Warfarin dosage response related pharmacogenetics in Chinese population.

OBJECTIVES:As the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1), rs7294 (VKORC1), rs1057910 (CYP2C9), rs2108622 (CYP4F2), and rs699664 (GGCX) involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population. METHODS:220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes. RESULTS:rs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D': 0.969). 158 of 220 recruited individuals had the target INR (1.5-2.5). Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender), rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR. CONCLUSIONS:A better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese

Basic Characteristics of patients with PQ poisoning.

*<p>: Comparison between Group A & C, p<0.05;</p> <p>: Comparison between Group B & C, p<0.05;</p>#<p>: Comparison between Group A & B, p<0.05.</p

The plasma PQ concentrations of patients receiving repeated HP.

<p>Note: C_0–1 was the plasma PQ concentration prior to the first session of HP; C_2–1 was the plasma PQ concentration after the first session of HP; C_0–2 was the plasma PQ concentration prior to the second session of HP. PQ concentration : ng/mL; Rebound rate  =  (C_0–2−C_2–1)/C_2–1.</p

The change of average plasma PQ concentration as HP going on.

<p>The X axis stands for the treatment time of haemoperfusion (hour), while the Y axis stands for average plasma PQ concentration (ng/ml).</p

The relationship between C₀ and the overall PQ clearance rate (R₂) (C₀<4000

<p> <b>ng/ml).</b> C₀ stands for the plasma PQ concentration at the beginning of haemoperfusion, R₂ stands for the overall PQ clearace rate of haemoperfusion. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040911#pone-0040911-g002" target="_blank">Figure 2A</a> stands for patients in group A with C₀≤200 ng/ml; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040911#pone-0040911-g002" target="_blank">Figure 2B</a> stands for patients in group B with 2000≤300 ng/ml; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040911#pone-0040911-g002" target="_blank">Figure 2C</a> stands for patients in group C with C₀>300 ng/ml.</p

Characteristics of patients with cardiac valve replacement.

<p>Values represented as mean±SD. INR: international normalized ratio.</p><p>Characteristics of patients with cardiac valve replacement.</p

Genotype and allelic frequencies of rs9923231, rs7294, rs1057910, rs2108622, rs699664 polymorphisms obtained in our population and in other references of Chinese.

<p>Genotype and allelic frequencies of rs9923231, rs7294, rs1057910, rs2108622, rs699664 polymorphisms obtained in our population and in other references of Chinese.</p

The effects of rs9923231, rs7294, rs1057910, rs2108622, rs699664 on warfarin maintenance dose and plasma concentration.

<p>Analyzed by stepwise multiple linear regression.</p><p>*:the dependent variable was maintenance dose and the independent variables included age, body weight, gender, rs9923231, rs1057910, rs7294, rs2108622 and rs699664;</p><p>p *:showed the effects of 5 SNPs on the maintenance dose;</p><p>Adjusted R2*:showed the contribution of rs9923231and rs1057910 to the variability in warfarin maintenance dose.</p><p>^△:the dependent variable was plasma concentration and the independent variables included age, body weight, gender, rs9923231, rs1057910, rs7294, rs2108622 and rs699664.</p><p>p ^△:showed the effects of 5 SNPs on the plasma concentration;</p><p>Adjusted R2^△: showed the contribution of rs7294 to the plasma concentration.</p><p>The effects of rs9923231, rs7294, rs1057910, rs2108622, rs699664 on warfarin maintenance dose and plasma concentration.</p

Relation between the maintenance dose and the tested genes.

<p>Panel A–E: rs9923231 (Panel A), rs7294 (Panel B), rs1057910 (Panel C), rs2108622 (Panel D), rs699664 (Panel E). Each box indicates 25 to 75 percentile of values, and the horizontal lines represent the median value of maintenance dose. *: p < 0.05 at ANOVA test.</p