Abstract
Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated.
Highlights
Personalized medicine deals with the notions related to what is necessarily targeted by therapeutics and associated diagnostics, and proposes to improve the effectiveness and safety of health interventions [1]
Given all the points mentioned above, the Iranome Browser consisting of a whole exome sequencing of 800 individuals from eight major ethnic groups of Iran was considered in this study as the main source of data to allow an accurate analysis of the genetic polymorphisms of the major cytochrome P450 enzymes across Iranian population
Many previous studies on the polymorphisms of major cytochrome P450 (CYP) isoforms in the Iranian population were based on the proximity of this population to the Caucasians, the results of this study indicate drastic genetic differences between IRNs and Caucasians, and even a major significant difference between the Iranian population and other ethnic groups (European, Latino/Admixed American, African, East Asian and South Asian populations) in terms of CYP allele frequencies
Summary
Personalized medicine deals with the notions related to what is necessarily targeted by therapeutics and associated diagnostics, and proposes to improve the effectiveness and safety of health interventions [1]. HapMap, NHLBI Exome, 1000 Genomes, and Genome Aggregation databases, were made available worldwide by introducing new technologies such as generation sequencing (NGS) [17] Such databases provide a completed analysis of the genetic variation and interethnic diversity of CYP alleles across a specific population, enabling the comparison of results with other ethnics of the world. Available online: http://www.iranome.ir (accessed on 14 August 2021) in collaboration with Iranian and Canadian researchers These individuals represent more than 80 million Iranians and nearly half a billion people living in the Middle East, a region with a rapid population growth expectation and to date, rare information about these ethnic groups has been provided in human genomic diversity databases. The genetic polymorphisms of the major cytochrome P450 enzymes in Iranian population, based on a literature review and Iranome database, were compared with other related data in this field, based on other available human genome variation databases. The resulting data of this meta-analysis, to our knowledge, are the most extensive overview of CYP allele distributions in Iranian population published to date and provide substantial information for the guidance of population-specific genotyping strategies in pharmacokinetic studies and eventually in personalized medicine
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