A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

Abstract

Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001). Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients.

International Warfarin Genotype-Guided Dosing Algorithms in the Turkish Population and Their Preventive Effects on Major and Life-Threatening Hemorrhagic Events

“…Although these algorithms can be used in clinical practice to predict the optimal warfarin dose before treatment initiation, their effectiveness has not completely demonstrated in clinical practice [31,32]. Moreover, human genetic variation could alter the accuracy of these algorithms when used in populations with genomic backgrounds different from those populations used for algorithm development and validation [16,17]. The Turkish population is a good example of a human group with peculiar genetic features that may affect the accuracy of the international warfarin algorithms.…”

“…These large efforts could provide reliable indications that could help clinicians define the warfarin dose on the basis of patient characteristics. However, human genetic diversity can significantly affect the reliability of these warfarin pharmacogenetic algorithms [16,17], as has been demonstrated in other pharmacogenomics contexts [18][19][20]. In particular, some human populations with peculiar genetic features, such as the Turkish population, have not been included in these large multiethnic investigations, and no information is available about the effectiveness of these warfarin pharmacogenetic algorithms in these human groups.…”

Identification and Characterization of a Novel Cyp2C9 Allelic Variant in a Warfarin-Sensitive Patient

“…Several genome-wide association studies indicated that there seemed to be no other common SNPs with great effects on warfarin maintenance dose outside of CYP2C9, VKORC1 and CYP4F2 [23][24][25]. Recent association studies with the Chinese population also confirmed this observation [12,[26][27][28]. In this study, genetic polymorphisms of these three candidate genes were systematically investigated in the warfarin-sensitive patient.…”

“…Recently, four research groups reported their retrospective study results using large-scale numbers (297-845) of Chinese patients with a stable maintenance dose of warfarin [12,[26][27]30]. According to their results, the warfarin maintenance dose of Chinese individuals with the genotype CYP2C9*1/*1 is usually 3.0-3.69 mg/day, while patients carrying the heterozygous genotype *1/*3 required 2.13-2.74 mg/day, which is only about a 35% lower dose requirement than those with wildtype.…”

Warfarin-induced life-threatening bleeding associated with a CYP3A4 loss-of-function mutation in an acute limb ischemia patient: Case report and review of the literature

“…Given that the clinicopathological findings were associated with genetic factors, written informed consent was obtained from the patient to perform genetic testing. Five genetic variations associated with a required increase in the warfarin dose, namely CYP4F2, γ glutamyl carboxylase, protease, serine 53 and NAD(P)H quinone dehydrogenase 1 were identified, besides the common mutation in VKORC1 (rs7294) in Chinese individuals (Table II) (12)(13)(14)(15)(16)(17).…”