PREVALENCE OF POLYMORPHIC CYP2C19 ALLELES PR

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一项初步研究，作为我们开发药物遗传学（PGt）指导的剂量优化方法的第一步。药物代谢酶中遗传多态性（生物标志物）的鉴定和表征可以提供关于药物反应中个体间差异机制的实质性知识，因此，应将其纳入风险评估和治疗决策（即，事先知道谁应该用什么和如何治疗）。已知人CYP 450酶参与此类药物的修饰和/或降解。CYP450酶的遗传差异导致血液药物暴露的重要个体间和种族间变异性，并可能导致临床反应的差异。弱代谢型受试者可能比强代谢型受试者对作为这些酶底物的药物更敏感。因此，这项工作的第一步将是确定波多黎各人中每种临床和功能相关的CYP 450酶变体的潜在弱代谢者和快代谢者以及携带者的频率。值得注意的是，波多黎各人的这一信息仍然是一个有待确定的未决问题。在这项研究中，我们的目的是确定一个随机的波多黎各人口的基因型谱，以确定波多黎各人之间的主要变异等位基因的患病率。将在存在于古特里卡上血斑中的人DNA样本（约500份）中评价主要CYP 2C19等位基因的频率。将通过分子生物学技术对外周血白细胞DNA进行基因分型（即，DNA提取和纯化，通过PCR扩增，通过PG微阵列和/或DHPLC分析）。长期目标是从波多黎各人的遗传背景产生有价值的数据，以便为临床感兴趣的任何CYP 450药物底物开发适当的给药算法，使利益-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.