Anna Tavridou

Heterogeneity of coronary heart disease risk factors in Indian, Pakistani, Bangladeshi, and European origin populations: cross sectional study

Abstract Objective: To compare coronary risk factors and disease prevalence among Indians, Pakistanis, and Bangladeshis, and in all South Asians (these three groups together) with Europeans. Design: Cross sectional survey. Setting: Newcastle upon Tyne. Participants: 259 Indian, 305 Pakistani, 120 Bangladeshi, and 825 European men and women aged 25-74 years. Main outcome measures: Social and economic circumstances, lifestyle, self reported symptoms and diseases, blood pressure, electrocardiogram, and anthropometric, haematological, and biochemical measurements. Results: There were differences in social and economic circumstances, lifestyles, anthropometric measures and disease both between Indians, Pakistanis, and Bangladeshis and between all South Asians and Europeans. Bangladeshis and Pakistanis were the poorest groups. For most risk factors, the Bangladeshis (particularly men) fared the worst: smoking was most common (57%) in that group, and Bangladeshis had the highest concentrations of triglycerides (2.04 mmol/l) and fasting blood glucose (6.6 mmol/l) and the lowest concentration of high density lipoprotein cholesterol (0.97 mmol/l). Blood pressure, however, was lowest in Bangladeshis. Bangladeshis were the shortest (men 164 cm tall v 170 cm for Indians and 174 cm for Europeans). A higher proportion of Pakistani and Bangladeshi men had diabetes (22.4% and 26.6% respectively) than Indians (15.2%). Comparisons of all South Asians with Europeans hid some important differences, but South Asians were still disadvantaged in a wide range of risk factors Findings in women were similar. Conclusion: Risk of coronary heart disease is not uniform among South Asians, and there are important differences between Indians, Pakistanis, and Bangladeshis for many coronary risk factors. The belief that, except for insulin resistance, South Asians have lower levels of coronary risk factors than Europeans is incorrect, and may have arisen from combining ethnic subgroups and examining a narrow range of factors. Key messages South Asians have more coronary heart disease than Europeans despite apparently lower levels of risk factors This study shows that Indians, Pakistanis and Bangladeshis differ in a wide range of coronary risk factors and combining their data is misleading Among South Asians, Indians were least and Bangladeshis most disadvantaged in a range of coronary risk factors. South Asians were disadvantaged in comparison with Europeans Future research and prevention strategies for coronary heart disease in South Asians should acknowledge a broad range of risk factors, the heterogeneity of these populations, linguistic and cultural needs, and environmental factors

A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

BACKGROUND Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).

Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population.

The aim of the present study was to determine the prevalence of the most common allelic variants of the polymorphic cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 and to predict the genotype frequency for each polymorphism in the Greek population. DNA isolated from peripheral blood samples derived from 283 non‐related Greek ethnic subjects was used to determine the frequency of CYP2D6*3, CYP2D6*4, CYP2C9*2, CYP2C9*3 and CYP3A5*3 allelic variants by the polymerase chain reaction (PCR)‐restriction fragment length polymorphism method, CYP2C19*2 and CYP2C19*3 with allelic specific amplification (PCR‐ASA), and CYP2D6*2 (gene duplications) by long PCR analysis. The allelic frequencies (out of a total of 566 alleles) for CYP2D6*3 and CYP2D6*4, were 2.3% and 17.8%, respectively, while gene duplications (CYP2D6*2) were found in 7.4% of the subjects tested. For CYP2C9*2 and CYP2C9*3 polymorphisms the allelic frequencies were 12.9% and 8.13% respectively. For CYP2C19, the *2 polymorphism was present at an allelic frequency of 13.1%, while no subjects were found carrying the CYP2C19*3 allele. Finally, the CYP3A5*3 allele was abundantly present in the Greek population with an allelic frequency of 94.4%. Overall our results show that the frequencies of the common defective allelic variants of CYP2C9, CYP2C19 and CYP3A5 in Greek subjects are similar to those reported for several other Caucasian populations. Finally, a high prevalence of CYP2D6 gene duplication among Greeks was found, a finding that strengthens the idea that a South/North gradient exists in the occurrence of CYP2D6 ultrarapid metabolizers in European populations.

Need for reassessment of reported CYP2C19 allele frequencies in various populations in view of CYP2C19*17 discovery: the case of Greece

INTRODUCTION CYP2C19*17 is a novel variant allele causing ultrarapid metabolism of CYP2C19 substrates. In the present study we investigated the CYP2C19*17 allelic frequency and recalculated previously reported frequencies of the CYP2C19*1/*1 genotype and of all genotype-derived phenotypes for CYP2C19 in the Greek population. MATERIALS & METHODS A total of 283 nonrelated healthy Greek ethnic subjects that had already been genotyped for CYP2C19*2 and *3 alleles as well as for CYP2D6 and CYP2C9 variant alleles participated in the study. The CYP2C19*17 allele was genotyped by the PCR-RFLP method. RESULTS The CYP2C19*17 allele frequency was 19.61%. The prevalence of CYP2C19*17 carriers in the Greek population was estimated at 31.80%, while the frequency of CYP2C19*1/*1 genotype was recalculated to 44.17% from 75.97% in our previous study. Several subjects possessing both CYP2C19*17 and variant alleles of CYP2D6 and CYP2C9 were also identified. DISCUSSION & CONCLUSION The CYP2C19*17 allele is present in Greeks at a high frequency similar to that found in other European populations of Caucasian origin. Our study highlights the need of reassessing and updating CYP2C19 allelic frequencies in various populations in view of the major role that CYP2C19*17 may have in predicting the clinical outcome of drugs metabolized by CYP2C19.

The association of adipokine levels in plasma and synovial fluid with the severity of knee osteoarthritis

OBJECTIVE We sought to determine the association between plasma and SF levels of leptin and adiponectin in patients with knee OA. METHODS Plasma and SF levels of adipokines and soluble leptin receptor (sOB-R) were determined by ELISA in 96 patients with knee OA at different stages, according to Ahlbacks classification. RESULTS Levels of adiponectin, leptin, sOB-R and free leptin in plasma and SF did not differ significantly across categories of OA severity. However, the ratio of SF to plasma leptin was significantly lower in the advanced OA stage compared with early stages of the disease (P = 0.02). After adjustment for sex and BMI, plasma leptin positively correlated with categories of OA severity (r = 0.23, P = 0.02), whereas SF/plasma leptin negatively correlated with OA stage (r = -0.27, P = 0.01). Cluster analysis showed that all men were included in one cluster and distributed in different stages of OA, whereas women formed three clusters with similar BMI, but those who were older and had the highest plasma leptin levels suffered from advanced OA. CONCLUSION Plasma leptin positively correlated with the severity of knee OA. The ratio of SF to plasma leptin might be a marker related to the severity of knee OA. Further studies should investigate whether similar associations exist in other joints affected by OA.

Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective.

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent disease. Several classes of drugs are currently available to treat T2DM patients; however, clinical response to these drugs often exhibits significant variation among individuals. For the oral antidiabetic drug classes of sulfonylureas, nonsulfonylurea insulin secretagogs, biguanides and thiazolidinediones, pharmacogenomic evidence has accumulated demonstrating an association between specific gene polymorphisms and interindividual variability in their therapeutic and adverse reaction effects. These polymorphisms are in genes of molecules involved in metabolism, transport and therapeutic mechanisms of the aforementioned drugs. Overall, it appears that pharmacogenomics has the potential to improve the management of T2DM and help clinicians in the effective prescribing of oral antidiabetic medications. Although pharmacogenomics can explain some of the heterogeneity in dose requirements, response and incidence of adverse effects of drugs between individuals, it is now clearly understood that much of the diversity in drug effects cannot be solely explained by studying the genomic diversity. Epigenomics, the field that focuses on nongenomic modifications that influence gene expression, may expand the scope of pharmacogenomics towards optimization of drug therapy. Therefore, pharmacoepigenomics, the combined analysis of genetic variations and epigenetic modifications, holds promise for the realization of personalized medicine. Although pharmacoepigenomics has so far been evaluated mainly in cancer pharmacotherapy, studies on epigenomic modifications during T2DM development provide useful data on the potential of pharmacoepigenomics to elucidate the mechanisms underlying interindividual response to oral antidiabetic treatment. In summary, the present article focuses on available data from pharmacogenomic studies of oral antidiabetic drugs and also provides an overview of T2DM epigenomic research, which has the potential to boost the development of pharmacoepigenomics in antidiabetic treatment.

Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas

AIMS Hypoglycemia is a common adverse effect of sulfonylurea oral hypoglycemic agents. Impaired metabolism of sulfonylureas due to gene polymorphisms in the metabolic enzyme CYP2C9 might lead to hypoglycemia. In the present study we explored the association of the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 with the incidence of hypoglycemic events in diabetic patients receiving the sulfonylureas glimepiride and gliclazide. MATERIALS & METHODS A total of 92 Type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea and reporting drug-associated hypoglycemia, and 84 T2DM patients receiving sulfonylurea and having never experienced hypoglycemia were included in the study. A sample of 283 nondiabetic controls that had been genotyped earlier served as a second control group. CYP2C9*2 and *3 alleles were detected by use of PCR-RFLP analysis. RESULTS Frequencies of CYP2C9*1/*3 genotype and CYP2C9*3 allele were significantly lower in T2DM patients than nondiabetic controls (p = 0.003 and p = 0.017, respectively). A total of 11 out of 92 subjects (12%) experiencing hypoglycemia carried the CYP2C9*3 allele, as opposed to only 1 out of 84 subjects (1.2%) free of sulfonylurea-induced hypoglycemia. In a model adjusted for age, BMI, mean daily dose of sulfonylurea, duration of T2DM and renal function, CYP2C9*1/*3 genotype increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 1.687; p = 0.011). However, no differences in CYP2C9*2 allele frequency between the two groups were found. DISCUSSION & CONCLUSION The presence of CYP2C9*3 appears to be protective for development of T2DM. Furthermore, in T2DM patients, CYP2C9*3 increases the risk of hypoglycemia when they are treated with sulfonylureas, possibly due to impaired metabolism of these drugs. CYP2C9 genotyping might thus be a useful tool for predicting adverse effects caused by sulfonylureas and help clinicians in safer prescribing of oral hypoglycemic agents. The potential T2DM protective effect of CYP2C9*3 allele requires further investigation.

Pharmacogenetics of coumarinic oral anticoagulants

Coumarinic oral anticoagulants are life-saving drugs, but are also one of the leading causes of drug-induced major bleeding events. Moreover, there is substantial individual variation in response to coumarinic oral anticoagulants caused by several factors including variations in the CYP2C9 and VKORC1 genes. Several retrospective and a few small prospective clinical studies have shown that polymorphisms in CYP2C9 and VKORC1 genes together account for 35-50% of the variability in warfarin initiation and maintenance dose requirements. Large randomized clinical trials are currently underway to further solidify the safety, clinical utility and cost-effectiveness of pharmacogenetic-guided dosing algorithms for warfarin, acenocoumarol and phenprocoumon. By 2020, coumarinic oral anticoagulant pharmacogenetic testing will be part of routine clinical practice in anticoagulant therapy.

The serotonin transporter promoter polymorphism (5-HTTLPR) is associated with type 2 diabetes.

BACKGROUND The serotonergic system contributes substantially to the regulation of glucose homeostasis and feeding. 5-HTTLPR is a serotonin transporter (5-HTT) gene-linked polymorphic region that regulates the transcriptional activity of 5-HTT. Our aim was to investigate the possible association of 5-HTTLPR polymorphism with type 2 diabetes mellitus and obesity. METHODS Study population consisted of 252 subjects diagnosed with Type 2 DM and 211 non-diabetic subjects, all Caucasians of Greek ethnic origin. Genomic DNA was extracted from peripheral blood and analyzed for 5-HTTLPR polymorphism with a novel PCR protocol. RESULTS The frequency of SS and SL genotypes of HTTLPR was significantly higher in the diabetic group (77.0%) than in the non-diabetic group (61.6%) (P<0.001). The genetic risk of Type 2 DM for subjects carrying at least one S allele was increased compared to non-diabetic subjects (OR=2.08, 95% CI=1.39-3.12). When subjects were divided according to BMI status, the frequency of S allele carriers was similar in obese and non-obese subjects. CONCLUSIONS The S allele of 5-HTTLPR is strongly associated with the presence of Type 2 DM. This association appears to be direct and not dependent on obesity status. Therefore, 5-HTTLPR LL genotype might be protective for development of Type 2 DM.

Endothelial nitric oxide synthase gene polymorphisms - 786T > C and 894G > T in coronary artery bypass graft surgery patients

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (-786T >C and 894G >T) enhance endo-thelial dysfunction and have been studied in relation to coronary artery disease (CAD). In the present study, we examined the association of the above polymorphisms with CAD, as well as with myocardial infarction (MI), hypertension, diabetes and smoking in CAD patients. Study subjects consisted of 154 consecutive coronary artery bypass graft (CABG) patients and 155 non-CAD controls. eNOS -786T >C and 894G >T polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. The estimated frequencies of the -786C and 894T alleles did not differ between the two groups (p = 0.46 and p = 0.84, respectively). The prevalence of eNOS polymorphisms was not associated with MI, hypertension or diabetes in CABG patients; however, we found that the 894TT genotype and 894T allele were significantly more frequent in current/past smoker CABG patients (16.7 per cent and 39.6 per cent, respectively) compared with never smoker CABG patients (6.1 per cent and 24.4 per cent, respectively) (p = 0.01 and p < 0.01, respectively). We found no association of eNOS -786C and 894T variant alleles with CAD; however, within CABG patients, a gene-environment interaction was found between the eNOS 894T allele and smoking.