PREVALENCE OF POLYMORPHIC CYP2C19 ALLELES PR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这是我们开发药物遗传学(PGT)指导的剂量优化方法的第一步，将进行试点研究。识别和表征药物代谢酶的遗传多态(生物标记物)可以提供关于药物反应个体间差异的机制的大量知识，因此，它应该被纳入风险评估和治疗决策(即事先知道谁应该接受什么治疗和如何治疗)。已知人类细胞色素P450酶参与了这类药物的修饰和/或降解。细胞色素P450酶的遗传差异导致血液药物暴露的重要个体间和种族间的差异，并可能导致临床反应的差异。代谢不良的受试者可能比过度代谢的受试者更容易受到作为这些酶底物的药物的影响。因此，这项工作的第一步将是确定潜在的劣质和广泛代谢物的频率，以及波多黎各人中每种临床和功能相关的CYP450酶变体的携带者。值得注意的是，波多黎各人的这一信息仍然是一个悬而未决的问题，有待确定。在这项研究中，我们的目的是确定一个随机的波多黎各人群的基因图谱，以确定波多黎各人中主要变异等位基因的流行率。主要的CYP2C19等位基因的频率将在格思里卡片上血液斑点中的人类DNA样本(约500个)中进行评估。将通过分子生物学技术(即DNA提取和纯化、聚合酶链式反应扩增、PG微阵列和/或DHPLC分析)对外周血白细胞DNA进行基因分型。长期目标是从波多黎各人的遗传背景中产生有价值的数据，以便为临床上感兴趣的任何CYP450药物底物开发适当的剂量算法，使益处-风险关系最大化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a pilot study to be conducted as our first step in developing a pharmacogenetic (PGt)-guided approach of dose optimization. Identification and characterization of genetic polymorphisms (biomarkers) in drug metabolizing enzymes may provide substantial knowledge about the mechanisms of inter-individual differences in drug response and, consequently, it should be incorporated in risk assessment and treatment decision (i.e., by knowing in advance who should be treated with what and how). Human CYP450 enzymes are known to be involved in the modification and/or degradation of such drugs. The genetic differences in CYP450 enzymes gives rise to important interindividual and interethnic variability in blood drug exposure and may cause differences in clinical responses. Subjects who are poor metabolizer may be more susceptible than extensive metabolizer to those drugs that are substrate of these enzymes. Accordingly, the first step in this effort will be to determine the frequencies of potential poor and extensive metabolizers as well as carriers for each clinically and functionally relevant variants of CYP450 enzymes in Puerto Ricans. Noteworthy, this information in Puerto Ricans is still an open question that remains to be determined. In this study, we are aimed at determining the genotype profile of a random Puerto Rican population in order to define prevalence of major variant alleles among Puerto Ricans. Frequencies for the major CYP2C19 alleles will be evaluated in human DNA samples (about 500) present in blood spots on Guthrie cards. Genotyping will be carried out on peripheral leukocytes DNA by molecular biology techniques (i.e., DNA extraction and purification, amplification by PCR, analysis by PG micro-array and/or DHPLC).The long-term goal is to generate valuable data from the genetic background of Puerto Ricans in order to develop appropriate dosing algorithm for any CYP450 drug substrate of clinical interest, that maximize the benefit - risk relationship.