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Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.
Guo, C, Kuang, Y, Zhou, H, Yuan, H, Pei, Q, Li, J, Jiang, W, Ng, CM, Chen, X, Huo, Y, et al
Circulation. Genomic and precision medicine. 2020;(4):e002602
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Abstract
BACKGROUND Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. METHODS We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ≥18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. RESULTS A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1-10.2]; P=0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1-24.4]). The incidence of adverse events was low in both groups. CONCLUSIONS The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02211326.
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Pharmacokinetics of Rasagiline in Healthy Adult Chinese Volunteers with Various Genotypes: A Single-Center, Open-Label, Multiple-Dose Study.
Chen, X, Zhao, Q, Jiang, J, Liu, J, Hu, P
Clinical drug investigation. 2016;(5):369-76
Abstract
BACKGROUND AND OBJECTIVE Although there is evidence indicating cytochome P450 (CYP) 1A2 is responsible for the metabolism of rasagiline, the role of other CYP isoforms is unclear. This study investigated the pharmacokinetics of rasagiline in adult Chinese healthy volunteers with various CYP genotypes. METHODS This single-center, open-label study was conducted in 12 subjects. Fasted subjects received rasagiline 1 mg daily for 7 days. Blood samples were taken to determine plasma concentrations of rasagiline, its major metabolite R-1-aminoindan (AI), and the genotyping of CYP2D6 and CYP2C19. Safety was also assessed. RESULTS After oral administration, rasagiline was absorbed with a median time to reach maximum concentration (tmax) of 0.5 h. Overall systemic exposure was approximately theefold on day 7 versus day 1. The mean terminal elimination half-life (t½) was nearly doubled on day 7 compared to day 1. AI was rapidly quantifiable in plasma with median t max occurring 1-1.5 h post-dose. Overall exposure to AI on day 7 was approximately twofold higher than on day 1. Overall systemic exposure to AI was approximately four- to sixfold greater than exposure to rasagiline, whereas maximum concentration (C max) was approximately half that of rasagiline. The mean t½ for AI was longer than for the parent drug, and was similar between the sexes and days. Inferred metabolic status did not appear to affect the pharmacokinetics of rasagiline or AI. All adverse events were mild to moderate in severity. CONCLUSION Multiple oral administration of rasagiline 1 mg tablet in Chinese healthy adults resulted in similar pharmacokinetics of both rasagiline and AI compared to those previously observed in Caucasians. Rasagiline was safe and well tolerated in Chinese healthy volunteers.
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The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: Evidence from 23 case-control studies.
Guo, S, Jiang, X, Chen, X, Chen, L, Li, X, Jia, Y
Gene. 2015;(1):90-5
Abstract
Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were considered to have some influence on both folate metabolism and cancer risk. Previous studies on the relation between MTHFR C677T polymorphism and prostate cancer (PCa) risk remained controversial. To derive a more precise estimation of the relationship, we carried out an update comprehensive meta-analysis to assess the associations of the MTHFR C677T polymorphism with the susceptibility of PCa. Twenty-three trials with a total of 24,024 participants on the MTHFR C677T polymorphism that met inclusion criteria were analyzed in the current study. Overall, no statistical relationship was found with any MTHFR C677T genetic model associated with susceptibility to PCa (TT versus CC, OR=0.83, 95% CI 0.68-1.02, P=0.07; CT versus CC, OR=0.95, 95% CI 0.85-1.07, P=0.43; Dominant, OR=0.93, 95% CI 0.83-1.03, P=0.17; Recessive, OR=0.84, 95% CI 0.70-1.02, P=0.09.). Nevertheless, subgroup analysis found a reduced PCa risk associated with polymorphism in Asian population (TT versus CC, CT versus CC, dominant and recessive model). Moreover, the protective effect of polymorphism against PCa risk was also shown upon hospital-based studies (TT versus CC, and recessive model). When benign prostate hyperplasia was chosen as controls, both TT versus CC and recessive model showed significant difference. In addition, the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference. Taken together, the existing evidence indicates the homozygote TT of MTHFR C677T should be viewed as a protective factor against PCa risk for clinical practice with the consideration of different gene background, study design as well as specific controls.
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Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.
Wu, C, Wang, Z, Song, X, Feng, XS, Abnet, CC, He, J, Hu, N, Zuo, XB, Tan, W, Zhan, Q, et al
Nature genetics. 2014;(9):1001-1006
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Abstract
We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.
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KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) polymorphisms affect therapeutic efficacy of repaglinide in Chinese patients with type 2 diabetes.
Yu, M, Xu, XJ, Yin, JY, Wu, J, Chen, X, Gong, ZC, Ren, HY, Huang, Q, Sheng, FF, Zhou, HH, et al
Clinical pharmacology and therapeutics. 2010;(3):330-5
Abstract
This study showed that the polymorphisms KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) are associated with a heightened risk of developing type 2 diabetes mellitus (T2DM). We also explored the effects of these polymorphisms on the efficacy of repaglinide therapy in Chinese patients with T2DM. A total of 259 patients with T2DM and 188 healthy controls were genotyped. Forty patients with various genotypes were randomly selected to undergo an 8-week repaglinide treatment regimen. Patients with the G allele of the KCNJ11 Lys23Glu polymorphism showed higher levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (P < 0.05). After repaglinide treatment, patients with the GA or AA genotype showed higher levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (P < 0.05). Patients with the C allele of TCF7L2 rs290487(C/T) had higher total cholesterol levels and lower body mass index (BMI) (P < 0.05). In patients with the TT genotype, the drug showed better efficacy with respect to levels of fasting insulin, triglycerides, and low-density lipoprotein cholesterol (LDL-c) than in patients with the CC or CT genotype (P < 0.05). The KCNJ11 and TCF7L2 polymorphisms were associated with repaglinide efficacy.
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Association analysis of retinoic acid receptor beta (RARbeta) gene with high myopia in Chinese subjects.
Ding, Y, Chen, X, Yan, D, Xue, A, Lu, F, Qu, J, Zhou, X
Molecular vision. 2010;:855-61
Abstract
PURPOSE High myopia or pathological myopia is a common refractive error. Individuals with high myopia are subject to increased risk of serious eye complications. Accumulating evidence has demonstrated the role for heritability in ocular growth and in the development of high myopia. Retinoic acid and retinoic acid receptors play important roles in ocular development and in experimentally induced myopia. The purpose of this study was to determine if high myopia is associated with single nucleotide polymorphism (SNP) variants in the retinoic acid receptor beta (RARbeta) gene in Chinese subjects. METHODS DNA samples were purified from venous lymphocytes of 175 unrelated Chinese patients with high myopia (less than -8.00 diopters) and 101 Chinese control subjects without high myopia (+/-1.00 diopters). Direct nucleotide sequence analysis in the RARbeta gene was performed, and the detected variations were further confirmed by reverse sequencing. Allelic frequencies of all detected SNPs were assessed for Hardy-Weinberg equilibrium. RESULTS Five variations in RARbeta were detected in Chinese subjects with high myopia, including 32574G>A, 32629G>A, 32645C>T, 32647T>G, and 151973C>T, of which only 32647T>G (NCBI notes as rs58244688 and rs2067964) had already been reported. The majority of SNP genotypes were heterozygous. While 32647T>G, 32629G>A, and 32645C>T were located in introns and 32574G>A and 151973C>T were located in coding regions, none of the SNPs affected the amino acid sequence. In the present study, no evidence of association was found between variations in the nucleotide sequence of RARbeta and high myopia. CONCLUSIONS Five SNP variants in RARbeta were detected in Chinese subjects with high myopia, none of them were associated significantly with high myopia. Further studies are needed to identify which genes are responsible for high myopia.