Polymorphic Variants Of Genes Research Articles

Polymorphic variants of the <i>PPP1R21</i> gene associated with the level of sex hormone-binding globulin and the risk of various stages of breast cancer

Aim. To assess the relationship of polymorphic gene variants associated with the level of sex hormone-binding globulin (SHBG) according to genome-wide association studies (GWAS) with the risk of stage I–II and stage III-IV breast cancer. Materials and methods. A comparative genetic analysis was carried out on samples of patients with breast cancer: 254 patients with stages I–II and 91 with stages III–IV, and 1140 females of the control group. The paper considers 4 single nucleotide substitutions associated with the level of circulating SHBG according to GWAS: g.107546375AG PRMT6 (rs17496332), g.27519736TC GCKR (rs780093), g.48419260TC PPP1R21 (rs10454142), g.98364050TA BAIAP2L1 (rs3779195). Results. Differences in the involvement of polymorphic variants of SHBG candidate genes in the development of stages I–II and III–IV breast cancer were revealed. The rs10454142 TC polymorphic variant in the PPP1R21 gene is associated with the risk of stage I–II breast cancer: women with an allelic variant of this locus have a higher risk of early-stage disease (T/T vs. T/C vs. C/C, odds ratio 1.35, 95% confidence interval 1.05-1.75; p=0.021; ppermutat=0.027). Also, an increase in the number of C alleles in the female genotype increased the risk of stage I–II breast cancer by 17–18% per allele. There were no associations of polymorphic variants of SHBG candidate genes with the risk of severe disease (stage III–IV). The single nucleotide substitution rs10454142 TC in the PPP1R21 gene and the single nucleotide polymorphisms strongly linked to it are functionally significant (located in the regions of enhancers and promoters) in the epithelial and myoepithelial cells of the mammary gland and liver, affect the level of genome methylation, and are associated with the level of GTF2A1L gene expression.

New in the prevention of undeveloped pregnanc

The problem of non-developing pregnancy (NB) remains relevant due to the rather wide spread of this complication and is due to the search for prognostically significant causes of this pathology, the development of adequate prevention of the detected disorders [1–4]. Polymorphic variants of folate genes lead to excessive accumulation of HC in the blood and hypomethylation of DNA, which contributes to an increase in early miscarriage (the frequency of this pathology is 20–25% of all pregnancies). Carrying out periconceptional prophylaxis with high doses of folic acidreduces the level of free HC in the blood, but this technique is effective only when it begins 3 months before conception and in the early stages of embryo and fetus development (up to 12 weeks). The evaluation of laboratory and clinical data in the course of the study confirmed the effectiveness of the use of folic acid at a dose of 800 mcg in a high risk group for the development of NB (pregnant women with hyperhomocysteinemia (GHZ)) 16 weeks before conception and 12 weeks after conception.

Polymorphism rs117585797 of the ANO2 gene as a genetic marker of a high risk of developing combined proliferative diseases of the uterus in women with endometriosis

Introduction. Endometriosis is a common gynecological disease that has important socio-economic significance for both sick women, their families, and society as a whole. It is often combined with other hyperplastic diseases of the uterus.Aim. To analyze the involvement of GWAS-significant polymorphic loci of sex hormone genes in the development of combined proliferative diseases of the uterus in women with endometriosis. Materials and methods. The sample for the study included 395 women, including 103 patients with isolated endometriosis and 292 patients with endometriosis in combination with uterine fibroids and/or endometrial hyperplasia. All women underwent molecular genetic testing of seven GWAS-significant single-nucleotide polymorphic variants of sex hormone genes (rs34670419, rs11031005, rs11031002, rs148982377, rs112295236, rs1641549, rs117585797). The analysis of associations of polymorphic variants with the risk of developing combined proliferative diseases of the uterus in patients with endometriosis was carried out. To assess the functional effects of SNP associated with the formation of combined proliferative diseases of the uterus in women with endometriosis, the online programs HaploReg and Gtex Portal were used.Results and discussion. Genetic variant A rs117585797 of the ANO2 gene is a risk factor for the development of combined proliferative diseases of the uterus in women with endometriosis (p = 0.05, рperm = 0.05, OR = 4.29). According to the data obtained in silico, the rs117585797 locus localized in the intron of the ANO2 gene affects the affinity of the regulatory DNA motif to the transcription factors Crx and Gsc.Conclusions. Polymorphic locus rs117585797 of the ANO2 gene is associated with a high risk of the formation of combined proliferative diseases of the uterus in patients with endometriosis.

Association of polymorphic variants of cytokines genes, endothelial growth factor and matrix metalloproteinases with the development of uterine fibroids among russian women

One of the factors in the development of uterine fibroids is a genetic predisposition to its occurrence in some women, but the real molecular genetic mechanisms of this phenomenon remain unknown. Aim of the study was the distribution analysis of gene polymorphism of cytokines TNFα, IL-1β, IL-4, IL-6, IL-10, factors of angiogenesis (vascular endothelial growth factor, VEGF) and remodeling of extracellular matrix (metalloproteinases MMP2, MMP3, MMP9), which are associated with their levels. Material and methods. Genotyping was performed by real-time PCR using commercial test systems SYBR GreenI (Litech, Russia) and TaqMan (Syntol, Russia) in accordance with the instructions of the developer. Cytokine content in blood serum was determined by flow cytometry using microspheres coated with monoclonal antibodies to cytokines (Bio-Plex ProTM Human Cytokine 27-plex Assay), according to the instructions for Bio-Plex 200 (Bio-Rad Laboratories, USA).To evaluate the results obtained, in addition to the generally accepted methods of statistical processing for case – control studies, computational methods of bioinformatics were used for comparative analysis of the diagnostic value of various combined genetic traits. Results. It was shown that the maximum odds ratio value of uterine fibroids development are combined genetic traits that include representatives of all four regulatory factors: cytokines with pro-inflammatory activity, cytokines with anti-inflammatory activity, vascular endothelial growth factors and metalloproteinases (p = 0.002). Conclusions. The presented data reveal the real mechanisms of manifestation of the genetic predisposition of individual women to the uterine fibroids development, associated with the presence of polymorphism of certain genes in their genome, which provide features of the structure of cytokine networks with the predominance of certain activities in the regulation of tissue processes in the uterus. In addition to purely scientific interest, these results indicate the real possibility of their clinical application in the form of prognostic criteria with a certain level of prognostic significance.

Fatty acid composition of erythrocyte membranes in carries of rs174544 polymorphism of FADS1 gene and rs174583 polymorphism of FADS2 gene from central region of the Russian Federation before and after supplementation of their diet with ω-3 PUFAs

Numerous publications have demonstrated that polymorphisms in FADS1 and FADS2 gene cluster influence the levels of long chain polyunsaturated fatty acids (LC PUFAs) synthesized in the body from essential precursors. They can be consumed through the diet as well. These LC PUFAs perform important plastic and regulatory functions in the body. The associations between the polymorphisms of FADS genes and the fatty acid (FA) composition of the body with some inflammatory and chronic diseases were shown. To date, very few studies in the Russian Federation researched the distribution of polymorphic variants in FADS1 and FADS2 genes and no studies examined the effects of these polymorphisms on the level of FAs in tissues.So, the purpose of this paper was to study the frequency of genotypes and alleles of the rs174544 polymorphism of the FADS1 gene and the rs174583 polymorphism of the FADS2 gene and their influence on the FA composition of erythrocyte membranes in residents of the Central region of the Russian Federation (RF). Additionally, the effect of ω-3 PUFAs fortified food products on this composition was examined. MethodsThe study included 70 volunteers aged 23–69 years from Moscow region who provided informed consent. They were genotyped for rs174544 polymorphism of FADS1 gene and rs174583 polymorphism of FADS2 gene by real-time PCR. The participants of the study consumed fruit or vegetable smoothies enriched with either vegetable (chia seeds flour) or animal (fish oil flour) sources of ω-3 PUFAs for 1 month. The fatty acid composition of erythrocyte membranes in some of the volunteers was analysed using gas-chromatography before and after fortification of their diet with ω-3 PUFAs. Statistical analysis was performed using SPSS 23. ResultsThe frequency of genotypes and alleles of polymorphisms studied were similar to those published for the European region. For rs174544, the genotype frequencies were CC (61%), CA (29%), and AA (10%), frequency of allele A was 24%. For rs174583, the genotype frequencies were CC (51%), CT (39%), and TT (10%), frequency of allele T was 29%. Carriers of minor alleles of both polymorphisms studied had significantly higher levels of ω-6 and ω-3 LC PUFAs in erythrocyte membranes compared to those carrying other genotypes. This differs from the results of other studies where carriers of minor alleles as were shown to be slow converters of precursors to LC PUFAs. The reason of the discrepancy was most likely associated with the obesity and dietary preferences of our study participants who carry the minor alleles. Over the period of one-month consumption of food sources providing an additional intake of either 2 g/day ω-3 PUFAs from fish oil or 6.5 g/day of ω-3 PUFAs from chia seed flour markedly reduced the incorporation of ω-6 PUFAs into erythrocyte membranes in carriers of minor alleles. Additionally, there was an increase in the content of saturated palmitic acid in the membranes that noticeably changed the fatty acid composition of erythrocyte membranes. ConclusionOur results confirm the observation that blood fatty acid composition related to polymorphisms of FADS gene is highly influenced by BMI. The incorporation of ω-6 PUFAs into erythrocyte membranes decreases when the diet is fortified with ω-3 PUFAs. This decrease can help reduce the formation of pro-inflammatory eicosanoids and the risk of various inflammatory and chronic diseases, especially in carriers of minor alleles of the genetic polymorphisms studied.

Associations between the VDR Gene rs731236 (TaqI) Polymorphism and Bone Mineral Density in Postmenopausal Women from the RAC-OST-POL.

Postmenopausal osteoporosis is not only related to hormonal factors but is also associated with environmental and genetic factors. One of the latter is the polymorphism of vitamin D receptor (VDR). The aim of the reported study was to comprehensively analyze the VDR gene polymorphic variants rs731236 (TaqI), rs1544410 (BsmI) and rs7975232 (ApaI) in the Polish population of postmenopausal women. The study group consisted of 611 women after menopause (their median age was 65.82 ± 6.29 years). Each of them underwent bone densitometry (DXA) of the non-dominant femoral neck and total hip with a biochemical analysis of vitamin D3 serum concentration and genotyping of the above-mentioned single nucleotide polymorphisms (SNPs); the obtained results were analyzed in the aspect of waist circumference (WC), body mass index (BMI) and past medical history. The genotype prevalence rates of all SNPs were compatible with Hardy-Weinberg equilibrium (p > 0.050). Out of the studied polymorphisms, only rs731236 genotype variants affected DXA, with AG heterozygotes showing the worst bone parameters. Neither patient age nor vitamin D3 concentration, BMI, WC or comorbidities was associated with rs731236 genotype. Out of the polymorphisms studied, only rs731236 genotypes differed among the DXA results, while the AG heterozygotes were characterized by the lowest median bone mineral density.

Two variants of NOD2 gene polymorphisms and their relation with Tuberculosis in Andhra Pradesh population, India

IntroductionTuberculosis (TB) remains one of the major infectious diseases even after the emergence of new diseases in the present era. Few polymorphic gene studies on Nucleotide-binding Oligomerization Domain 2 (NOD2) gene reveal that they are associated with the risk of TB in some populations. An attempt has been made to find such association in the Andhra Population of India. MethodsTwo variants (rs2066847 and rs2066842) of NOD2 gene were analyzed genotypically using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR–RFLP) analysis, on TB patients and negative controls. Statistical tests like Chi-square, Odds ratio (OR) and 95 % Confidence Interval (CI) were considered to evaluate the susceptibility of the NOD2 gene polymorphism with TB. ResultsThe analysis of the results obtained revealed that the two variants of NOD2 gene rs2066842 (OR = 1.278; 95%CI = 0.436–3.746; P = 0.653), and rs2066847 (OR = 0.809; 95%CI = 0.015–41.227; P = 0.915) do not attribute to the risk of TB in this population. ConclusionThe final results of the study reveal that these two polymorphisms of the NOD2 gene do not show an association with the susceptibility of TB in the Andhra Population of India. Further studies in different ethnic groups with larger sample sizes are necessary to evaluate the proper associative gene expression of NOD2 with TB.

The Genetic Markers of Knee Osteoarthritis in Women from Russia.

Osteoarthritis is a chronic progressive joint disease that clinically debuts at the stage of pronounced morphologic changes, which makes treatment difficult. In this regard, an important task is the study of genetic markers of the disease, which have not been definitively established, due to the clinical and ethnic heterogeneity of the studied populations. To find the genetic markers for the development of knee osteoarthritis (OA) in women from the Volga-Ural region of Russia, we conducted research in two stages using different genotyping methods, such as the restriction fragment length polymorphism (RFLP) measurement, TaqMan technology and competitive allele-specific PCR-KASPTM. In the first stage, we studied polymorphic variants of candidate genes (ACAN, ADAMTS5, CHST11, SOX9, COL1A1) for OA development. The association of the *27 allele of the VNTR locus of the ACAN gene was identified (OR = 1.6). In the second stage, we replicated the GWAS results (ASTN2, ALDH1A2, DVWA, CHST11, GNL3, NCOA3, FILIP/SENP1, MCF2L, GLT8D, DOT1L) for knee OA studies. The association of the *T allele of the rs7639618 locus of the DVWA gene was detected (OR = 1.54). Thus, the VNTR locus of ACAN and the rs7639618 locus of DVWA are risk factors for knee OA in women from the Volga-Ural region of Russia.

SERPINE-1 gene polymorphism in patients with cardiovascular diseases

Currently, the issues of recurrent course of cardiovascular diseases are given great importance. Today, there is a search for more and more new factors and causes, including genetic ones, that contribute to the increase in the incidence of circulatory system diseases. The study of polymorphic variants of hemostasis system genes made it possible to study the molecular mechanisms underlying the causes of cardiovascular complications. Polymorphism of theSERPINE-1gene, encoding plasminogen activator inhibitor-1, is associated with the occurrence of cardiovascular diseases. This literature review examines the influence ofSERPINE-1gene polymorphism and the concentration of the plasminogen activator inhibitor-1 it encodes on the development and severity of circulatory system diseases; as well as the role of plasminogen activator inhibitor-1 as one of the indicators reflecting the antifibrinolytic potential of the blood. Taking into account the opinion of most authors, we can conclude that the polymorphism of theSERPINE-1gene and its homozygous variant 4G/4G, due to which the synthesis of plasminogen activator inhibitor-1 is increased, is an unfavorable predictor of many pathological processes. However, most of the data have been obtained on the association of theSERPINE-1gene polymorphism with cardiovascular diseases, where, according to most authors, the 4G/4G genotype is a prognostically negative variant. However, a number of researchers believe that the heterozygous 5G/4G variant is likely associated with the occurrence of cerebral ischemia. The inconsistency of the data obtained, ofcourse, requires further study of the characteristics of theSERPINE-1gene polymorphism in various pathological conditions, which is an important prerequisite for understanding the mechanisms of a number of diseases. To prepare the review, a literature search method in PubMed databases for the period 2013–2023 was used.

Changes in <i>DNMT1</i> expression as a marker of epigenetic regulation disturbanses in multiple sclerosis patients

BACKGROUND: Multiple sclerosis is a chronic neurodegenerative autoimmune disease characterized by the presence of foci of inflammation and demyelination in the central nervous system. The initiation of pathological processes in multiple sclerosis is caused by a complex interaction of genetic factors, unfavorable environmental factors and epigenetic influences. Progressive neurological symptoms caused by axonal conduction disorders, axonal death and neurodestruction lead to a significant decreased patients’ quality of life and disability. The search for a new markers to improve diagnostic and therapeutic methods, including taking into account the genetic background and epigenetic interactions, is an urgent task.
 AIM: The work was aimed to study the changes in DNMT1 mRNA expression in multiple sclerosis patients with different disease duration, to analyze methylation of DNMT1 promoter, and compare the changes in the level of DNMT1 expression with the homocysteine content in the blood, and the presence of polymorphic variants in genes coding the key folate cycle enzymes.
 MATERIALS AND METHODS: The level of DNMT1 mRNA expression in peripheral mononuclear blood cells was assessed by reversed transcription followed by polymerase chain reaction. Fluorescent polymerase chain reaction followed by methyl-sensitive analysis of high-resolution melting curves was used to analyze methylation of the DNMT1 promoter. The content of homocysteine in the blood was determined by chemiluminescence immunoassay. The real-time polymerase chain reaction was used for genotyping by polymorphism of folate cycle genes; the fluorescent probes with the LNA modifications were used to discriminate alleles.
 RESULTS: It has been shown that in multiple sclerosis patients, including those at the onset of the disease, the level of DNMT1 mRNA expression is significantly lower than in the control group. No relationship was found between the decrease in DNMT1 expression and the level of promoter methylation. Strong positive relationship between the level of DNMT1 mRNA expression and homocysteine content in patients with multiple sclerosis and the combined effects of the genotypes of MTR A2756G and MTHFR C677T polymorphism on the expression of DNMT1 have been shown. These findings suggest that genetically determined features of folate metabolism may contribute to the disruption of epigenetic regulation in multiple sclerosis.
 CONCLUSIONS: The obtained results indicate the promise of research aimed to identifying the factors causing epigenetic changes in multiple sclerosis. Studying the mechanisms of the folate cycle genes polymorphic variants contribution to the pathogenesis of multiple sclerosis could be one of the possible ways to improve diagnostic and therapeutic approaches.

Polymorphisms of genes of interleukin-6 and alpha-1 chain of collagen type 1 in postmenopausal women with knee osteoarthritis

BACKGROUND: To date in the Russian Federation insufficient attention has been paid to the study of IL6 and COL1A1 gene polymorphisms role in the development of knee osteoarthritis. And the results of the single carried out to date studies, devoted to the research of polymorphic variants of the above genes influence on the osteoarthritis development, are insufficient for substantiated conclusions.
 AIM: To study the frequency of alleles and genotypes of the IL6 gene rs1800795 polymorphism and COL1A1 gene rs1107946 and rs1800012 polymorphisms in postmenopausal women with knee osteoarthritis.
 MATERIALS AND METHODS: The results of 157 postmenopausal women survey with knee osteoarthritis were selected and analyzed. The control group consisted of 326 women of the same age without signs of joint disease. The study of polymorphisms rs1800795, rs1107946 and rs1800012 was performed by real-time polymerase chain reaction.
 RESULTS: The conducted studies showed that in the general group of examined women the frequency of all three studied polymorphisms genotypes registration corresponded to the Hardy-Weinberg law. An uneven (p = 0.043) distribution of rs1800795 polymorphism genotypes was found in the group of women with osteoarthritis and in the control group in the study of the IL6 gene polymorphic variants frequency detection. This difference was due to more frequent GG genotype registration of the above polymorphism (odds ratio = 1.75; 95% confidence interval: 1.12–2.72; p = 0.021) among women with knee osteoarthritis. Associations of rs1107946 and rs1800012 COL1A1 gene polymorphisms were not found (p 0.05).
 CONCLUSIONS: An association between GG genotype of the IL6 gene rs1800795 polymorphism and knee osteoarthritis in postmenopausal women has been established. Genotypes and alleles of COL1A1 gene rs1107946 and rs1800012 polymorphisms were not associated with joint disease.

Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience

BackgroundLong-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. MethodsWe selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients (“case series”), who experienced TIC, were compared to 37 “control group” matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. ResultsIn this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. ConclusionReal-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren’t available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Association of polymorphic variants of genes of xenobiotic biotransformation enzymes with susceptibility to pulmonary tuberculosis, taking into account gender features

Aim of the study was to investigate susceptibility to pulmonary tuberculosis in men and women depending on polymorphism of genes of xenobiotic biotransformation enzymes NAT2 (590G> A (rs1799930)), CYP2E1 (9896C> G (rs2070676)), ABCB1 (3435T> C (rs1045642)), GSTM1 (E/D) and GSTT1 (E/D). Material and methods. The study included 335 patients with pulmonary tuberculosis aged 18 to 65 years (212 patients with newly diagnosed pulmonary tuberculosis and 123 people with chronic pulmonary tuberculosis receiving intensive phase of chemotherapy). Statistical data processing was carried out on a personal computer using IBM SPSS Statistics 26 and MS Excel 2013 software packages. The control group consisted of relatively healthy individuals without chronic diseases. Genotyping of polymorphisms NAT2 (590G>A (rs1799930)), CYP2E1 (9896C>G (rs2070676)), ABCB1 (3435T>C (rs1045642)) and extended deletions GSTM1 (E/D), GSTT1 (E/D) was performed using real time PCR. Results. It has been established that the genotype EЕ of GSTT1 gene identified in 89.1 % men was statistically significantly associated with increased susceptibility to pulmonary tuberculosis, while the genotype DD of the GSTT1 gene (10.9 % cases) was associated with reduced susceptibility. A similar trend is observed in women: the greatest susceptibility to pulmonary tuberculosis is characteristic for the genotype ЕЕ GSTT1 gene (87.2 %), the least (12.8 %) – for the DD genotype. Conclusions. It is advisable to introduce genotyping of genes of xenobiotic biotransformation enzymes into the practice of a phthisiologist in order to develop measures to improve the effectiveness of prevention and treatment of patients with pulmonary tuberculosis.

ГЕНЫ НЕЙРОМЕДИАТОРНЫХ СИСТЕМ МОЗГА, ДЕТЕРМИНИРУЮЩИЕ ПСИХОЭМОЦИОНАЛЬНЫЙ СТАТУС ЧЕЛОВЕКА

Background. In recent decades, there has been a significant interest worldwide in the clarification of the genetic mechanisms of the human psychoemotional status. The identification of genetic markers associated with psychoemotional status expands the possibilities of considering individual characteristics in career guidance, as well as in choosing methods of individual psychotherapy. Purpose. To identify the most informative polymorphic variants of genes associated with the human psychoemotional status. Material and methods. Psychological and molecular genetic testing was conducted among representatives of two groups of the Belarusian population: a control group (518 people) and a group of patients with personality disorders and deviant behavior (534 people). The following psychological testing methods were used: PSS-10 and PSS-14 – Russian-language versions of the Perceived Stress Scale-10, HADS-T – a test that measures symptoms of anxiety, and HADS-D – a test that measures symptoms of depression. DNA isolated from buccal epithelial cells was used as biological material for molecular genetic research. Genomic DNA was isolated using an extraction kit from Primetech LLC (Belarus). DNA concentration was assessed using a Qubit fluorimeter (Invitrogen, USA), as well as a Promega GloMax® Explorer Multimode Microplate Reader (USA). Results. A total of 33 polymorphic variants of genes of the brain neurotransmitter systems have been studied. 8 polymorphic variants were found to have statistically significant different frequencies in the studied groups, and 3 ones to have frequencies that differ at the level of tendency. Conclusions. The results obtained made it possible to form a panel of the most informative polymorphic variants of genes of the brain neurotransmitter systems, which can be used to determine individual psycho-emotional characteristics.

Pre-pregnancy training of women with early pregnancy loss and adenomyosis, taking into account folate cycle gene polymorphisms

Polymorphisms in folate cycle genes (methylene tetrahydrofolate reductase – MTHFR, methionine synthase reductase – MTRR and methionine synthase – MTR) and associated hyperhomocysteinemia and folate deficiency play an important role among multiple genetic causes early pregnancy loss.The results of studies examining the influence of polymorphic variants of the folate cycle genes in women with pregnancy losses are quite contradictory. It has been proven that prescribing folic acid preparations or in combination with other vitamins and trace elements at the stage of preparation for pregnancy and during pregnancy significantly reduces the risk of miscarriage and pregnancy loss, is an important prevention of defects in the development of the nervous system of the fetus and disorders of the autistic spectrum in newborns and children. Adenomyosis remains a complex and urgent problem in obstetrics and gynecology, as today there is convincing evidence of the negative impact of adenomyosis both on fertility and on the course and outcomes of pregnancy.The objective: to study the prevalence of folate cycle gene polymorphisms and to assess the effectiveness of vitamin-mineral complex use in the pre-gravid preparation taking into account the genetic peculiarities of folate metabolism in women with early pregnancy loss (EPL) and adenomyosis.Materials and methods. Data from the examination at the stage of pre-gravid preparation of 40 women with early pregnancy loss – EPL (5–13 weeks of gestation) and adenomyosis, which were included in the main group, and 34 women with adenomyosis without a history of EPL (control group) were analyzed.Resuts. In 73,5% of women of the control group, the C/C genotype of the MTHFR 677 C>T gene prevailed, in women with EPL and adenomyosis, a significant increase in the frequency (50%) of the heterozygous polymorphism for this C/T allele of the MTHFR 677 gene and a decrease in the frequency of detection of neutral A/A allele and increased frequency (80%) of MTHFR 1298 gene allele polymorphism (A/C and C/C). In women with EPL and adenomyosis, a significant increase in homocysteine (12,8±2,3мμmol/l) and a deficiency of folic acid (5,0±0,9 ng/ml) in blood serum compared to reference values were found.Conclusions. The use of vitamin-mineral complex, which includes betaine (200 mg), cystine (200 mg), zinc (10 mg), niacin (16 mg), folic acid (in the form of 5-MTHF-glucosamin – 400 mcg), vitamin B12 (in the form of methylcobalamin – 2.5 mcg), vitamin B6 (1.4 mg) and riboflavin (1.4 mg), 1 tablet 1-2 times a day for 3 months for the pre-gravid preparation leaded to significant decrease of homocysteine concentration, normalization of folic acid concentration. This formed favorable conditions for pregnancy course and for risk reduction of possible obstetrical complications.

Relationship of calcium-sensing receptor gene polymorphism CASR rs 1042636, CASR rs 1802757, and cinacalcet response among Egyptian hemodialysis patients with secondary hyperparathyroidism

Introduction: Secondary hyperparathyroidism (SHPT) is a common complication associated with morbidity and mortality among hemodialysis (HD) patients. Objectives: The current study aims to evaluate the frequency of CASR gene polymorphism variants related to parathyroid hormone (PTH) regulation (CASR rs1042636 and CASR rs1802757) and to test the hypothesis that single nucleotide polymorphisms (SNPs) in the CASR gene alter the response to cinacalcet among Egyptian HD patients with SHPT. Patients and Methods: A case-control study that included 50 HD patients with intact parathyroid hormone (iPTH) ≥300 pg/mL treated with cinacalcet for a 6-month duration and 40 healthy volunteers as a control group. Eligible patients were recruited from Ain Shams university hospitals. Blood samples were collected from patients and controls to assess allele frequencies of CASR gene polymorphism variants using real-time polymerase chain reaction (PCR), corrected calcium (Ca), phosphorus (P), Ca×P product, iPTH level, and alkaline phosphatase before and after treatment. HD patients were categorized into two groups based on the reduction percentage; responders’ patients (iPTH ≥20%) and non-responders to cinacalcet treatment. Results: Of 50 HD patients, 48 (96%) carried the rs1042636 AA wild gene, while only two (4%) carried the rs1042636 AG mutant gene, 42 (87.5%) carried the rs1802757 CC wild genotype, and 6 (12.5%) carried the CT mutant genotype. The minor alleles T and G were (6.3% and 2%) respectively, with no statistically significant difference between the patient and control groups regarding the CASR genotypes or alleles distribution. There was no significant difference between responders and non-responder’s patient groups regarding CASR genotypes or allele frequencies. Moreover, no significant correlation between CASR genotypes or alleles to delta change of Ca, P, Ca×P product, or PTH was seen. However, CASR rs1802757 CT mutant genotype was associated with a significant reduction in alkaline phosphatase levels after treatment. Conclusion: There is no significant association between the gene polymorphism CASR rs1042636 or CASR rs1802757 and the reduction in PTH levels as a response to cinacalcet treatment among Egyptian HD patients with SHPT.

The impact of polymorphic variants of interferon receptor genes on COVID-19 severity and antibiotic resistance

Single nucleotide substitutions in gene sequence associated with conformational changes in protein receptor or in expression of interferon receptors may explain variations in human susceptibility to infection and severity of COVID-19 along with other well-known risk factors. The study aimed to investigate associations between polymorphic variants of interferon receptor genes, COVID-19 severity and prevalence of antibiotic resistance genes in the gut microbiota. Materials and methods. The study was conducted using a random sample of Arkhangelsk population aged 42 to 76 years (n = 305). The research involved gathering COVID-19 data from the Federal Register, conducting blood tests for SARS-CoV-2 antibodies and polymorphic interferon receptor gene variants, and identifying antibiotic resistance genes in stool samples. Results. During the first 12–15 months of the COVID-19 pandemic, 17.4% of the study participants had symptomatic COVID-19, while 32.8% were asymptomatic. By the Autumn of 2022, symptomatic COVID-19 cases rose up to 36.4%, while asymptomatic cases increased to 61.3%. We reveal an association between the CC genotype of the IFNAR1 gene rs2257167 variant, the presence of the T allele of IFNAR2 gene rs2229207 variant, the CCTT haplotype and symptomatic COVID-19. The GCTC haplotype was associated with pneumonia and COVID-19 severity. In November 2022, macrolide resistance genes were observed in 98.4% of cases, whereas those to beta-lactams and glycopeptides — in 26.9% and 13.8% cases, respectively. Resistance to three classes of antibiotics was observed in 4.9% and was more frequently detected in individuals with the ССТТ haplotype. Genes encoding beta-lactamases were more often found in individuals with the GCTC haplotype, those who had COVID-19 with pneumonia and those who received hospital treatment. Glycopeptide resistance genes were associated with the CC genotype of the rs2257167 variant of IFNAR1 gene. Conclusion. We identified genetic determinants of susceptibility, symptomatic infection and COVID-19 severity. The associations between polymorphic variants of interferon receptor genes and COVID-19 severity can be used to identify people with a genetic predisposition to severe infection and to determine priority groups for vaccination, including the prevention of antibiotic resistance in complicated course of viral infections.

Polymorphic Variants of SCN5A Gene (rs41312433 and rs1805124) Associated with Coronary Artery Affliction in Patients with Severe Arrhythmias.

A group of 32 unrelated individuals, aged 63 ± 12 years, was included in the study. All the patients were examined, diagnosed and treated with an implantable cardioverter defibrillator at the Department of Internal Cardiology Medicine, Faculty Hospital Brno. The control group included 87 persons of similar age without afflicted coronary circulation, which was confirmed coronagraphically. Genomic DNA was extracted from samples of peripheral blood according to the standard protocol. Two SCN5A polymorphisms-IVS9-3C/A (rs41312433) and A1673G (rs1805124, H558R)-were examined in association with coronary artery stenosis in the patients. In the case-control study, no significant differences in genotype distribution/allelic frequencies were observed for IVS9-3c>a and A1673G gene polymorphisms between patients with severe arrhythmias and healthy persons. The distribution of SCN5A double genotypes was not significantly different among different types of arrhythmias according to their ejection fraction in arrhythmic patients (p = 0.396). The ventricular arrhythmias with an ejection fraction below 40% were found to be 10.67 times more frequent in patients with multiple coronary stenosis with clinically valid sensitivity, specificity and power tests. In the genotype-phenotype study, we observed a significant association of both SCN5A polymorphisms with the stenosis of coronary vessels in the patients with severe arrhythmia. The double genotype of polymorphisms IVS9-3C/A together with A1673G (CCAA) as well as their simple genotypes were associated with significant multiple stenosis of coronary arteries (MVS) with high sensitivity and specificity (p = 0.05; OR = 5 (95% CI 0.99-23.34); sensitivity 0.70; specificity 0.682; power test 0.359) Moreover, when a concrete stenotic coronary artery was associated with SCN5A genotypes, the CCAA double genotype was observed to be five times more frequent in patients with significant stenosis in the right coronary artery (RCA) compared to those without affliction of this coronary artery (p = 0.05; OR = 5 (95% CI 0.99-23.34); sensitivity 0.682; specificity 0.700; power test 0.359). The CCAA genotype was also more frequent in patients without RCA affliction with MVS (p = 0.008); in patients with ACD affliction but without MVS (p = 0.008); and in patients with both ACD affliction and MVS compared to those without ACD affliction and MVS (p = 0.005). Our study presents a highly sensitive and specific association of two polymorphisms in SCN5A with significant coronary artery stenoses in patients with potentially fatal ventricular arrhythmias. At the same time, these polymorphisms were not associated with arrhythmias themselves. Thus, SCN5A gene polymorphic variants may form a part of germ cell gene predisposition to ischemia.

Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and β-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

Association of polymorphic variants of HHIP, ADRB2 and IL-33 genes with clinical manifestations of bronchial asthma in children

Objective. To study the association of polymorphic variants HHIP, ADRB2 and IL-33 genes with phenotypes of clinical course of bronchial asthma in children and effective treatment. Materials and methods. 90 patients aged from 5 to 17 with the diagnosis of bronchial asthma were included in the investigation. Diagnostic procedures were carried out in all the patients. They included the study of genetic polymorphism of HHIP, ADRB2 and IL-33 genes to establish the association with the clinical phenotypes, findings of laboratory and instrumental study determining the course of bronchial asthma and the degree of its control. Results. The study of polymorphism of HHIP, ADRB2 and IL-33 genes in children with bronchial asthma with different phenotypes of the disease revealed the association of genetic polymorphism with the severity of course of the disease as well as concomitant diseases. It was determined that allele T of genetic variant rs12504628 (TC) of HHIP gene reduces the risk of a severe course of BA. Its protective role in the development of drug allergy was also proved. Genotype AA of ADRB2 gene is associated with reduced risks of the development of congenital defects of the tracheobronchial tree in BA. Polymorphic variants in the 4th and 6th exon of IL-33 gene are more frequently associated with moderate and severe course of asthma and base substitution in the 4th and 6th exon are associated with the severe course. Conclusions. Associations of polymorphic variants of HHIP, ADRB2 and IL-33 genes with clinical manifestations of BA in children are determined in this study. They can be considered in a personalized monitoring of the patients and can help to control the disease totally.