Academic Entitlement Among Pharmacy Students in the Arab World: A Multi-National Exploratory Study.

OBJECTIVE: The study's aim was to explore academic entitlement among pharmacy students in different pharmacy colleges in the Arab World and assess associated factors. METHODS: This study design was a cross-sectional survey. Data were collected using a self-administered electronic questionnaire posted across pharmacy college networks in 10 Arab countries (Egypt, Iraq, Jordan, Lebanon, Libya, Oman, Palestine, Qatar, Saudi Arabia, and United Arab Emirates). The electronic survey was administered through Qualtrics Survey Software, and its link was open from January 23, 2022 to May 13, 2022. The multiple linear regression measured the association between different predictors and the academic entitlement. RESULTS: A total of 2386 surveys were received from students studying in 10 different Arab countries. The majority of responding students were male and studying in a Bachelor of pharmacy program. Students reported an agreeable attitude in 4 areas: rewards for efforts, customer orientation, customer service expectation, and general academic entitlement. In accommodation, a neutral attitude was reported, while they reported a disagreeing attitude in the responsibility avoidance domain. In grade haggling, the 3 items of the domain had different attitudes. Only 3 factors had a significant negative association with student entitlement (professionalism, GPA, and year in the study program). CONCLUSION: The academic entitlement scores among pharmacy students in the Arab World were high and had a negative association with professionalism perceptions. This study finding is a call for pharmacy programs to consider the effect of academic entitlement on pharmacy education and to obtain in-depth evidence on its magnitude and associated factors.

Impact of an educational flyer and sensitization on performance-enhancement attitudes of bodybuilders in United Arab Emirates.

Background: A high proportion of bodybuilders use supplements to improve performance, with some turning to prohibited substances and methods. The attitudes of bodybuilders towards performance enhancement may be gauged through surveys such as the Performance Enhancement Attitude Scales (PEAS). Educational interventions are recommended as part of anti-doping measures. The objective of this project was to assess the impact of a pharmacy-led intervention using an antidoping educational flyer and the performance enhancement attitude scale to measure the attitude of bodybuilders in the United Arab Emirates (UAE). Methods: The PEAS eight-item short form questionnaire was administered to male bodybuilders in the UAE. The PEAS was conducted before and after administration of an educational flyer concerning the problems associated with supplement use among bodybuilders. The Wilcoxon Signed-Rank and Kruskal Wallis tests were used for data analysis. Results: A total of 218 bodybuilders, who reported taking dietary supplements, filled out the survey both pre and post viewing the antidoping educational flyer. A difference was observed between the full-time professional bodybuilders, students, and part-time bodybuilders with other primary occupations (p-value <0.05). In addition, PEAS score decreased among the study population for all eight PEAS items (p-value <0.05). Conclusions: The pharmacy-led intervention using an antidoping educational flyer and sensitization by PEAS achieved more favorable scores, suggesting a significant shift of opinion toward avoiding use of performance enhancing substances among the bodybuilder study population. More research is required on sustaining the attitude and demonstrating the impact on doping behavior.

Pharmacists' readiness and willingness to vaccinate the public in United Arab Emirates community pharmacies: A cross-sectional study.

Background: Pharmacist-administered vaccination is currently implemented in many countries worldwide. It has contributed to increased vaccine access and vaccine uptake. This observational cross-sectional study assessed community pharmacists' willingness, and readiness to administer vaccines to the public in the United Arab Emirates (UAE) and relate it to national and international policies on vaccination. Methods: This research was an online survey of 24-questions that was made available to community pharmacists via social media and WhatsApp. The survey was open for six weeks (from April to June 2022). Descriptive and inferential analysis was performed. Results: The questionnaire was completed by 374 of 575 (65%) respondents. More than half (64.2%) of the respondents agreed or strongly agreed that pharmacists should be able to vaccinate and 68.4% responded that they were willing to administer vaccines if local regulations allowed them to vaccinate. Most (81.8%) expressed willingness to complete training required to be able to administer vaccines in their pharmacies. Logistic regression showed that pharmacists defined as having high readiness were significantly more willing to undergo all essential training to start a vaccination service in their pharmacies than were pharmacists with poor readiness (OR 2.647; 95% CI: 1.518-4.615; p=0.001). High readiness was also significantly associated with agreement on safety of pharmacy-based vaccination (p=0.027). Conclusions: The majority of community pharmacists surveyed showed readiness to commence pharmacy-based vaccination services. Those with high readiness characteristics are amenable to receiving essential training and consider that vaccination in the community pharmacy setting would be safe.

Exploring job satisfaction among pharmacy professionals in the Arab world: a multi-country study.

OBJECTIVES: The study objectives were to (1) describe the characteristics of the pharmacy professionals and (2) explore the association between job satisfaction and factors, such as work control, work stress, workload and organization and professional commitments. METHODS: This study was a cross-sectional design. The survey items were mainly adapted from the US National Pharmacist Workforce Survey. An electronic (Qualtrics) questionnaire was posted on pharmacist social media in several Arab countries. The survey link was posted from 22 March 2021 to 1 May 2021. The multiple linear regression measured the association between 12 independent variables and pharmacist job satisfaction. KEY FINDINGS: A total of 2137 usable surveys were received from pharmacists (54.7% female) working in 18 Arabic countries. The job satisfaction rate varied among countries in the Arab world. The fields with the highest satisfaction average included pharmaceutical marketing, academia and the pharmaceutical industry. At the same time, pharmacists working in community pharmacy and Ministry of Health/administrative positions had the lowest satisfaction rates. Overall, pharmacist satisfaction was average (3.1 out of 5). The pharmacists had the lowest satisfaction averages with income and job expectations. The pharmacists with bachelor's degrees had significantly lower satisfaction than pharmacists with postgraduate degrees. Male pharmacists had significantly higher job satisfaction compared with female pharmacists. Workload and the feelings of organization and professional commitments had significant positive associations with job satisfaction. CONCLUSIONS: The pharmacy profession in Arabic countries faced several challenges that negatively impacted job satisfaction. Improving work environment, professional management, income and organization loyalty is necessary to enhance pharmacist job satisfaction.

Standard-Setting for Continuing Education Assessment of Select New Competencies.

INTRODUCTION: Completion of continuing education hours might not guarantee the achievement of new competencies. Influenza vaccination training was provided to pharmacists in the United Arab Emirates (UAE), who had no similar training in their pharmacy degree. The training was developed and conducted at Gulf Medical University, UAE. Influenza vaccine administration is not yet a privilege for pharmacists in the UAE. This study focuses on determining whether a defensible cut score for the influenza vaccination training multiple-choice questions examination is feasible. METHODS: Influenza vaccination training and assessment happened on the same day. The Angoff (modified), Beuk, and Hofstee methods were used for standard-setting. Six subject matter experts who were involved in developing and conducting the first influenza vaccination training in the UAE evaluated the cut score using the Angoff method with the Delphi technique. RESULTS: The criterion-based cut score was 34.23 of 46 questions, with mean 74% and SD 2.24. Inter-rater reliability was 0.92 with standard errors of judgment 0.29 (0.63%). DISCUSSION: The modified Angoff is a credible method to set cut scores, reassured with Beuk and Hofstee methods for assessment of influenza continuing education. It is feasible and perhaps essential to determine a formal cut score for the continuing education assessment of health professionals on select new competencies.

Genomewide association analysis of warfarin dose requirements in Middle Eastern and North African populations.

To date, there has been no genomewide association study (GWAS) from the Middle East and North African (MENA) region to identify genetic variants associated with warfarin dose variability using this approach. In this study, we aimed to conduct the first GWAS of warfarin dose requirements in patients from the MENA region. A total of 132 Qatari (discovery) and 50 Egyptians (replication) were genotyped using Illumina Multi-Ethnic Global BeadChip Array. A GWAS was performed on log-transformed weekly warfarin dose in the studied population, adjusting for clinical characteristics and ancestry. The genomewide signals from the discovery cohort were tested in the Egyptian cohort. A GWAS meta-analysis, including the Qatari and Egyptian cohorts, was also performed and the output from this analysis was used in a gene-based analysis. The discovery analysis in Qatari identified five genomewide single-nucleotide polymorphisms (SNPs) in chromosome 16. These signals were replicated in the Egyptian cohort. Combining the two data through a GWAS meta-analysis strengthened the association in chromosome 16 with VKORC1 rs9934438 being the lead genomewide signal (ß = -0.17, 6 × 10-15 ). Other SNPs were identified in chromosome 10 at a p value less than 1 × 10-5 . The genetic variants within VKORC1 rs9934438 and CYP2C9 rs4086116 explained 39% and 27% of the variability in the weekly warfarin dose requirement in the Qatari and Egyptians, respectively. This is the first GWAS of warfarin dose variability in the MENA region. It confirms the importance of VKORC1 and CYP2C9 variants in warfarin dose variability among patients from the MENA region.

Bioactive marine metabolites derived from the Persian Gulf compared to the Red Sea: similar environments and wide gap in drug discovery.

Marine life has provided mankind with unique and extraordinary chemical structures and scaffolds with potent biological activities. Many organisms and secondary metabolites derived from fungi and symbionts are found to be more environmentally friendly to study than the marine corals per se. Marine symbionts such as Aspergillus sp., a fungus, which can be isolated and grown in the lab would be a potential and continuous source of bioactive natural compounds without affecting the marine environment. The Red Sea is known for its biodiversity and is well-studied in terms of its marine-derived bioactive metabolites. The harsh environmental conditions lead to the development of unique metabolic pathways. This, in turn, results in enhanced synthesis and release of toxic and bioactive chemicals. Interestingly, the Persian Gulf and the Gulf of Oman carry a variety of environmental stresses, some of which are similar to the Red Sea. When compared to the Red Sea, the Persian Gulf has been shown to be rich in marine fungi as well, and is, therefore, expected to contain elaborate and interesting bioactive compounds. Such compounds may or may not be similar to the ones isolated from the Red Sea environment. Astoundingly, there are a very limited number of studies on the bioactive portfolio of marine-derived metabolites from the Persian Gulf and the Gulf of Oman. In this perspective, we are looking at the Red Sea as a comparator marine environment and bioactive materials repertoire to provide a futuristic perspective on the potential of the understudied and possibly overlooked bioactive metabolites derived from the marine life of the Persian Gulf and the Gulf of Oman despite its proven biodiversity and harsher environmental stress.

Imperatorin as a Promising Chemotherapeutic Agent Against Human Larynx Cancer and Rhabdomyosarcoma Cells.

Naturally occurring coumarins are bioactive compounds widely used in Asian traditional medicine. They have been shown to inhibit proliferation, induce apoptosis, and/or enhance the cytotoxicity of currently used drugs against a variety of cancer cell types. The aim of our study was to examine the antiproliferative activity of different linear furanocoumarins on human rhabdomyosarcoma, lung, and larynx cancer cell lines, and dissolve their cellular mechanism of action. The coumarins were isolated from fruits of Angelica archangelica L. or Pastinaca sativa L., and separated using high-performance counter-current chromatography (HPCCC). The identity and purity of isolated compounds were confirmed by HPLC-DAD and NMR analyses. Cell viability and toxicity assessments were performed by means of methylthiazolyldiphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, respectively. Induction of apoptosis and cell cycle progression were measured using flow cytometry analysis. qPCR method was applied to detect changes in gene expression. Linear furanocoumarins in a dose-dependent manner inhibited proliferation of cancer cells with diverse activity regarding compounds and cancer cell type specificity. Imperatorin (IMP) exhibited the most potent growth inhibitory effects against human rhabdomyosarcoma and larynx cancer cell lines owing to inhibition of the cell cycle progression connected with specific changes in gene expression, including CDKN1A. As there are no specific chemotherapy treatments dedicated to laryngeal squamous cell carcinoma and rhabdomyosarcoma, and IMP seems to be non-toxic for normal cells, our results could open a new direction in the search for effective anti-cancer agents.

The effect of genetic and nongenetic factors on warfarin dose variability in Qatari population.

The objective of this study is to estimate the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants and their contribution to warfarin dose variability in Qataris. One hundred and fifty warfarin-treated Qatari patients on a stable dose and with a therapeutic INR for at least three consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. The population was stratified into derivation and validation cohorts for the dosing model. The minor allele frequency (MAF) of VKORC1 (-1639G>A) was A (0.47), while the MAF's for the CYP2C9*2 and *3 and CYP4F2*3 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one CYP2C9 decreased function allele (*2 or *3) required lower median (IQR) warfarin doses compared to noncarriers [24.5 (14.5) mg/week vs. 35 (21) mg/week, p < 0.001]. Similarly, carriers of each additional copy of (A) variant in VKORC1 (-1639G>A) led to reduction in warfarin dose requirement compared to noncarriers [21(7.5) vs. 31.5(18.7) vs. 43.7(15), p < 0.0001]. CYP4F2*3 polymorphism on the other hand was not associated with warfarin dose. Multivariate analysis on the derivation cohort (n = 104) showed that a dosing model consisting of hypertension (HTN), heart failure (HF), VKORC1 (-1639G>A), CYP2C9*2 & *3, and smoking could explain 39.2% of warfarin dose variability in Qataris (P < 0.001). In the validation cohort (n = 45), correlation between predicted and actual warfarin doses was moderate (Spearman's rho correlation coefficient = 0.711, p < 0.001). This study concluded that VKORC1 (-1639G>A), CYP2C9*2 & *3 are the most significant predictors of warfarin dose along with HTN, HF and smoking.

Instructional design and assessment of an elective course on the use of drugs in sport.

BACKGROUND AND PURPOSE: The use and misuse of drugs in sport is becoming increasingly important globally, and the role of pharmacists is evolving in this regard. This paper describes the design and implementation of an elective course "Drugs in Sport" in an undergraduate pharmacy curriculum. EDUCATIONAL ACTIVITY AND SETTING: The elective course was designed to introduce BSc pharmacy students to an evidence-based approach to safe, effective, and legal use of drugs in sport. The course covered why athletes take drugs, evolution of doping in sport, the international regulations regarding doping and anti-doping in sport including the World Anti-doping Agency Prohibited List, as well as testing and monitoring for drug use in sport. It also included the role of athlete support personnel (ASP) in preventing the use of prohibited substances by athletes. A web-based survey was conducted at the end of the course to assess the students' perspectives of the course. FINDINGS: Students provided an evaluation of the course in terms of its content, methods of delivery, and assessment. Overall, the students demonstrated competence. They gained insight into international and national regulations regarding doping and anti-doping in sport and the potential role of pharmacists as ASP in providing support and advice for athletes and the public. SUMMARY: Designing and implementing an evidence-based course on the use of drugs in sport customized for pharmacy students was achieved successfully. Such courses could provide an opportunity to advance the scope of pharmacy practice and possibly provide a new career path for future pharmacists.

Perspective of pharmacists in Qatar regarding doping and anti-doping in sports.

BACKGROUND: The aim of this study was to evaluate the current knowledge and perceptions of pharmacists in Qatar with regard to the use of drugs in sport and to explore their views on the introduction of education and training in the area of sports pharmacy. METHODS: A cross-sectional survey was conducted targeting both hospital and community pharmacists in Qatar. A questionnaire consisting of three domains pertaining to participants' knowledge, perceived role of healthcare professionals, and attitudes towards educational needs on the use of drugs in sports was developed and validated. The online survey link and paper-based questionnaires were distributed to the target population. Data analyses were performed using IBM SPSS Statistics. Descriptive and inferential statistics were utilized for the analyses, where P<0.05 indicates statistical significance. RESULTS: A total of 300 pharmacists responded to the survey. Respondents had a limited awareness of doping and anti-doping and achieved an average knowledge score of 53.2% regarding the prohibited status of drugs that may be used by athletes, particularly with respect to over-the-counter medicines and supplements. The majority (81.7%) of the pharmacists expressed an interest in receiving education and training on sports pharmacy. CONCLUSIONS: Specialized training programs are warranted to ensure that pharmacists have the knowledge and skills required to provide athletes with accurate information about anti-doping issues and the safe and effective use of medicines in sport. The development of these programs should be supported by national pharmacy policy makers and designed in collaboration with anti-doping agencies and sports pharmacy experts and educators.

Knowledge and Perceptions of Pharmacy Students in Qatar on Anti-Doping in Sports and on Sports Pharmacy in Undergraduate Curricula.

Objective. To assess pharmacy students' knowledge and perceptions of doping and anti-doping in sports and to explore the curricular needs for undergraduate pharmacy in the field of sports pharmacy. Methods. A cross-sectional, descriptive, web-based survey of pharmacy students was conducted at Qatar University College of Pharmacy from March to May 2014. Data were analyzed using descriptive and inferential statistics. Results. Eighty respondents completed the online survey (80% response rate). Sixty percent were unaware of the World Anti-Doping Agency, and 85% were unaware of the International Pharmaceutical Federation's statement on the pharmacist's role in anti-doping. Students' knowledge score regarding the prohibited status of drugs that may be used by athletes was around 50%. Fourth-year pharmacy students had significantly higher knowledge scores than the other groups of students. Respondents acknowledged the important role of health care professionals, including pharmacists, as advisors on the safe and effective use of drugs in sports. Ninety percent of the students supported the inclusion of sports pharmacy in the curriculum. Conclusion. Pharmacy students indicated a strong desire to play a role in doping prevention and ensure safe and rational use of drugs among athletes. They suggested requiring an education and training strategy for sports pharmacy in undergraduate pharmacy curricula.

A course-based cross-cultural interaction among pharmacy students in Qatar and Canada.

OBJECTIVE: To develop, implement, and evaluate a course-based, cross-cultural student interaction using real-time videoconferencing between universities in Canada and Qatar. DESIGN: A professional skills simulation practice session on smoking cessation was run for students in Qatar (n=22) and Canada (n=22). Students role played cases in small group situations and then interacted with colleagues from the other country regarding culturally challenging situations and communication strategies. ASSESSMENT: Students were assessed on analytical content and communication skills through faculty member and peer evaluation. Cultural competency outcomes were assessed using a postsession survey. Overall, 92.3% of respondents agreed that learning was enhanced through the cross-cultural exchange, and 94.9% agreed that insight was gained into the health-related issues and needs of people from another culture. CONCLUSION: A course-based, cross-cultural interaction was an effective method to incorporate cultural competency principles into student learning. Future initiatives should increase direct student interaction and focus on culturally sensitive topics.

Attitudes of pharmacy and nutrition students towards team-based care after first exposure to interprofessional education in Qatar.

Little is known regarding attitudes of healthcare professional students towards team-based care in the Middle East. As modernization of health systems is rapidly occurring across the Gulf Cooperation Council countries, it is important for students to engage in interprofessional education (IPE) activities. The objective of this study was to assess pre-clinical students' attitudes towards interprofessional healthcare teams after completion of their first IPE activity. A previously validated questionnaire was distributed to 25 pharmacy and 17 nutrition students at Qatar University after participation in an IPE event. Questions related to quality of team-based care and physician centricity. Results showed high agreement regarding high quality care provided by teams yet students were unsure of the value of team-based care when considering required time for implementation. Results provide baseline data for future studies to assess student attitudes throughout the professional programs and give valuable insight for future IPE program design in the Middle East.

Evaluation of anti-melanoma activities of (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol from the Red Sea soft coral Sarcophyton glaucum.

Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were evaluated for their inhibitory effects on mouse melanoma B16F10 cell growth. Results show that all the cembranoids strongly inhibit viability of melanoma cells particularly during 48 -72 hrs treatment and also inhibit de novo DNA synthesis and PARP activity and stimulate fragmentation of DNA. (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol was not cytotoxic to monkey kidney CV-1 cells at the concentration that produces the anti-melanoma effects which indicates that this compound may be a good candidate for further development. (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were found to be cytotoxic to healthy cells.

Evaluation of the anti-melanoma activities of sarcophine, (+)-7alpha,8beta-dihydroxydeepoxysarcophine and sarcophytolide from the Red Sea soft coral Sarcophyton glaucum.

Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely sarcophine (1), (+)-7alpha,8beta-dihydroxydeepoxysarcophine (2) and sarcophytolide (3) were evaluated for their potential inhibitory effects on growth of mouse melanoma B16F10 cells. Compounds (1) and (2) maximally inhibit viability of melanoma cells during 48 hr and 72 hr treatment at concentrations that show no cytotoxicity on monkey kidney CV-1 cells and also inhibit de novo DNA synthesis and PARP activity. Compound (3) produced cytotoxic effects at the same concentration range it produces its antitumor effects. These data suggest that (1) and (2), but not (3), have potential for further development as antitumor agents against melanoma.

Microbial production of 1α-hydroxyvitamin D3 from vitamin D3.

The microbial transformation of vitamin D3 (1) by the fungi Candida maltosa R42 and Botrytis allii NRRL 2502 was investigated. Incubation of compound 1 with C. maltosa R42 and B. allii NRRL 2502 produced the same three more polar metabolites in small yields. The main metabolite was identified as 1α-hydroxyvitamin D3 (2). This biotransformation has utility as a possible tool for the production of 1α-hydroxyvitamin D3 from the readily available vitamin D3 for patients with compromised kidney function.

Differential binding of latrunculins to G-actin: a molecular dynamics study.

Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculin A (1), latrunculin B (2), 16-epi-latrunculin B (3), and latrunculin T (4) were isolated from the Red Sea sponge Negombata magnifica. In the present study, after testing compounds 2-4 for cytotoxic activity, they were docked into the crystal structure of G-actin and subjected to binding energy calculation and a 20 ns MD simulation. The modeling study shows that latrunculins binding depends on both hydrophobic interaction of the macrocycle as well as H bonding of the thiazolidinone ring with Asp157 and Thr186. It was noticed that epimerization at C16 of latrunculin B was well tolerated as it could form an alternative H bonding network. However, opening of the macrocyclic ring deteriorates the actin binding due to reduced hydrophobicity. MD simulation showed that latrunculin B (2) possesses a more significant stabilizing effect on G-actin than latrunculin T (4) and could efficiently hinder the flattening transition of G-actin into F-actin. These findings could explain, at the molecular level, the impact of epimerization and macrolide ring-opening on latrunculins activity, an issue that has not been addressed before. Also, the study gives insights into the mechanism of cytotoxicity of diverse latrunculins and provides direction for future lead optimization studies.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

BACKGROUND: VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. METHODS: We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. FINDINGS: The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). INTERPRETATION: A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. FUNDING: National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians.

The VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. One thousand samples were analysed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. A total of 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1 ± 29.4 mg/week) than those with the Asp36Asp genotype (35.8 ± 16.6 mg/week; p=0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.