title: DNA sensors to assess the effect of VKORC1 and CYP2C9 gene polymorphisms on warfarin dose requirement in Chinese patients with atrial fibrillation.
abstract: The optimal dose of warfarin depends on polymorphisms in the VKORC1 (the vitamin K epoxide reductase complex subunit (1) and CYP2C9 (cytochrome P450 2C9) genes. To minimize the risk of adverse reactions, warfarin dosages should be adjusted according to results from rapid and simple monitoring methods. However, there are few pharmacogenetic-guided warfarin dosing algorithms that are based on large cohorts from the Chinese population, especially patients with atrial fibrillation. This study aimed to validate a pharmacogenetic-guided warfarin dosing algorithm based on results from a new rapid electrochemical detection method used in a multicenter study. Three SNPs (CYP2C9 *2, *3 and VKORC1 c.-1639G > A) were genotyped by electrochemical detection using a sandwich-type format that included a 3' short thiol capture probe and a 5' ferrocene-labeled signal probe. A total of 1285 samples from four clinical hospitals were evaluated. Concordance rates between the results from the electrochemical DNA biosensor and the sequencing test were 99.8%. The results for gene distribution showed that most Chinese patients had higher warfarin susceptibility because mutant-type and heterozygotes were present in the majority of subjects (99.4%) at locus c.-1639G > A. When the International Warfarin Pharmacogenetics Consortium algorithm was used to estimate therapeutic dosages for 362 patients with AF and the values were compared with their actual dosages, the results revealed that 56.9% were similar to actual dosages (within the 20% range). A novel electrochemical detection method of CYP2C9 *2, *3and VKORC1 c.-1639G > A alleles was evaluated. The warfarin dosing algorithm based on data gathered from a large patient cohort can facilitate the reasonable and effective use of warfarin in Chinese patients with AF.
authors.affiliation: Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Rd. 2, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Tao-Sheng
authors.initials: TS
authors.lastname: Huang
authors.affiliation: Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Vascular Surgery, Linyi People's Hospital, Shandong, People's Republic of China.
authors.forename: Yu-Bin
authors.initials: YB
authors.lastname: Li
authors.affiliation: Department of Cardiology, Luan Affiliated Hospital of Anhui Medical University, Anhui, People's Republic of China.
authors.forename: Zhong-Li
authors.initials: ZL
authors.lastname: Dai
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Jian-Rui
authors.initials: JR
authors.lastname: Zheng
authors.affiliation: School of Biotechnology, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Pei-Qi
authors.initials: PQ
authors.lastname: Cheng
authors.affiliation: Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Rd. 2, Guangzhou, Guangdong, 510080, People's Republic of China. htaosh@mail2.sysu.edu.cn.
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: He
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics*; D001483:Base Sequence; D015374:Biosensing Techniques / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004247:DNA / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D014859:Warfarin; D004247:DNA; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: Atrial fibrillation; Electrochemical DNA sensor; Frequency; Warfarin dosing