Warfarin Dose Model for the Prediction of Stable Maintenance Dose in Indian Patients.

The main aim of this study was to screen various genetic and nongenetic factors that are known to alter warfarin response and to generate a model to predict stable warfarin maintenance dose for Indian patients. The study comprised of 300 warfarin-treated patients. Followed by extensive literature review, 10 single-nucleotide polymorphisms, that is, VKORC1-1639 G>A (rs9923231), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), FVII R353Q (rs6046), GGCX 12970 C>G (rs11676382), CALU c.*4A>G (rs1043550), EPHX1 c.337T>C (rs1051740), GGCX: c.214+597G>A (rs12714145), GGCX: 8016G>A (rs699664), and CYP4F2 V433M (rs2108622), and 5 nongenetic factors, that is, age, gender, smoking, alcoholism, and diet, were selected to find their association with warfarin response. The univariate analysis was carried out for 15 variables (10 genetic and 5 nongenetic). Five variables, that is, VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3, age, and diet, were found to be significantly associated with warfarin response in univariate analysis. These 5 variables were entered in stepwise and multiple regression analysis to generate a prediction model for stable warfarin maintenance dose. The generated model scored R2 of .67, which indicates that this model can explain 67% of warfarin dose variability. The generated model will help in prescribing more accurate warfarin maintenance dosing in Indian patients and will also help in minimizing warfarin-induced adverse drug reactions and a better quality of life in these patients.

The Epidemiology of FVIII Inhibitors in Indian Haemophilia A Patients.

A serious complication of replacement therapy in patients with bleeding disorders is the development of 'inhibitors', particularly FVIII inhibitors in haemophilia A patients. This leads to an increase in the management cost, morbidity and mortality, especially post-operatively. The mechanism of FVIII inhibitor development is quite complex and it is difficult to predict inhibitor development, but a prompt and accurate diagnosis is critical as early therapy can save lives. The aim of this study was to screen patients with bleeding disorders in India for inhibitors, and to analyse and compare the prevalence of inhibitors in different regions in India. Patient details were recorded and blood samples were collected in sodium citrate vacutainers from 1,505 patients with bleeding disorders, in different cities in India. Coagulation and inhibitor screening assays were performed, followed by the Bethesda assay in inhibitor positive samples to quantify the FVIII inhibitor titre. Out of the 1,505 samples analysed, 1,285 were Haemophilia A patients, out of which 78 (6.07 %) were positive for 'FVIII Inhibitors'. The highest incidence of FVIII Inhibitors was seen in South India (13.04 %). The highest incidence of 20.99 % was observed in Chennai, followed by Hyderabad (13.33 %), Jammu (9.90 %) and Guwahati (8.51 %), respectively, with respect to the samples analysed. The other regions showed an inhibitor incidence <8 %. The incidence of inhibitors in haemophilia A patients is different in different regions of India; this may be due to the intensity of treatment, type of product or the genetic characteristics of these patients.

VKORC1 and CYP2C9 genotype distribution in Asian countries.

BACKGROUND: Warfarin is the most widely used anticoagulant all over the world for prevention and treatment of different thrombotic conditions. Polymorphisms in two genes i.e. CYP2C9 (Cytochrome P450 2C9) and VKORC1 (Vitamin K epoxide reductase complex subunit 1) play a major role in warfarin dose variation and its related adverse effects. Different ethnic groups have shown significant differences in dose requirement. METHOD: A systematic electronic search was carried out in PUBMED and ScienceDirect using different key words like, 'warfarin', 'CYP2C9', 'VKORC1', 'pharmacokinetics', 'metabolites' and 'genetic'. Till date, data from 15 Asian countries for CYP2C9 genotypes and 14 Asian countries for VKORC1 genotypes could be retrieved. RESULTS: Approximately 90% of the subjects from East Asian countries were found to be carriers for VKORC1 1639 'A' or 1173 'T' allele (associated with low dose warfarin), while the prevalence of these alleles in the rest of the Asian countries (except Iran) i.e. South, South East, West and Central Asia ranged between 14 and 80%. Interestingly, an increase in carrier rate for CYP2C9 2 or 3 alleles was observed as we move from East to West Asia and an opposite trend was observed with VKORC1 1639 'A' or 1173 'T' alleles. Countries like Iran, Oman, India and Russia showed a drastic variation in the distribution pattern of these genotypes from that of the neighboring countries. CONCLUSION: The analysis further highlights the importance of genotype based warfarin dosing in each country. Since many Asian countries are still underrepresented in pharmacogenomic research, addition of data from these underrepresented countries will be beneficial for safe warfarin dosing in these patients.

Influence of CYP2C9 and VKORC1 gene polymorphisms on warfarin dosage, over anticoagulation and other adverse outcomes in Indian population.

The aim of this study was to determine the frequencies of SNPs in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes and their effect on warfarin dose requirement, over anticoagulation and other adverse outcomes in Indian population. A total of 145 warfarin treated patients for various clinical conditions were screened for VKORC1 and CYP2C9 gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. We found that homozygous VKORC1-1639 AA and CYP2C9 (*)3/(*)3 polymorphisms showed 100% association with risk of over anticoagulation and other adverse events. Carriers of two heterozygous variant genotypes also showed significant association with risk of over anticoagulation and bleeding. Single variant carrier patients were found to require low warfarin dose as compared to wild type (CYP2C9(*)1/(*)1 and VKORC1- 1639 GG) patients. The major impact of VKORC1 and CYP2C9 genotypes was observed in the first month of anticoagulation. A drastic variation from other Asian countries was observed in Indian population with regard to the distribution of different VKORC1 -1639 genotypes. Our results suggest that both VKORC1 and CYP2C9 genotypes showed significant impact on warfarin dose requirement, over anticoagulation in the first month of anticoagulation and number of bleeding episodes. The variation in therapeutic dosage of warfarin and the associated adverse events across different populations is due to the wide differences in the frequency of these warfarin sensitive alleles.