Genotype-phenotype association in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children.

OBJECTIVE: The purpose of this study was to investigate the clinical manifestation of various forms of congenital adrenal hyperplasia (CAH) in children of the Republic of Kazakhstan, depending on their genotype. DESIGN: The study analysed 50 patients diagnosed with CAH from 7 regions of Kazakhstan with different ethnic origins: 35 Kazakhs (70.0%), 8 Russians (16.0%), 2 Turks (4.0%), 2 Ukrainians (4.0%), 2 Uzbeks (4%), 1 Uighur (2%). All the children studied were from 0 to 18 years old, and their average age was 5.7 years ±3.9. In addition, all children were divided into groups depending on the form of the disease according to the phenotypic manifestation of the disease: salt-wasting (SW) and simple virile (SV) forms. Most of the patients suffered from SW - 32 (64.0%), and a smaller group had SV - 18 (36.0%), also one boy with SW was diagnosed with TART syndrome. MEASUREMENTS: 50 Kazakh children with the classical form of CAH were analysed. Depending on the severity of the mutations, patients were divided into 4 groups: zero groups (the most severe mutations), A, B, and C. RESULTS: According to the results of the study, the salt-wasting form of CAH turned out to be more common than the simple virile form. A high correlation was observed in groups with mutations of high and moderate severity - 0 and A, while group C showed a strong variability of the phenotype. Thus, the correspondence between genotype and phenotype decreased along with the decrease in the severity of the disease. CONCLUSIONS: The relationship between the genotype and the phenotype of both forms of CAH exists indirectly, through the activity of the 21-hydroxylase enzyme. Mutations in the CYP21A2 gene affect the level of the synthesized enzyme, which, in turn, determines the degree of hormone production in the blood.

Candidate genes related to acute cerebral circulatory disorders in Preeclampsia in the Kazakh Population.

BACKGROUND: The purpose of this study is to conduct a comparative analysis of the population frequencies of alleles and genotypes of polymorphic variants of coagulation and fibrinolysis genes SERPINE1 rs1799889, ITGA2 rs1126643, THBD rs1042580, FII rs1799963, FV rs6025, FVII rs6046, angiogenesis and endothelial dysfunction PGF rs12411, FLT1 rs4769612, KDR rs2071559, ACE rs4340, GWAS associated with the development of acute cerebral circulatory disorders in preeclampsia, in an ethnically homogeneous population of Kazakhs with previously studied populations of the world. METHODS: The genomic database was analysed based on the results of genotyping of 1800 conditionally healthy individuals of Kazakh nationality ∼2.5 million SNPs using OmniChip 2.5 M Illumina chips at the DECODE Iceland Genomic Center as part of the joint implementation of the project "Genetic Studies of Preeclampsia in Populations of Central Asia and Europe" (InterPregGen) within the 7th Framework Programme of the European Commission under Grant Agreement No. 282540. RESULT: The study discovered a significantly higher population frequency of carrying the unfavorable rs1126643 allele of the ITGA2 gene polymorphism when compared with European populations. The population frequencies of carrying minor alleles of the SERPINE1 (rs179988) and KDR (rs2071559) genes in the Kazakh population were significantly lower when compared with the previously studied populations of Europe and Asia. An intermediate frequency of unfavorable minor alleles between European and Asian populations was found in Kazakhs for gene polymorphisms: FV rs6025, PGF rs12411, and ACE rs4340. The genomic analysis determined the choice of polymorphisms for their further replicative genotyping in patients with ACCD in PE in the Kazakh population. CONCLUSION: The obtained results will serve as a basis for the development of effective methods of early diagnosis and treatment of PE in pregnant women, carriers of unfavorable genotypes.

Population features of alleles and genotypes frequency distribution of polymorphic genetic markers of antipsychotic medications pharmacokinetics in the Kazakh population.

The presented article is relevant, as the main goals of schizophrenia treatment are to achieve a response to psychopharmacotherapy, reduction and stabilization of psychopathological symptoms, qualitative remission, which in general implies the creation of a stable quality of life for the patient. The purpose of the study was to evaluate the population features of the frequency distribution of alleles and genotypes of polymorphic genetic variants of according to genome-wide association studies analysis of pharmacokinetics-associated antipsychotic medications, in an ethnically homogeneous Kazakh population. The research material was deoxyribonucleic acid (DNA) isolated from the peripheral blood of 1,800 conditionally healthy persons of Kazakh nationality. DNA isolation was carried out by the magnetic polyvinyl alcohol magnetic particle separation method. The analysis of the frequency distribution of the studied genotypes in the Kazakh population showed their compliance with the Hardy-Weinberg equilibrium for all studied polymorphisms (p > .05). The obtained results showed that CYP2C19 (rs4244285, rs4986893) polymorphisms occurs in Kazakhs significantly more often than European and a number of Asian populations, which significantly affects the decrease in effectiveness and increases the risk of side complications during therapy with antipsychotic medications in the Kazakh population.

InterPregGen: genetic studies of pre-eclampsia in three continents.

Pre-eclampsia is a major cause of maternal and fetal mortality in pregnancy. The identification of genetic variants which predispose to pre-eclampsia demands large DNA collections from affected mothers and babies and controls, with reliable supporting phenotypic data. The InterPregGen study has assembled a consortium of researchers from Europe, Central Asia and South America with the aim of elucidating the genetic architecture of pre-eclampsia. The MoBa collection is playing a vital role in this collaborative venture, which has the potential to provide new insights into the causes of pre-eclampsia, and provide a rational basis for novel approaches to prevention and treatment.

Genes of Inflammation and Placental Function GWAS Associated with Idiopathic Recurrent Miscarriage in the Kazakh Population.

Background: The loss of two or more pregnancies is considered recurrent miscarriage (RM). One of the causes of this pathology is the occurrence of mutations both in pleiotropic and pathway-specific regulators and in structural genes. The simplest type of such mutations is single nucleotide polymorphisms. Aims: The aim of the study is to study the relationship between gene polymorphisms of anti- and pro-inflammatory cytokines - interferon-gamma (T874A), interleukin (IL1B) (C3954T), IL6 (G572C) and IL10 (G1082A); placental function, apoptosis and angiogenesis - apolipoprotein C-III (APOC3) (G5163C), kinase insert domain receptor (A1719T, G1192A), P53 (Arg72Pro) and signal transducer and activator of transcription 3 (STAT3) (C1697G) with the development of idiopathic RM (iRM) in the Kazakh population. Settings and Design: This was a case-control study. Materials and Methods: Molecular genetic studies were performed by TaqMan using a single site-specific amplification and real-time genotyping method in 302 women with iRM and 300 with normal reproduction. DNA isolation from the biomaterial was carried out using kits containing binding magnetic particles. Both samples were analysed for alleles and genotypes for the studied polymorphisms. Statistical Analysis Used: For statistical data processing, Pearson's criterion, confidence interval (CI) and probability value were taken into account. Results: It was found that the carriage of unfavourable genotypes (G/C, C/C) for the G5163C polymorphism of the APOC3 gene increases the risk of developing iRM by three times (odds ratio = 3.0; 95% CI = 2.24-4.07). Other studied polymorphisms in the genes of ILs, interferon, P53 proapoptotic protein, kinase domain receptor and STAT3 transcription activator were not associated with RM. Conclusion: Significant associations of APOC3 gene genotypes with the development of iRM in the Kazakh population indicate the involvement of the placental system, which is realised by vascularisation defects and defective embryo implantation and leads to early pregnancy termination.

Frequencies of Diagnostically Significant Polymorphisms of Hereditary Breast Cancer Forms in BRCA1 and BRCA2 Genes in the Kazakh Population.

OBJECTIVE: Breast cancer is the most common form of cancer in women in the world with more than 400,000 deaths each year worldwide. The aim of this study is to compare population frequencies of alleles and genotypes of polymorphic variants of BRCA1 and BRCA2 genes associated with breast cancer risk in an ethnically homogenous Kazakh population with previously studied world populations. The material of the study was DNA isolated from peripheral blood of the enrolled population control group, represented by 1800 conditionally healthy individuals of Kazakh ethnicity. METHODS: The DNA extraction was possible with the use of M-PVA magnetic particle separation method on the Prepito (PerkinElmer) automatic analyser for extraction of Chemagic Prepito (Wallac, Finland) nucleic acids using the PrepitoDNACytoPure reagent kit. Statistical calculations of allele and genotype frequencies, significance tests, and non-parametric χ2 analysis were carried out using PLINK software. RESULTS: The results favour for the high genetic heterogeneity of the studied polymorphisms, which reflects the specifics of the Kazakh population structure resulted from complex evolutionary and migration processes, as well as the median geographic location between the populations of Asia and Europe. CONCLUSION: Knowledge of the spectrum and frequency of mutations in BRCA1 and BRCA2 genes predisposing to breast cancer, which are present in varying frequencies in the Kazakh population, will provide a more effective approach to the screening protocol and allow for a faster, less expensive and more accessible genetic testing strategy for the Kazakhstan citizens.

Genes of Predisposition to Childhood Beta-Cell Acute Lymphoblastic Leukemia in the Kazakh Population.

BACKGROUND: Today, acute lymphoblastic leukemia is one of the most common malignant diseases of the hematopoietic system. The genetic predisposition to ALL is not fully explored in various ethnic populations. OBJECTIVE: The study aimed to conduct a comparative analysis of the population frequencies of alleles and genotypes of polymorphic gene variants: immune regulation GATA3 (rs3824662); transcription and differentiation of B cells: ARID5B (rs7089424, rs10740055), IKZF1 (rs4132601); differentiation of hematopoietic cells: PIP4K2A (rs7088318); apoptosis: CEBPE (rs2239633), tumor suppressors: CDKN2A (rs3731249), TP53 (rs1042522); carcinogen metabolism: CBR3 (rs1056892), CYP1A1 (rs104894, rs4646903), according to genome-wide association studies analyses associated with the risk of developing pediatric beta-cell acute lymphoblastic leukemia (B-cell ALL), in an ethnically homogeneous population of Kazakhs with studied populations. METHODS: The genomic database consists of 1800 conditionally healthy persons of Kazakh nationality, genotyped using OmniChip 2.5-8 Illumina chips at the deCODE genetics as part of the InterPregGen 7 project of the European Union (EU) framework program under Grant Agreement No. 282540. RESULTS: High population frequencies of single nucleotide polymorphism (SNP) minor alleles identified for immune regulation genes - GATA3 rs3824662 - 42.5%; transcription and differentiation of B-cells genes - ARID5B rs7089424 - 33.1% and rs10740055 - 48.5%, which suggests their significant genetic contribution to the risk of development and prognosis of the effectiveness of B-cell ALL therapy in the Kazakh population. The significantly lower population frequency of the minor allele G rs1056892 CBR3 gene - 38.6% in the Kazakhs suggests its significant protective effect in reducing the risk of childhood B-cell ALL and the smaller number of cardiac complications after anthracycline therapy. CONCLUSION: The obtained results will serve as a basis for developing effective methods for predicting the risk of development, early diagnosis, and effectiveness of treatment of B-cell ALL in children.

Genetic predisposition to gestational diabetes mellitus in the Kazakh population.

BACKGROUND AND AIMS: The purpose of the study was to conduct a comparative analysis of population frequencies of alleles and genotypes of polymorphic variants of genes for impaired insulin synthesis and associated with insulin signal transduction. METHODS: This investigation uses a genomic database of 1800 conditionally healthy individuals of Kazakh ethnicity, who underwent full genome genotyping using OmniChip 2.5-8 Illumina chips of ∼2.5 million Single Nucleotide Polymorphism at deCODE Iceland Genomic Centre. RESULTS: The highest frequency of carriage of minor A allele - 17.6% rs4607517 polymorphism of Glucokinase gene, unfavorable genotypes A/G - 29.5% and A/A - 3.0% in comparison with European and Asian populations, indicates a contribution of hereditary family forms of Maturity-onset diabetes of the young type 2 to gestational diabetes mellitus in Kazakh population. CONCLUSIONS: The study of the associations of genetic markers of gestational diabetes mellitus will allow timely identification of high-risk groups before and at an early stage of pregnancy, carrying out the necessary effective preventive measures and, in the case of gestational diabetes mellitus development, optimizing the correction of carbohydrate metabolism disorders and predicting outcomes for the mother and the fetus.

Genetic Factors of Idiopathic Recurrent Miscarriage in Kazakh Population.

Background: It seems that 50% of the possible causes of recurrent miscarriage do not have any explainable etiology and they require in-depth etiopathogenesis analysis. The purpose of this research was to study polymorphisms relationship of the immune response genes including Val249Ile CX3CR1 (rs3732379), CT60 G/A CTLA4 (rs3087243), and HLA DQA1, DQB1, DRB1 (major histocompatibility complex, class II) with development of idiopathic form of recurrent miscarriage (iRM) in Kazakh population. Methods: TagMan genotyping for 302 patients with iRM and 300 women with normal reproduction was performed. Molecular genetic studies were carried out by the TaqMan method of unified site-specific amplification and real-time genotyping using test systems. Statistical tests and Chi Square were carried out using PLINK, STATA13 software and p<0.05 was considered statistically significant. Results: It has been shown that carriage of unfavorable genotypes (Val/Ile, Val/Val) by the Val249Ile polymorphism of CX3CR1 gene increases the risk of developing iRM by 1.43 times. Search for associations of genes allelic variants of HLA class 2 complex with iRM revealed 501 allele in DQA1 locus, 0301 in DQB1 locus, 10, 12, 15, 16 alleles in DRB1 locus, which increase the risk of developing iRM in Kazakh population. Conclusion: The highly significant associations of immune response genes with development of iRM in Kazakh population indicate the possible involvement of the immune system interaction of mother cells with syncytiotrophoblast, which is realized by vascular defects and defective embryo implantation, causing termination of pregnancy.

Immunogenetic aspects of idiopathic recurrent miscarriage in the Kazakh population.

There are numerous scientific studies of recurrent miscarriage (RM) with possible causes, such as fetal chromosomal abnormalities, infectious agents, adverse environmental factors, bad habits, anatomical defects, thrombophilic disorders, etc. However, RM causes in 50% of cases remain unknown. These RM cases do not have any explainable etiology, and they require in-depth etiopathogenesis study, thus they are considered idiopathic RM. The purpose of this research is to study polymorphisms relationship of the immune response genes CX3CR1 (rs3732379, Val249Ile), CTLA4 (rs3087243, CT60 G/A), and HLA DQA1, DQB1, DRB1 (major histocompatibility complex, class II) with the idiopathic form of recurrent miscarriage (iRM) development in Kazakh population. Independent replicative TagMan genotyping for 302 patients with iRM and 300 women with normal reproduction was performed. It has been shown that carriage of unfavorable genotypes (Val/Ile, Val/Val) by the Val249Ile polymorphism of the CX3CR1 gene increases the risk of developing iRM by 1.43 times. Search for associations of genes allelic variants of HLA class 2 complex with iRM revealed *501 allele in DQA1 locus, *0301 in DQB1 locus, *10, *12, *15, *16 alleles in DRB1 locus, which increases the risk of developing iRM in Kazakh population with OR from 1.34 to 4.5. As a result of the study, obtained highly significant associations of immune response genes with the development of iRM in the Kazakh population indicate the possible involvement of the immune system interaction of mother cells with syncytiotrophoblast, which is realized by vascularization defects, defective embryo implantation, and leads to early pregnancies' termination.

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

Forensic and population genetic characteristics of 62 X chromosome SNPs revealed by multiplex PCR and MALDI-TOF mass spectrometry genotyping in 4 North Eurasian populations.

X chromosome genetic markers are widely used in basic population genetic research as well as in forensic genetics. In this paper we analyze the genetic diversity of 62 X chromosome SNPs in 4 populations using multiplex genotyping based on multi-locus PCR and MALDI-TOF mass spectrometry, and report forensic and population genetic features of the panel of X-linked SNPs (XSNPid). Studied populations represent Siberian (Buryat and Khakas), North Asian (Khanty) and Central Asian (Kazakh) native people. Khanty, Khakas and Kazakh population demonstrate average gene diversity over 0.45. Only East Siberian Buryat population is characterized by lower average heterozygosity (0.436). AMOVA analysis of genetic structure reveals a relatively low but significant level of genetic differentiation in a group of 4 population studied (FST=0.023, p=0.0000). The XSNPid panel provides a very high discriminating power in each population. The combined probability of discrimination in females (PDf) for XSNPid panel ranged between populations from 0.99999999999999999999999982 in Khakas to 0.9999999999999999999999963 in Buryats. The combined discriminating power in males (PDm) varies from 0.999999999999999792 to 0.9999999999999999819. The developed multiplex set of X chromosome SNPs can be a useful tool for population genetic studies and for forensic identity and kinship testing.