Carmel Kealey

Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans.

The objective of this study was to determine whether warfarin dosing algorithms developed for Caucasians and African Americans on the basis of clinical, environmental, and genetic factors will perform better than an empirical starting dose of 5 mg/day. From April 2002 through December 2005, 259 subjects (Caucasians and African Americans) who started using warfarin were prospectively followed until they reached maintenance dose. The Caucasian algorithm included 11 variables (R2 = 0.43). This model (which predicted 51% of the doses to within 1 mg of the observed dose) performed better than 5 mg/day (which predicted 29% of the doses to within 5 ± 1 mg). The African‐American algorithm included 10 variables (R2 = 0.28). This model predicted 37% of the doses to within 1 mg of the observed dose, representing a small improvement compared with 5 mg/day (which predicted 34% of the doses to within 1 mg of 5 mg/day). These results were similar to the results we obtained from testing other published algorithms. The dosing algorithms explained <45% of the observed variability in Caucasians, and the algorithms performed only marginally better for African Americans when compared with giving 5 mg empirically.

Warfarin Response and Vitamin K Epoxide Reductase Complex 1 in African Americans and Caucasians

The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and −1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (−12.10 mg/week±4.93; P=0.02) and Caucasians (−14.41 mg/week±3.28; P<0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio >3 (odds ratio=3.10; 95% confidence interval: 1.73–5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over‐anticoagulation among African Americans.

Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans

Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the ɛ4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the ɛ4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in ɛ4 carriers versus 35.0 mg in non-ɛ4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (ɛ2/ɛ2 or ɛ2/ɛ3: 30.0 mg; ɛ3/ɛ3: 35.0 mg; ɛ3/ɛ4 or ɛ4/ɛ4: 45.0 mg; P=0.012), although the ɛ4/ɛ4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.

Warfarin and cytochrome P450 2C9 genotype: possible ethnic variation in warfarin sensitivity

INTRODUCTION Warfarin is a widely prescribed, efficacious oral anticoagulant. S-warfarin, the more active form, is metabolized by the cytochrome P450 (CYP)2C9 enzyme. The aim was to evaluate the influence of two CYP2C9 functional polymorphisms (*2 and *3) on warfarin dose in African-Americans, an unstudied population and Caucasians, and also to assess the effect of these polymorphisms on anticoagulation response after accounting for nongenetic factors and genetic factors that might also impact the dose-response relationship of warfarin. PATIENTS AND METHODS A prospective cohort of 362 patients with a target international normalized ratio of between 2.0 and 3.0 were genotyped. Warfarin sensitivity stratified by genotype was investigated using univariate and multivariate analyses. RESULTS The maintenance dose of warfarin was significantly related to genotype (p < 0.01) (variant carriers: 31.25 mg/week; wild-type: 37.5 mg/week), even after adjustment for possible confounding factors (p = 0.046). However, the effect of genotype was restricted to Caucasians, in whom variant carriers had a significantly lower maintenance dose compared with wild-type homozygotes (unadjusted: p < 0.01; adjusted: p = 0.02). There was a greater risk of over-anticoagulation among Caucasian variant carriers, although this was only observed prior to reaching maintenance dose. For African-American variant carriers, there was no difference in warfarin response based on CYP2C9 genotype. DISCUSSION CYP2C9 *2 and *3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.

The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women

Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor or marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within SLC19A1, the gene that encodes RFC1, may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland.

Linkage and candidate gene analysis of 14q22‐24 in bipolar disorder: support for GCHI as a novel susceptibility gene

Using a collection of Irish sib‐pair nuclear families, we previously obtained modest evidence of linkage implicating 14q22‐24 in bipolar disorder (BPD). To follow‐up on this preliminary finding, an extended linkage analysis was performed which employed thirteen microsatellite markers, spanning a total distance of 85 cM on 14q. Effectively, P‐values <0.05 were observed for a region extending over 41.88 cM, with the marker D14S281 displaying a peak multipoint non‐parametric lod (NPL) score of 2.72 and an associated P‐value of 0.003. Support for this finding was also obtained from flanking markers indicating excess allele sharing at 14q22‐24 in Irish bipolar sib‐pairs. A web‐based candidate gene search of 14q22‐24 resulted in the selection of GTP cyclohydrolase I (GCHI), located 200 kb 3′ of D14S281, as the best plausible candidate gene for involvement in BPD. GCHI is the rate‐limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), a natural cofactor for tyrosine and tryptophan hydroxylases. These enzymes play an essential role in the biosynthesis of various hormones and neurotransmitters such as dopamine, noradrenaline, adrenaline, and serotonin. Numerous studies have also suggested that the clinical symptoms of depression might be related to a deficiency of BH4. An association study between BPD and a novel single nucleotide polymorphism (SNP) in GCHI (G to A at position −959 bp, upstream of the ATG codon), is also presented here. This study revealed that the variant A allele is preferentially transmitted to BPI probands (χ2 = 4.54, P = 0.033) suggesting that variants within GCHI may contribute to BPD in the Irish population.

Association between the NAT1 1095C > A polymorphism and homocysteine concentration.

Anna Stanisławska-Sachadyn, Liselotte E. Jensen, Carmel Kealey, Jayne V. Woodside, Ian S. Young, John M. Scott, Liam Murray, Colin A. Boreham, Helene McNulty, J.J. Strain, and Alexander S. Whitehead* Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Cardiovascular Research Centre, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom Northern Ireland Centre for Food and Health, University of Ulster, Coleraine, Northern Ireland, United Kingdom Department of Clinical Medicine, Trinity College, Dublin, Ireland