Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice

Abstract Aim The anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range. Methods We conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR. Results A total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4. Conclusion We confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period

Assessment of Human Tribbles Homolog 3 Genetic Variation (rs2295490) Effects on Type 2 Diabetes Patients with Glucose Control and Blood Pressure Lowering Treatment

Effects of human tribbles homolog 3 (TRIB3) genetic variation (c.251 A > G, Gln84Arg, rs2295490) on the clinical outcomes of vascular events has not been evaluated in patients with type 2 diabetes after blood pressure lowering and glucose controlling treatment. We did an analysis of a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled clinical trial at 61 centers in China, with a follow-up period of 5 years. The major vascular endpoints were the composites of death from cardio-cerebral vascular diseases, non-fatal stroke and myocardial infraction, new or worsening renal and diabetic eye disease. A total of 1884 participants were included in our research with a 4.8 years median follow-up. For glucose lowering axis, patients with TRIB3 (rs2295490) AA (n = 609) genotype exhibited significantly reduced risk of major vascular events compared with AG + GG (n = 335) genotype carriers (Hazard ratio 0.72, 95% CI 0.55–0.94, p = 0.016), Paradoxically, the risk of vascular events were significantly increased in patients with AA (n = 621) compared to AG + GG (n = 319) genotype for intensive glucose control (Hazard ratio 1.46, 95% CI, 1.06–2.17, 35 p = 0.018). For blood pressure lowering axis, marginally significant difference was found between TRIB3 variant and coronary events. Our findings suggest that good glucose and blood pressure control exhibited greater benefits on vascular outcomes in patients with TRIB3 (rs2295490) G allele