Comprehensive studies of novel SNPs affecting warfarin dose in African Americans

影响非裔美国人华法林剂量的新型 SNP 的综合研究

基本信息

批准号：
8299048
负责人：
Minoli A Perera
金额：
$ 19.54万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299048
关键词：
Adverse effects Affect African American Age Algorithms Anticoagulation Asians Automobile Driving Binding Sites Bioinformatics Biological Assay Biological Markers CYP2C9 gene Candidate Disease Gene Caucasians Caucasoid Race Chicago Clinical Code DNA Resequencing Databases Dose Drug Delivery Systems Drug Kinetics Enzymes Gene Expression Regulation Gene Mutation Genes Genetic Polymorphism Genetic Transcription Genetic Variation Genome Genotype Goals Haplotypes Human Illinois In Vitro Individual Knowledge Lead Linkage Disequilibrium Liver Maintenance Methods Mutation Nature Oxidoreductase Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Plasma Population Population Study Proteins Prothrombin Proxy Quantitative Trait Loci Regulation Research Role Sampling Series Solid Surrogate Markers Targeted Research Testing Transcript Transcriptional Regulation Translations Universities Validation Variant Vitamin K Warfarin Warfarin Sodium Washington Weight base clinical effect clinical practice clinically relevant cohort comparative genomics drug metabolism evidence base functional disability genome-wide in vitro Assay in vivo interest non-genetic novel protein function tool vitamin K epoxide reductase

项目摘要

DESCRIPTION (provided by applicant): Warfarin (Coumadin (R)) has been a long-standing target of research because it is both difficult to determine the correct dose and has serious adverse effects. Currently, algorithms using polymorphisms in the CYP2C9 and VKORC1 genes have been developed to predict the correct maintenance dose of warfarin in Caucasians and Asians. However these algorithms, which include known non-genetic variables such as age, weight and concomitant medications, are much less predictive in African Americans. Discovery of which SNPs affect dose in African Americans and the mechanism underlying their effect remain a gap in the current knowledge. We hypothesize that these studies will identify clinically relevant SNPs that affect warfarin dose in African Americans. The aims of this proposal are to provide validated evidence for novel genetic variation that affects warfarin dose in African Americans, to investigate the effect these SNPs have on the gene regulation, and to show the effect of these SNPs on both the pharmacokinetics of warfarin and its drug target Vitamin K epoxide reductase (VKOR). In pursuit of these goals, we have determined and genotyped the relevant haplotype tagging SNPs (htSNPs) in CYP2C9 and VKORC1 in African Americans, using comparative genomics and putative transcriptional binding sites prediction. By looking at htSNPs we can genotype just one SNP in the haplotype and capture the variation in linkage disequilibrium (LD) with that SNP. Tests for association in the discovery cohort have revealed interesting novel variation in both genes. However, validation of these findings is needed. To further evaluate regulation, we used a genome-wide bioinformatics tool (SCAN) to identify expression Quantitative Trait Loci (eQTLs), a method that has never been used to identify novel SNPs associated with warfarin dosing. To this end, we plan on genotyping the most highly associated SNPs in two independent African American anticoagulation cohorts. Those that replicate will then be assayed for function in a series of in vitro assays. We will then investigate the direct clinical effect of these SNPs on drug metabolism and the target protein by conducting a pharmacokinetic study evaluating the effect of CYP2C9 SNPs on S- to R-warfarin plasma concentration ratio and a pharmacodynamic study evaluating the effect of VKORC1 SNPs on a surrogate marker of VKOR protein function, Prothrombin induced by vitamin K absence or antagonism II (PIVKA-II). This proposed research is both timely and necessary to fill gaps in the current knowledge and to affect real translation of pharmacogenetics into clinical practice.

描述（由申请人提供）：华法林（Coumadin（R））一直是研究的长期目标，因为这既难以确定正确的剂量并具有严重的不良影响。当前，已经开发了使用CYP2C9和VKORC1基因多态性的算法，以预测高加索人和亚洲人的华法林的正确维持剂量。但是，这些算法包括已知的非遗传变量，例如年龄，体重和随之而来的药物，在非洲裔美国人中的预测性要低得多。 SNP影响非裔美国人的剂量的发现，其作用的基础机制在当前知识上仍然是差距。我们假设这些研究将确定影响非裔美国人华法林剂量的临床相关SNP。该提案的目的是为影响非裔美国人的华法蛋白剂量的新型遗传变异提供验证的证据，以研究这些SNP对基因调节的影响，并显示这些SNP对华法蛋白的药代动力学对华法蛋白及其药物靶标的维生素K氧化物氧化物还原酶（VKOR）的影响。为了实现这些目标，我们使用了比较基因组学和推定的转录结合点预测，我们已经确定并确定了CYP2C9和VKORC1中相关的单倍型标记SNP（HTSNP）。通过查看HTSNP，我们可以在单倍型中只有一个SNP进行基因型，并使用该SNP捕获链接不平衡（LD）的变化。发现队列中关联的测试揭示了这两个基因的有趣新变化。但是，需要对这些发现的验证。为了进一步评估调节，我们使用了全基因组生物信息学工具（SCAN）来识别表达定量性状基因座（EQTLS），这种方法从未用来识别与华法林给药相关的新型SNP。为此，我们计划在两个独立的非裔美国人抗凝人群中对基因分型进行基因分型。然后将在一系列体外测定中分析复制的人。然后，我们将通过进行一项药代动力学研究来研究这些SNP对药物代谢和靶蛋白的直接临床作用，该研究评估CYP2C9 SNP对S-至R-毒蛋白血浆浓度率的影响，并评估VKORC1 SNP对VKORC1 SNP对vkor vkor proth off vkor proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth proth protromb的影响。 II（Pivka-II）。这项拟议的研究既及时又需要填补当前知识的空白，并影响了药物遗传学为临床实践的真实翻译。