Polymorphisms in genes involved in the absorption, distribution, metabolism, and excretion of drugs in the Kazakhs of Kazakhstan.

BACKGROUND: Studies of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are crucial to the development of therapeutics in clinical medicine. Such data provide information that may improve our understanding of individual differences in sensitivity or resistance to certain drugs, thereby helping to avoid adverse drug reactions (ADRs) in patients and improve the quality of therapies. Here, we aimed to analyse single nucleotide polymorphisms (SNPs) involved in the ADME of multiple drugs in Kazakhs from Kazakhstan. RESULTS: A total of 158 SNPs involved in the ADME of various drugs were studied. We analysed 320 Kazakh DNA samples using OpenArray genotyping. Of the 158 SNPs, 75 were not found in heterozygous or homozygous variants. Comparative analysis among Kazakhs and world populations showed a fairly high percentage of population differentiation. CONCLUSION: These results provide further information for pharmacogenetic databases and may contribute to the development of personalized approaches and safer therapies for the Kazakh population. Moreover, these data provide insights into the different racial groups that may have contributed to the Kazakh population.

Frequency of NAT2 and GSTP1 polymorphisms in the Kazakh population.

INTRODUCTION: Phase II xenobiotic biotransformation enzymes perform detoxification of hydrophilic and often toxic Phase I products through glutathionetransferase (GST), UDP-glucuronosyltransferase (UDF), N-acetyltransferase (NAT) families and other enzymes. GST protein families metabolize a large number of electrophilic xenobiotics, by conjugating fusing them with glutathione. Arylamine-N-acetyltransferase (NAT) catalyzes the acetylation of the aromatic and heterocyclic amines. MATERIALS AND METHODS: This study assesses the frequency of NAT2 and GSTP1 gene polymorphisms in 326 healthy individuals from different regions of Kazakhstan by using Real-Time PCR and direct sequencing methods. RESULTS: The allele frequencies were calculated for NAT2*5 (0.54) and GSTP1 (0.27). GSTP1 alleles were in the Hardy-Weinberg equilibrium (p > 0.05), while NAT2*5 (p = 0.00) were not. The population differences between North, Northeast and South Kazakhstan regions were also analyzed. No statistically significant differences in the frequency of genotypes were found. CONCLUSION: Allelic polymorphisms of NAT2*5 and GSTP1 genes greatly varied indifferent populations. The Kazakh population was significantly different from the Asian, Caucasoid, African-American and Hispanic populations by NAT2*5 and GSTP1 genes. Allelic variants of the NAT2*5 had a low frequency in Asian populations. Allelic frequency in other world populations varied from 30 to 50%. The differences between Kazakh (0.54) and the world population were statistically significant (p < 0.05). The frequency of GSTP1 (rs1695) in the African American population was 42%. The frequency of GSTP1 in Asian populations varied from 11% to 23%. The frequency in Caucasoid populations was around 30%. The differences between Kazakh population (0.27) and other populations selected were statistically significant (p < 0.05).The study of mutations in GSTP1 and NAT2 genes is necessary in assessing the risk of the development of various diseases, such as cancer. Information on allelic polymorphisms might also be useful for personal perscriptions such as cyclophosphamide, cisplatin, methotrexate, isoniazid, pyrazinamide, and rifampin.

Pharmacogenetic research in Kazakhstan.

INTRODUCTION: Pharmacogenomics is an emerging field of medicine that combines genetics and pharmacology. Pharmacogenomic research is relatively new in Kazahkstan, but, in recent years, significant progress has been made in this field. The National Scientific Laboratory for Biotechnology has launched several government-funded research projects focused on finding genetic markers that determine susceptibility to various drugs. Another goal of pharmacogenetic research in the laboratory is to find the pharmacogenomic markers that target cardiovascular diseases, accounting for allelic frequencies in selected genes in the Kazakh population. In addition, pharmacogenomic testing kits allow patients to choose the drug dosage. For example, the drug Warfarin has been developed within the framework of the "Technology Commercialization Project," funded jointly by the Ministry of Education and Science of the Republic of Kazakhstan and the World Bank. MATERIAL AND METHODS: The pharmacogenomic studies were conducted using the real-time PCR and direct DNA sequencing. DNA was isolated from venous blood or buccal cells, collected from patients. RESULTS: To date, we have identified the most promising areas of research in the field of pharmacogenomics in Kazakhstan. The allelic frequencies of a number of polymorphisms in the Kazakh population have been calculated (CYP2C9, CYP2C19, CYP3A4, VKORC1, CYP4F2, GGCX, CYP2D6, CYP1A2, NAT2, GSTP1, SLC47A1). A unique repository of DNA samples was established and is being replenished during the implementation of aforementioned projects. Development of the testing kit for individual selection of Warfarin dosage is nearing completion. A patent, named "Method of Selection Based Dose Warfarin Genotyping for the Kazakh Population" has been recently obtained. An application for another patent, titled "Express Method of Correction of Warfarin Dosing, Based on Real-time PCR" has received positive evaluation. The results of domestic pharmacogenomic studies will allow a more rational selection of drugs and their dosage regimens specific to the Kazakh population.