine. PGx research, conducted at discovery and implementation levels, resulted in validated PGx biomarkers and tests. Despite many clinically relevant PGx associations that could be translated into clinical applications, worldwide implementation is lagging far behind. The current review examines the intersection zones between MR and PGx research. MR can provide supporting evidence that allows generalizing PGx findings supporting its implementation. Interchangeability, PGx research can fuel MR studies with libraries of genetic variants of validated biological relevance. Furthermore, PGx and MR exhibit a synergistic relationship in drug discovery that can accelerate identifying new targets and repurposing old drugs. Interdisciplinary research applied by PGx researchers, epidemiologists with MR experience, and data scientists' collaborations can unlock unforeseen opportunities in accelerating precision medicine acquisition.

An assessment of the current practice of community pharmacists for the disposal of medication waste in the United Arab Emirates: A deep analysis at a glance.

Objective: The study aimed to identify the current practice carried out by community pharmacists to dispose of expired medications in their workplace and assess any practical steps utilized to reduce medication waste. Method: A cross-sectional study was conducted among community pharmacists in the United Arab Emirates (UAE). The participants were asked about their routine practice in disposing of different expired medications and the current actions taken to reduce the number of disposed medicines. Results: The study included (n = 418) community pharmacists. More than a third of expired liquid, solid, and semi-solid dosage forms were collected by licensed contractors. In addition, more than a third of the pharmacists disposed of different dosage forms via unauthorized methods (general garbage, sink and toilet). Most expired drugs were skin and hair products, antibiotics and analgesics. The majority of pharmacists (68.4 %, n = 286) agreed that expired pharmaceutical and non-pharmaceutical products, other than those disposed of via contractor, should be done through a specialized centre. This opinion was found to be strongly associated with years of practice as community pharmacists (P < 0.05). Conclusion: Part of the existing disposal practices for expired pharmaceutical products in the UAE is carried out by contractors licensed by health authorities. However, concern remains regarding some pharmaceutical and non-pharmaceutical products that have not been disposed of correctly. Additionally, there is a need for a specialized center for medication disposal (p < 0.05). A stock limitation is the best practice for managing medication quantities in stock (p < 0.05).

Prevalence of musculoskeletal pain in association with serum 25-hydroxyvitamin D concentrations in patients with type 2 diabetes mellitus.

The aim of the present study was to investigate the prevalence of musculoskeletal pain in patients with type 2 diabetes mellitus (T2DM) in association with 25-hydroxyvitamin D levels, anxiety, depression and neuropathy. A cross-sectional study was conducted involving a total of 124 T2DM patients. Musculoskeletal pain was determined by self-reporting of painful body sites. Pain intensity was assessed using a scale of 0-10. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Neuropathy was assessed using the PainDETECT questionnaire. The concentration of 25-hydroxyvitamin D was measured using liquid chromatography-tandem mass spectrometry. Fasting blood sugar (FBS) was determined using the hexokinase method and glycated hemoglobin (HbA1c) level was determined using turbidimetric inhibition immunoassay. The neck, lower back and head were reported as the most common painful sites (affected in 60.5, 60.5 and 56.5% of patients, respectively). Pain in the lower extremities, including the knees, lower legs and feet, was more common compared with pain in the upper extremities. The pain measurements of number of painful sites and pain intensity did not differ significantly among patients with sufficient (>30 ng/ml), insufficient (20-30 ng/ml) and deficient (<20 ng/ml) vitamin D levels (P>0.05). The pain measurements were identified to have no correlation with age, body mass index, FBS, HbA1c level, 25-hydroxyvitamin D concentration, anxiety or depression (P>0.05). However, the pain measurements were correlated with duration of T2DM and neuropathy score (P<0.05). Further regression analysis demonstrated that the pain measurements were significantly associated with the neuropathy score (P<0.05). In conclusion, musculoskeletal pain in patients with T2DM was not associated with 25-hydroxyvitamin D concentration, but was associated with neuropathy score. This may encourage further investigations to assess the etiology of musculoskeletal pain in T2DM, and whether vitamin D supplementation and management of neuropathy would be of value as pain relief treatment.

High Prevalence of Vitamin D Deficiency and Correlation of Serum Vitamin D with Cardiovascular Risk in Patients with Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MetS) identifies subjects with increased risk of cardiovascular disease when they have a combination of insulin resistance, obesity, hypertension, hyperglycemia, low high-density lipoprotein cholesterol (HDL-C), and elevated triglycerides (TGs). Increasing evidence suggests that vitamin D deficiency could be associated with diabetes and MetS. The aim is to assess if 25-hydroxyvitamin D (25-OHD) is correlated with cardiovascular risk components of MetS. METHODS: A cross-sectional study involved 124 diabetic patients with MetS according to International Diabetes Federation definition. 25-OHD was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fasting insulin, lipid profile, glucose, and hemoglobin-A1c (HbA1c) were determined using routinely standard laboratory methods. Insulin resistance was assessed using homeostatic model assessment (HOMA). RESULTS: 59.68% and 27.42% of patients have vitamin D deficiency and insufficiency, respectively. Systolic blood pressure (SBP) was significantly higher in patients with vitamin D deficiency compared to patients with sufficient vitamin D (P < 0.05). Serum log (25-OHD) was inversely correlated with SBP, HbA1c, low-density lipoprotein cholesterol (LDL-C), TGs, and total cholesterol and directly correlated with pancreatic ß cell function (HOMA-ß) (P < 0.05). Multiple linear regression analysis has shown that SBP can be predicted from log (25-OHD) (B = -9.388, P < 0.05), while HbA1c, LDL-C, TGs, total cholesterol, and HOMA-ß cannot be predicted from log (25-OHD), (P > 0.05). CONCLUSIONS: Vitamin D deficiency was very prevalent among patients with MetS. 25-OHD was inversely correlated with glycemic control and cardiovascular risk components of MetS except HDL-C, insulin resistance, and obesity. SBP was the only cardiovascular risk component that can be predicted from vitamin D concentrations.