Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n ‫؍‬ 181) and 2 independent replication patient populations (n ‫؍‬ 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P ‫؍‬ 6.2 ؋ 10 ؊13 ) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P ϳ 10 ؊4 ). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable. IntroductionThe determination of safe yet effective doses of warfarin for individual patients is one of the most promising clinical applications of pharmacogenetics. [1][2][3] There are large variation in warfarin dose from patient to patient and significant clinical consequences of doses that produce insufficient or excessive pharmacologic effects. Thus, reducing uncertainty in establishing the therapeutic dose in individual patients could improve quality of care as well as expand the range of patients who could be treated. 4 In white patients, genetic factors are more strongly correlated with stabilized warfarin dose than all other known patient-related factors. Warfarin pharmacokinetics are affected by functional polymorphisms (*2, Arg144Cys; *3, Ile359Leu) in cytochrome P450 2C9 (CYP2C9). 5,6 In addition, warfarin's effects are modulated by polymorphisms (eg, Ϫ1639, rs9923231) in the vitamin K epoxide reductase complex 1 (VKORC1) enzyme, a critical component of the vitamin K cycle discovered in part because of its contribution to bleeding disorders and warfarin resistance. 7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range. [11][12][13] Combined polymorphisms in VKORC1 and CYP2C9 explain approximately 30% (20%-25% for VKORC1; 5%-10% for CYP2C9) of the variance in the stabilized warfarin dose distribution. 10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awar...

Objectives-(i) determine if montelukast undergoes carrier mediated uptake; (ii) classify the carrier protein(s) responsible for uptake; (iii) identify specific transporters that mediate transport of montelukast; (iv) evaluate whether variation in the gene encoding the transport protein(s) influences the pharmacokinetics and pharmacodynamics of montelukast.Methods-In vitro permeability studies of montelukast are conducted using Caco-2 cell culture, a standard model of human intestinal drug transport. In vivo plasma concentrations of montelukast in an asthmatic population are determined by HPLC, and genotyping of transport proteins is by LightTyper analysis.Results-Permeability of montelukast has an activation energy of 13.7±0.7 kcal/mol, consistent with carrier mediated transport. Permeability is saturable at high concentrations of montelukast and follows Michaelis-Menten kinetics. Permeability is subject to competition by sulfobromophthalein, estrone 3-sulfate, pravastatin, taurocholic acid, and cholic acid (p<0.05, % of control; 72±7 -86±7) and is inhibited by 5-10% citrus juice (p<0.05, maximal inhibition % of control; 31±2). An MDCKII cell line expressing OATP2B1 (coded for by the SLCO2B1 gene) displays significantly increased permeability of montelukast (p<0.05, % of control; 140±20). A nonsynonymous polymorphism in SLCO2B1, (rs12422149; SLCO2B1{NM_007256.2}:c.935G>A) associates with significantly reduced plasma concentration in subjects measured on the morning after an evening dose (p<0.025, square root mean transformed plasma concentration ± SE; c. Conclusions-Together these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast.

BackgroundPersonal health records (PHRs) have the potential to improve patient self-management for chronic conditions such as diabetes. However, evidence is mixed as to whether there is an association between PHR use and improved health outcomes.ObjectiveThe aim of this study was to evaluate the association between sustained use of specific patient portal features (Web-based prescription refill and secure messaging—SM) and physiological measures important for the management of type 2 diabetes.MethodsUsing a retrospective cohort design, including Veterans with diabetes registered for the My Health e Vet patient portal who had not yet used the Web-based refill or SM features and who had at least one physiological measure (HbA1c, low-density lipoprotein (LDL) cholesterol, blood pressure) in 2009-2010 (baseline) that was above guideline recommendations (N=111,686), we assessed portal use between 2010 and 2014. We calculated the odds of achieving control of each measure by 2013 to 2014 (follow-up) by years of using each portal feature, adjusting for demographic and clinical characteristics associated with portal use.ResultsBy 2013 to 2014, 34.13% (38,113/111,686) of the cohort was using Web-based refills, and 15.75% (17,592/111,686) of the cohort was using SM. Users were slightly younger (P<.001), less likely to be eligible for free care based on economic means (P<.001), and more likely to be women (P<.001). In models adjusting for both features, patients with uncontrolled HbA1c at baseline who used SM were significantly more likely than nonusers to achieve glycemic control by follow-up if they used SM for 2 years (odds ratio—OR=1.24, CI: 1.14-1.34) or 3 or more years (OR=1.28, CI: 1.12-1.45). However, there was no significant association between Web-based refill use and glycemic control. Those with uncontrolled blood pressure at baseline who used Web-based refills were significantly more likely than nonusers to achieve control at follow-up with 2 (OR=1.07, CI: 1.01-1.13) or 3 (OR=1.08, CI: 1.02-1.14) more years of Web-based refill use. Both features were significantly associated with improvements in LDL cholesterol levels at follow-up.ConclusionsAlthough rates of use of the refill function were higher within the population, sustained SM use had a greater impact on HbA1c. Evaluations of patient portals should consider that individual components may have differential effects on health improvements.

Diagnostic study, Level II.