This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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