To evaluate a possible role of a novel c.A212G substitution in the PUS3 gene at intellectual disability (ID). Methods. The observed group consisted of the ID Ukrainian family members (parents and two affected children) and the control group-of 300 healthy individuals from general population of Ukraine. Sanger sequencing of the PUS3 gene exon 1 was performed for the family members. Polymorphic variants of c.A212G were analyzed using ARMS PCR. The homology models of wild type and p.Y71C mutant catalytic domains of human Pus3 were generated using the crystal structure of the human Pus1 catalytic domain (PDB ID: 4NZ6) as a template. Results. It was shown that the father of the affected siblings was the c.A212G substitution heterozygous carrier whereas the mother was a wild type allele homozygote, and the exom sequencing result was confi rmed-the affected children are 212G homozygotes. We supposed de novo mutation in the maternal germ line. A low frequency of 212G allele (0.0017) was shown in the population of Ukraine. Homology modelling of the wild type and p.Y71C mutant catalytic domain of human Pus3 revealed that substitution p.Y71C is located in close proximity to its active site. Conclusions. The absence of hypoproteinemia in our patients, homozygous for the 212C allele allows us to assume that the mutation c.A212G PUS3 is rather neutral and cannot be the major cause of ID. However, considering a low frequency of the 212G allele in the population and close localization of p.Y71C substitution to the active site of hPus3 we cannot exclude that the c.A212G mutation in PUS3 may be a modifi er for some pathologies including syndromic ID.
To study the association of polymorphisms of the enzymes genes CYP1A1 (T6235C), first phase, and NAT2 (Ñ481Ò, G590A, G857A), GSTM1 («0»), GSTT1 («0») and GSTP1 (A313G), second phase of the detoxication system, as well as the ADRB2 (C79G) gene variants with the development of bronchial asthma in children. Methods. Polymorphic variants were analyzed using PCR followed by RFLP analysis in 86 healthy individuals and in 114 patients with clinical diagnosis of bronchial asthma. Results. The frequency of gene polymorphic variants of the enzymes of first and second phases of detoxification system as well as the ADRB2 gene was established in the children with bronchial asthma and healthy individuals. Conclusions. Ðolymorphic variants of the genes NAT2 (481Ò), GSTP1 (313G) and ADRB2 (79G) and their combinations in genotype were observed more frequently in the patients with bronchial asthma comparing to the control group, which indicates their involvement in the pathogenesis of asthma in children
We assessed the predictive ability of a combined genetic variant panel for the risk of recurrent pregnancy loss (RPL) through a case-control study. Our study sample was from Ukraine and included 114 cases with idiopathic RPL and 106 controls without any pregnancy losses/complications and with at least one healthy child. We genotyped variants within 12 genetic loci reflecting the main biological pathways involved in pregnancy maintenance: blood coagulation (F2, F5, F7, GP1A), hormonal regulation (ESR1, ADRB2), endometrium and placental function (ENOS, ACE), folate metabolism (MTHFR) and inflammatory response (IL6, IL8, IL10). We showed that a genetic risk score (GRS) calculated from the 12 variants was associated with an increased risk of RPL (odds ratio 1.56, 95% CI: 1.21, 2.04, p = 8.7 × 10−4). The receiver operator characteristic (ROC) analysis resulted in an area under the curve (AUC) of 0.64 (95% CI: 0.57, 0.72), indicating an improved ability of the GRS to classify women with and without RPL. Ιmplementation of the GRS approach can help define women at higher risk of complex multifactorial conditions such as RPL. Future well-powered genome-wide association studies will help in dissecting biological pathways previously unknown for RPL and further improve the identification of women with RPL susceptibility.
Analysis the EPHA1 gene G1475A and G1891A alleles distribution in the population of Ukraine, and to study the protein secondary structure as the first step in the investigation of EPHA1 gene involvement in intellectual disability pathogenesis. Methods. Observation group consisted of 300 individuals, including 164 (54.6 %) male and 136 (45.3 %) female individuals. Polymorphic variants were detected using PCR followed by Kpn1 RFLP analysis for G1475A and ARMS PCR analysis for G1891A. Results. The data concerning EPHA1 genotypes and allelic variants distribution were obtained. The low frequency of 1475A allele (0,012) and the absence of 1891A allele (not previously described) were revealed in the population of Ukrainian. Conclusions. Assays for the detection of EPHA1 gene G1475A and G1891A SNPs based on ARMS and restriction analysis were developed and the preliminary data on distribution of G1475A and G1891A polymorphisms in the population of Ukraine were obtained.
19Recurrent pregnancy loss (RPL) affects nearly 5% of the women of reproductive age. Its heterogeneous 20 and multifactorial nature complicate both diagnosis and treatment, as well as identification of the genetic 21 contribution to RPL. Evidence about the aetiology of RPL is controversial; however, several biological 22 mechanisms have been proposed. Given the current knowledge about the genetic susceptibility to 23 idiopathic RPL, we aimed to evaluate the predictive ability of a combined variant panel to the risk of 24 RPL in the Ukrainian sample of 114 cases and 106 healthy controls. We genotyped variants within the 25 12 genetic loci reflecting the main biological pathways involved in pregnancy maintenance: blood 26 coagulation (F2, F5, F7, GP1A), hormonal regulation (ESR1, ADRB2), endometrium and placental 27 function (ENOS, ACE), folate metabolism (MTHFR) and inflammatory response (IL6, IL8, IL10). We 28 showed that a genetic risk score (GRS) calculated from the 12 variants was associated with an increased 29 risk of RPL (odds ratio 1.56, 95% CI: 1.21,2.04, P=8.7x10 -4 ). The receiver operator characteristic 30 (ROC) analysis resulted in the area under the curve (AUC) of 0.64 (95% CI: 0.57, 0.72), indicating an 31 improved ability of the GRS to classify women with and without RPL. In summary, implementation of 32 the GRS approach can help defining women at higher risk to complex multifactorial conditions such as 33 RPL. Future well-powered genome-wide association studies will help in the dissection of biological 34 pathways not hypothesised previously for RPL and further improve the prediction and identification of 35 those at risk for RPL. 36 37 38
Aim.To investigate a possible association of the EPHA1 gene polymorphism with mild intellectual disability (ID). Methods. The group of patients with mild (IQ score between 50 and 70) idiopathic intellectual disability consisted of 65 individuals including 41 (63.1 %) males and 24 (36.9 %) females. The control group consisted of 250 healthy volunteers from different regions of Ukraine. The genotyping was performed using PCR followed by RFLP analysis for rs11768549, rs11767557, rs11771145 and ARMS PCR analysis for novel c.1891G>A EPHA1 gene mutation. Results. The data concerning the EPHA1 genotypes and allelic variants distribution in ID patients and control group were obtained. Statistical analysis showed a signifi cant association of minor rs11768549-A allele (OR = 3.96, 95 % CI = 1.13-13.89) and wild-type rs11767557-T (OR = 1.99, 95 % CI = 1.18-3.37) and rs11771145-G (OR= 1.55, 95 % CI = 1.02-2.37) alleles with a higher risk of mild ID development (p < 0.05 for all). Conclusions. Our results suggest that SNPs (rs11768549, rs11767557, rs11771145) in the EPHA1 gene are associated with idiopathic mild intellectual disability. Therefore, we propose the EPHA1gene as a new candidate gene and the polymorphisms rs11768549, rs11767557, rs11771145 as new markers of genetic susceptibility for intellectual disability. K e y w o r d s: EPHA1 gene, intellectual disability, polymorphism, genetic susceptibility.
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