CC BY
72
Polymorphisms (rs1048943) (1799853) (rs 2740574) of CYP1 А1, CYP2 С9, CYP3 A4 genes at Uzbek population
DOI: http://dx.doi.org/10.20534/ESR-17-1.2-65-67
Karimov Khamid Yakubovich, Professor. MD. PhD., Abdurakhmanova Nigora Nazimavna, the junior scientific researcher.
Department of molecular medicine and cell technologies.
Research Institute of haematology and blood transfusion at the Ministry of Public Health of the Republic of Uzbekistan
E-mail: dok.mzt@mail.ru
Polymorphisms (rs1048943) (1799853) (rs 2740574) of СУР1 А1, CYP2 С9, CYP3 А4 genes at Uzbek population
Abstract: Clinically important genes CYP1 А1, CYP2 C9, CYP3 А4 were studied for the first time in Uzbek population, for 217 healthy voluntaries. The frequencies of minor alleles CYP1 А1*2 С, CYP2 C9*2, CYP3 А4*1 В were 6,7, 9,4, and 3,2% respectively and corresponded to Caucasian. For 3 alleles the genotype frequencies were in accordance with Hardy-Weinberg equilibrium. The absence of homozygous CYP1 А1*2 С, CYP2 C9*2, CYP3 А4*1 В was revealed. 86,6, 81,1, and 93,5% were homozygous for wild alleles, 13,4, 18,9 и 6,5% were heterozygotes CYP1 А1*2 С, CYP2 С9*2, CYP3 А4*1 В respectively. The intermediate surplus of observed heterozygotes on expected heterozygotes was shown for CYP1 А1*2 С, CYP2 C9*2.
Keywords: polymorphism, CYP1 А1, CYP2 C9, CYP3 А4, Uzbek population.
due to the accumulation of inter current carcinogenic products [2].
In this regard the objective of the present research worksite study the development (extension) of main polymorphic variants
Introduction. Clinical significant CYP1 A1, CYP2 C9, CYP3 A4 genes have been first studied at the Uzbek population in samples of 217 healthy volunteers. Minor CYP1 A1*2 C, CYP2 C9*2, CYP3 A4*1 Balleles frequency was 6,7,9,4 and 32% respectively, which is typical to representatives of European ethnicity. Genotypes distribution by three polymorphic variants comply Hardy Weinberg principle on equilibrium. The absence of CYP1 A1*2 C, CYP2 C9*2, CYP3 A4*1 Balleles' homozygote has been detected, homozygotes ofwild type accounted 86.6, 81.1 and 93.5%, heterozygote-13.4, 18.9 h 6.5% respectively. There is a moderate excess of detected heterozygotes with respect to expected ones for CYP1 A1*2 C, CYP2 C9*2 shown.
The human body constantly has to cope with the huge flow of drugs, artificial chemicals, food additives and preservatives in addition to natural substances produced by plants, fungi, bacteria and other organisms. These low molecular weight species, LMWS — «xenobiotic» is neutralized in the cells ofvarious organs and tissues by host-mediated assay system. P450 super family available in the liver, lungs and intestinal canal, kidney, brain, uterine cake, mucous coat of epic pharynx, and skin at cet. Performs 95% of all reactions ofbiotransformation wherein the most significant biocatalysts are CYP1 A1, CYP2 C9, CYP3 A4 involved in 7.9 and 20% of metabolism [1]. Changes of these and other biocatalysts of neutralization caused by polymorphism of encoding gene impacts on different medication pharmacokinetics, severity of adverse effect as well as trigger the progression of oncological diseases
of CYP1 A1, CYP2 C9, CYP3 A4 at Uzbek population.
The aim of the study. Determine (rs1048943) rs (1799853) (rs 2740574) polymorphism frequency of CYP1A1, CYP2C9, CY-P3A4gene at Uzbek population.
Materials and methods. The research Institute of Hematology and blood transfusion Ministry ofhealth care of Uzbekistan. Department of molecular medicine and cell technologies investigated sample DNA 434 unrelated chromosomes Uzbeks, one of the most numerous indigenous peoples of Uzbekistan. Work done on DNA samples isolated from peripheral blood. Extraction of DNA from whole blood was performed using standard sets of RIBO-Sorb (AmpliSens®, Russia). The concentration and purity of the purified DNA was determined by the apparatus of NanoDrop 2000 (USA). Genotyping of the polymorphic variant CYP1 A1 CYP2C9, CYP3A4 gene was performed by standard PCR. Testing was conducted on a programmable thermal cycler of «Applied Biosystems» company (USA) using the test-kit of «Liteh» company (Russia) according to manufacturer's instructions. Statistical analysis of the results was carried out using statistical software package «2009 Open Epi, Version 2.3».
Findings and discussions
Basic information on the polymorphic variants of the genes studied is presented in the Table 1.
Table 1. - General information about CYP1A1, CYP2C9, CYP3 A4 polymorphic alleles
CYP1A1*2 С (rs1048943) CYP2C9*2 (rs 1799853) CTP3 А4*^ (1A/1B) (rs 2740574)
Genelocalisationatchromosome. Mutation
15q24.1 Replacement of2455A>G At 7 exon 10q23.33 Replacement of430 C>T At 3 exon 7q22.1 Replacement of -392A>G at 5'regulatory site
Substitution at the enzyme. Assumed (estimated) changes in enzyme activity.
Replacement of isoleucine to amino is ovaleric acid at 462 codon, Ile462Val Increment in activity Replacementofarginine to cysteine at144codon. Arg144Cys Decrease in activity Upregulation
Section 8. Medical science
The study ofCYP1 A1*2 C, CYP2 C9*2, CYP3 A4*1 Bgenes poly- 434 non-relative chromosomes (217 heal the volunteers). According morphism frequency at the Uzbek population has been conducted on of endings alleles frequency is 6,7, 9,4 and 3.2% respectively (tabl.2).
Table 2. - Distribution of alleles and genotypes by three polymorphism at Uzbek population
Title CYP1A1*2 С CYP2C9*2 CTP3А4*1B
Minor allele frequency 6.7% 9.4% 3.2%
Genotyping assay by minor allele
Homozygotewt/wt, n (%) 188 (86.6%) 176 (81.1%) 203 (93.5%)
Heterozygotewt/m, n (%) 29 (13.4%) 41(18/9%) 14 (6.5%)
Homozygotem/m, n (%) 0 (0%) 0 (0%) 0 (0%)
Compliant to ERW X2=1,11, P=0,29 X2=2,36, P=0,1 ^=0,24, P=0,62
D* +0.08 +0.1 +0.03
Note: D *is theindex of the relative deviation of the observed heterozygosis from the expected one, wt — wild allele, m — the mutant allele
Distribution of genotypes by three polymorphic variants complies ERW, wherein absence of homozygotes for 3 mutant alleles was detected, that is typical at the low frequency of alleles in population. Homozygotes for 3 alleles of CYP1 Al, CYP2 C9, CYP3 A4 genes amount 86.6, 81.1 h 93.5%, heterozygotes — 13.4, 18.9 h 6.5% respectively. Indices related to deviation of observed heterozygosis from expected (D*) one for 3 alleles denote low level of inbreeding at Uzbek population, as well as moderate excess
As expected, the allele frequency of CYP1 A1*2 C, CYP2 C9*2, CYP3 A4*1 Bat the Uzbek population complies the rates (indices) of the Caucasians. This findings can be later be applied in advancing personalized medicine and cancer diseases prevention in Uzbekistan.
Conclusions
1. Minor CYP1 A1*2 C, CYP2 C9*2, CYP3 A4*1 B alleles frequency was 6,7,9,4 and 32% respectively, which is typical to representatives of European ethnicity (Caucasoid).
of heterozygote for CYP1 A1*2 C, CYP2 C9*2 is detected.
According to investigations of haplotypes of m DNA and Y chromosome [3; 4]. Uzbek population has more than half of the Caucasoid, less than half of Mongoloid and small quantity of Austro-Asiatic roots. Therefore findings received further were compared with indices of minor alleles frequency at the Caucasoid and Mongoloids, significantly differ from each other by many indices (table 4).
2. Genotypes distribution by three polymorphic variants complied Hardy Weinberg principle on equilibrium.
3. The absence of CYP1 A1*2 C, CYP2 C9*2, CYP3 A4*1 B alleles' homozygote has been detected, homozygotes of wild type accounted 86.6, 81.1 and 93.5%, heterozygote- 13.4, 18.9 h 6.5% respectively.
4. There is a moderate excess of detected heterozygote with respect to expected ones for CYP1 A1*2 C, CYP2 C9*2 shown.
Table 3. - Distributionofallelesstudied in other ethnic groups
CYP1A1*2 C CYP2C9*2 CYP3 A4*1B
Caucasians 5,0-13,0% [5; 6] 10,0-15,0% [7] 3,0-10,0% [8]
Mongoloids ~25% [6] 0-3% [7] 0% [9]
Ethnically close population
Tadjiks (China) 0% [10] 1,5% [10]
Iranians 10% [11] 12,0% [12] 0% [13]
the Uigurs (China) 7,8% [14]
References:
1. Rendic S., Guengerich P. Survey of Human Oxidoreductases and Cytochrome - P. 450. Enzymes Involved in the Metabolism of Xe-nobiotic and Natural Chemicals//Chem. Res. Toxicol. - 2015. - V.28. - No. 1. - C. 38-42.
2. Wahlang B., Falkner K. C., Cave M. C., Prough R. A. Role of Cytochrome P450 Monooxygenase in Carcinogen and Chemotherapeutic Drug Metabolism//Advances in Pharmacology. - 2015. - V. 74. - C. 1-33.
3. Wells R., Yuldasheva N., Ruzibakiev R., Underhill P., Evseeva I., Blue-Smith J., Jin L., Su B., Pitchappan R., Shanmugalakshmi S., Bal-akrishnan K., Read M., Pearson N. M., Zerjal T., Webster M. T., Zholoshvili I., Jamarjashvili E., Gambarov S., Nikbin B., Dostiev A., Aknazarov O., Zalloua P., Tsoy I., Kitaev M., Mirrakhimov M., Chariew A., Bodmer W. The Eurasian heartland: a continental perspective on Y - chromosome diversity//Proc Natl Acad Sci. - 2001. - V. 98. - C. 10244-10249.
4. Irwin J. A., Ikramov A., Saunier J., Bodner M., Amory S., Rock A., O'Callaghan J., Nuritdinov A., Atakhodjaev S., Mukhamedov R., Parson W., Parsons T. J. The mtDNA composition of Uzbekistan: a microcosm of Central Asian patterns//Int J Legal Med. - 2010. - V. 124. - C. 195-204.
5. Inoue K., Asao T., Shimada T. Ethnic-related differences in the frequency distribution of genetic polymorphisms in the CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations//Xenobiotica. - 2000. - V. 30. - C. 285-295.
6. Zhan P., Wang Q Qian Q., Wei S. Z., Yu L. K. CYP1A1 MspI and exon7 gene polymorphisms and lung cancer risk: an updated metaanalysis and review//J. of Experimental & Clinical Cancer Research. - 2011. - T. 30. - No 1. - C. 1-17.
7. Céspedes-Garro C., I. Fricke-Galindo, M. Naranjo, F. Rodrigues-Soares, H. Fariñas, F.de Andrés, M. López-López, E. Peñas-Lledó, A. LLerena Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes//Expert Opin. Drug Metab. Toxicol. - 2015. - V. 11. - No. 12. - C. 1893-1905.
8. Keshava C., McCanlies E., Weston A. Cyp 3A4 polymorphisms potential risk factors for breast and prostate cancer: a huge review//Am J Epidemiol. - 2004. - V. 160. - C. 825-841.
Current state of the problem sudden infant death at home
9. Lee J. S., Cheong H. S., Kim L. H., Kim J. O., Seo D. W., Kim Y. H., Chung M. W., Han S. Y., Shin H.D Screening of genetic polymorphisms of CYP3A4 and CYP3A5 genes//The Korean Journal of Physiology & Pharmacology. - 2013. - T. 17. - No. 6. - C. 479-484.
10. Zhang J., Jin T., Yunus Z., Li X., Geng T., Wang H., Cui Y., Chen C. Genetic polymorphisms of VIP variants in the Tajik ethnic group of northwest China//BMC genetics. - 2014. - V.15. - No. 1. - C. 1-9.
11. Razmkhah F., Pazhakh V., Zaker F., Atashrazm F., Sheikhi M. Frequency of CYP1A1*2C polymorphism in patients with leukemia in the Iranian population//Laboratory Medicine. - 2011. - T. 42. - No. 4. - C. 220-223.
12. Hashemi-Soteh S., Shahabi-Majd N., Gholizadeh A.-R., Shiran M.-R. Allele and Genotype frequencies of CYP2C9 within an Iranian population (Mazandaran)//Genetic testing and molecular biomarkers. - 2012. - V. 16. -No. 7. - C. 817-821.
13. Badavi E., Safavi B., JalaliA., Shahriary G., Mohammadi-Asl J., Babaei, J. Association of CYP3A4 and CYP3A5 polymorphisms with Iranian breast cancer patients//Egyptian J. of Med Hum Genetics. - 2015. - T. 16. - No 3. - C. 219-225.
14. Jin T., Xun X., Du S., Geng T., Wang H., Feng T., Chen C., Yuan D., Kang L. Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population//Xenobiotica. - 2016. - T. 46. - No. 8. - C. 709-714.
DOI: http://dx.doi.org/10.20534/ESR-17-1.2-67-70
Berlay Margarita Vasilievna, Assistant of Department of Forensic Medicine and Law Stavropol State Medical University Kopylov Anatoliy Vasilievich, PhD, head of Department of Forensic Medicine and Law Stavropol State Medical University head of Regional Bureau of forensics Karpov Sergey Mikhailovich, MD, professor, head of the department of neurology, Stavropol State Medical University, Russia Department of neurology, neurosurgery and medical genetics
Regional Bureau of forensics E-mail: Karpov25@rumbler.ru
Current state of the problem sudden infant death at home
Abstract: The "Sudden Infant Death Syndrome" stands for unexpected nonviolent death of apparently healthy chest age child when there is no history or pathomorphological features which can be adequate explanations for death reasons. In Russian Federation, the death rate from this syndrome in the range of 0,06 to 2,8 per 1000 live births. In Stavropol region, average figures are equal to 0,36 per 1000 live births in the period of 2005-2014. Rates of incidence sudden infant death syndrome are similar to the rates of incidence associated with infectious diseases, and as a result of injury or poisoning. Currently paid attention to neurogenic mechanisms of sudden infant death syndrome, as a consequence in combination cranio-spinal birth injury with delayed fatal in infancy, in the period of residual effects.
Keywords: sudden infant death syndrome, cranio-spinal birth injury, a heterogeneous phenomenon, genetic disorders, immunological and endocrine failure.
Introduction. Throughout human history there are descriptions of sudden infants death. Despite the fact that the first one can be found in the Bible, in the king Solomon court scene, today this problem has not lost its acuity and relevance. According to the definition adopted at the second International Conference on sudden infant death (1970), "sudden infant death syndrome (SIDS) is understood as an unexpected non-violent death of an apparently healthy infant, when there are no data of the anamnesis and a patho-anathomical research, adequate for an explanation" [1].
Patho- and morphogenesis of sudden infant death syndrome are a subject of a continuing discussion of clinical physicians and pathomorphologists. Some researchers deny the existence of SIDS, others consider it as a heterogeneous phenomenon developing as a result of genetic disorders or immuno-endocrine insufficiency. It is accepted to distinguish two types according to the mechanism: respiratory and cardiac teratogenesis [2; 3; 4; 5; 6; 7; 18; 22; 23].
It should be noted that pediatricians place emphasis on the presence of neurologic symptomatology at 20-25% of all newborns [8; 9]. Many authors described the clinical manifestations preceding the sudden death of children of the first year of life, which speak of neurologic deficiency and autonomic deregulation. These include: vomiting and choking during feeding or within 30 min after it; apnea; signs of imbalance of the sympathetic system in various sleep phases; hypertonicity of the muscles and hypotension combined with abnormal movements of the body; regurgitation, diaphoresis, hypothermia, transient bradycardia. A number of researchers call the above-stated clinical manifestations life-threatening factors that may have a neurogenic origin, and arise as consequences of a birth trauma of the central and parasympathetic nervous systems [10; 11; 12; 13].
In the majority of industrialized countries the frequency of SIDS makes 0,6-2,0 on 1000 live births [4]. Today the lowest mortality rate from this syndrome is in Japan — 0,09 per 1000 live
