MODIS Research Articles

HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart.

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 μM Benfluorex, 5 μM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.

Molecular Genetic Study in a Cohort of Iranian Families Suspected to Maturity-Onset Diabetes of the Young, Reveals a Recurrent Mutation and a High-Risk Variant in the CEL Gene.

Background:Diabetes mellitus (DM) is a group of metabolic disorders in the body, accompanied with increasing blood sugar levels. Diabetes is classified into three groups: Type 1 DM (T1DM), Type 2 DM (T2DM), and monogenic diabetes. Maturity-onset diabetes of the young (MODY) is a monogenic diabetes that is frequently mistaken for T1D or T2D. The aim of this study was to diagnose MODY and its subtype frequency in a diabetic population in Iran.Materials and Methods:In this study among ten diabetic families that were highly suspected to MODY by nongenetic biomarkers and without any pathogenic mutation in GCK and HNF1A genes, two patients from two unrelated families were examined via whole-exome sequencing (WES) in order to detect the causative gene of diabetes. Co-segregation analysis of the identified variant was performed using Sanger sequencing.Results:In this study, no pathogenic variant was found in GCK and HNF1A genes (MODY2 and MODY3), while these two types of MODY were introduced as the most frequent in other studies. By using WES, a pathogenic variant (p.I488T) was found in one of the patients in CEL gene causing MODY8 that its frequency is very rare in other studied populations. A high-risk variant associated with diabetes was found in another patient.Conclusion:WES was applied in this study to reveal the cause of MODY in 1 family. This pathogenic mutation was previously reported as a disease causing mutation.

Анализ влияния запечатанности почвенного покрова и озеленения на поле температур Волгоградской агломерации по данным MODIS

Анализ влияния запечатанности почвенного покрова и озеленения на поле температур Волгоградской агломерации по данным MODIS

Clinical, Laboratory and Genetic Characteristics of Children with GCK-MODY (MODY2): Report of Four Novel Variants in GCK Gene

Objective: Maturity-Onset Diabetes of the Young (MODY) is the most common type of monogenic diabetes. Heterozygous inactivating variants in glucokinase (GCK) gene are related to MODY2 (GCK–MODY). In this study, we aimed to investigate the phenotype and genotype characteristics of patients with GCK–MODY. Methods: Anthropometric and clinical characteristics (age, gender, weight, height and body mass index, complaints, family history), laboratory data (glucose, insulin, glycated hemoglobin, lipid levels) and molecular analysis of the GCK gene were collected from the hospital records. Results: The median age was 9.50 y (1.0–16.0), weight SDS -0.27 (-1.50–2.50), height SDS -0.09 (-2.20–1.60), and body mass index SDS -0.10 (-1.30–2.40). The median level of fasting blood glucose was 121 mg/dL (101–143), insulin was 9.50 mIU/mL (1.80–21.0), and HbA1c was 6.35% (6.20–6.60) at the time of diagnosis. Fourteen patients (78%) were diagnosed incidentally with asymptomatic hyperglycemia, while 4 patients (22%) had symptoms of polyuria and polydipsia. Ten different variants were detected in the GCK gene of 18 cases; one variant was nonsense, one variant was deletion, and the rest of the variants were missense mutations. Exon 7 was the most common location in coding regions and missense was the primary mutation type. The most common variant was c.802G>T (p.Glu268Ter) and detected in 5 (28%) patients. Four (22%) of the variants were novel; seven missense (p.Asp132Gly, p.Arg191Gln, p.Met238Thr, p.Met238Ile, p.Leu243Pro, p.Arg250Cys, p.Arg275Cys), one deletion (p.Pro153del) and one splice site mutation (c.863+3A>G). Conclusion: Since there is no specific treatment for GCK–MODY, GCK gene mutation screening should be considered in cases with early onset mild hyperglycemia, family history of impaired fasting glycemia and negative beta-cell antibodies to avoid unnecessary use of insulin or oral antidiabetic drugs. In this study, ten different variants were detected in the GCK gene of the 18 cases, four of which were novel.

Трудности дифференциальной диагностики MODY

Maturity-onset diabetes of the young (MODY) is a monogenic variant of diabetes characterized by the primary dysfunctions of pancreatic β-cells. MODY accounts for 1–2% of all variants of diabetes. MODY is generally associated with HNF1A gene mutation. The hallmarks of MODY are an autosomal dominant inheritance pattern, the onset of the disease in the young age, stable C-peptide level over a long period, the lack of the autoantibodies considered as the markers of diabetes, and the lack of ketoacidosis at disease onset. Considering that MODY manifests in children and young individuals, these patients are commonly diagnosed with type 1 diabetes. However, due to the atypical clinical signs of type 1 diabetes and the similarity of this disease to type 2 diabetes, these patients are often misdiagnosed with type 2 diabetes. This case report illustrates the differential diagnosis of diabetes in a patient with unusual disease course. The attention is focused on the features of MODY course. The indications to molecular genetic testing to verify the diagnosis are addressed.KEYWORDS: diabetes, maturity-onset diabetes of the young, monogenic diabetes, sulfonylureas, molecular genetic testing, LADA, pancreatogenic diabetes.FOR CITATION: Lobanova K.G., Titova V.V., Dolgova K.S. Maturity-onset diabetes of the young: difficult differential diagnosis. Russian Medical Inquiry. 2020;4(6):372–376. DOI: 10.32364/2587-6821-2020-4-6-372-376.

Maturity-onset type diabetes of young people: from genetics to practice. Part 1

MODY (maturity-onset type diabetes of young people) is a heterogeneous group of diseases with autosomal dominant type of inheritance, caused by mutations of genes involved in insulin synthesis and secretion. MODY is the most common group of monogenic forms of diabetes mellitus. Mutations of GCK and HNF1A genes are the most frequent. The first part of this article presents a literature review on GCK­MODY (MODY 2) and the role of glucokinase as a cellular glucose sensor. The enzyme performs this function due to a number of unique kinetic properties. More than 800 mutations of the glucokinase gene have been described. The carriers of homozygous mutations have permanent neonatal diabetes, while heterozygous mutations lead to a partial deficiency of glucokinase. GCK­MODY is characterized by persistent asymptomatic fasting hyperglycemia and moderate increase in glucose level after meals. Production of endogenous insulin is preserved. Most often, GCK­MODY is detected by an accidental examination orduring pregnancy. Thegold standard of diagnostics is molecular genetic analysis. Since in patients with this subtype of diabeteshyperglycemia does not reach high values, micro­ and macrovascular complications rarelydevelop. Therapy with insulin and oral hypoglycemic drugs does not always contribute toglucose levelreduction, asadministration of low dose of insulin leads to compensatory decrease ofendogenous hormone production. Only supraphysiological doses of insulin cause glucose lowering. Insulin therapy is recommended only for pregnant women when the fetus has not inherited the mutation of GCK.

Mucinous lung adenocarcinoma, particularly referring to EGFR-mutated mucinous adenocarcinoma.

The current 2015 World Health Organization (WHO) classification of lung tumors does not adequately categorize mucinous lung adenocarcinoma. Thus far, only two variants of mucinous adenocarcinoma have been studied: invasive mucinous adenocarcinoma and colloid adenocarcinoma. Moreover, common types of invasive adenocarcinoma when they produce mucin are yet to be elucidated, particularly epidermal growth factor receptor (EGFR)-mutated mucinous adenocarcinoma. In this study, we extracted mucinous adenocarcinoma of both the common types and the two variants. Further, we immunohistochemically and molecular-biologically examined their clinicopathological characteristics, mutation patterns, and expressions of thyroid transcription factor-1 (TTF-1), hepatocyte nuclear factor-4 alpha (HNF-4a) and mucins, particularly referring to EGFR-mutated adenocarcinoma. Among 1159 surgically resected invasive adenocarcinomas, 189 mucinous adenocarcinomas (16%) were identified. Among these, 20%, 34% and 9.5% were EGFR mutated, KRAS mutated and ALK rearranged, respectively. Compared with EGFR-mutated nonmucinous adenocarcinoma, EGFR-mutated mucinous adenocarcinoma had no female predominance, lower grades of histological differentiation and lower TTF-1 and higher HNF-4a expressions. Moreover, for the first time, we indicated that mucin production was an independent prognostic factor for EGFR-mutated adenocarcinomas and the mucin-staining pattern of negative MUC5AC and positive MUC5B was characteristic in these adenocarcinomas. We suggest that EGFR-mutated mucinous adenocarcinoma has a different tumorigenic pathway than nonmucinous EGFR-mutated adenocarcinoma.

HNF1A gene p.I27L is associated with co-existing preeclampsia in gestational diabetes mellitus

The association of the FTO gene and HNF1α gene on gestational diabetes mellitus (GDM) and preeclampsia remains unclear. This is the first study to examine whether HNF1α gene and FTO gene were associated with having GDM and preeclampsia in Turkish women. Healthy pregnant women (n = 101) and women with GDM (n = 169) were included. GDM was divided into two groups as GDM-only (n = 90) and GDM-preeclampsia (n = 79). Genotyping of HNF1α gene p.I27L, p.A98V, and p.S487N, and FTO gene rs9939609 SNPs were performed using RT-PCR. The frequency of p.S487N, p.A98V, and FTO genotype were similar between the groups (p > .05). p.I27L GG-wild, GT, and TT genotype were 56.5%, 36.6%, and 6.9% in controls; 40.0%, 51.1%, and 8.9% in GDM-only; and 26.6%, 51.9%, and 21.5% in GDM-preeclampsia (p = .034). TT and GT genotype was more frequent in GDM-preeclampsia than in controls (p < .05). GT genotype was increased in GDM-only compared with controls (p < .05). TT genotype was more frequent in GDM-preeclampsia than in GDM-only (p < .05). p.I27L TT genotype was independently associated with increased blood pressure (BP) and urinary protein. p.I27L TT genotype was associated with increased preeclampsia risk in patients with GDM by increasing BP and urinary protein.

Assessment of Karst rocky desertification based on MODIS: Exemplified by Guizhou Province

Assessment of Karst rocky desertification based on MODIS: Exemplified by Guizhou Province

Clinical Management and Gene Mutation Analysis of Children with Congenital Hyperinsulinism in South China

Objective:To explore the clinical presentation and molecular genetic characteristics of a cohort of congenital hyperinsulinism (CHI) patients from southern China and also to explore the most appropriate therapeutic approaches.Methods:We retrospectively reviewed a cohort of 65 children with CHI. Mutational analysis was performed for KCNJ11 and ABCC8 genes. The GLUD1 gene was sequenced in patients with hyperammonaemia. GCK gene sequencing was performed in those patients with no mutation identified in the ABCC8, KCNJ11 or GLUD1 genes.Results:ABCC8 mutations were identified in 16 (25%) of the cohort, GLUD1 mutations were identified in five children, and no KCNJ11 or GCK mutations were identified. Moreover, some unique features of ABCC8 gene mutations in southern Chinese CHI patients were found in this study. The most common mutation was a deletion/insertion mutation p.Thr1042GlnfsX75 was found in five unrelated patients, which possibly represents a relatively common mutation in southern China. Five novel ABCC8 mutations were detected. The mutations were p.Phe5SerfsX72, p.Gln273ArgfsX85, p.Leu724del, p.Asp1447Gly and IVS 25-1G>T. Five compound heterozygous mutations of ABCC8 gene were identified in this study, and three of these patients were diazoxide-responsive. Forty patients were diazoxide-responsive, 13 patients were diazoxide-unresponsive and 12 patients received dietary treatment only. A pancreatectomy was performed in 10 patients who were unresponsive to medical treatment.Conclusion:To the best of our knowledge, this is the first study of CHI in south China. Mutations in ABCC8 are the most common causes of CHI in this cohort. Diazoxide and dietary treatment were effective in most patients. Multicentre studies are necessary to obtain the long-term follow-up characteristics of such patients at a national level.

Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 Ameliorates Liver Fibrosis via Mitigation of Intestinal Endotoxemia.

Lipopolysaccharide (LPS) is demonstrated to cause "two-hit" injury to liver. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in LPS clearance. Hepatocyte nuclear factor-1 alpha (HNF-1α) and sterol regulatory element-binding protein 2 (SREBP2) were reported to be responsible for PCSK9 gene transcription and regulation. We aim to clarify the expression status of PCSK9 during the process of liver fibrosis and to verify the effect on liver fibrosis via PCSK9 inhibition. In this study, we found that PCSK9 increased significantly in human and BDL mouse injured liver tissues, so did HNF-1α and SREBP2. No significant difference of plasma PCSK9 was observed. Inhibited PCSK9 using CRISPR-PCSK9 adeno-associated virus in BDL mice ameliorated liver inflammation and fibrosis, with LPS decrease in serum, without any change in intestinal wall integrity. PCSK9 expression of L02 hepatocytes can be induced by LPS; however, they lose the ability at high content of LPS. L02 cells increased LPS uptake after PCSK9 knockout. Taken together, these results suggest that, with PCSK9 increasing during liver fibrosis advancement, its inhibition can ameliorate liver injury by enhancing LPS uptake in hepatocytes; however, the enhancement is limited for destruction to hepatocytes by high LPS.

Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile

Non-alcoholic fatty liver disease (NAFLD) culminates in insulin resistance and metabolic syndrome. Because there are no approved pharmacological treatment agents for non-alcoholic steatohepatitis (NASH) and NAFLD, different signaling pathways are under investigation for drug development with the focus on metabolic pathways. Hepatocyte nuclear factor 4-alpha (HNF4A) is at the center of a complex transcriptional network where its disruption is directly linked to glucose and lipid metabolism. Resetting HNF4A expression in NAFLD is therefore crucial for re-establishing normal liver function. Here, small activating RNA (saRNA) specific for upregulating HNF4A was injected into rats fed a high-fat diet for 16 weeks. Intravenous delivery was carried out using 5-(G5)-triethanolamine-core polyamidoamine (PAMAM) dendrimers. We observed a significant reduction in liver triglyceride, increased high-density lipoprotein/low-density lipoprotein (HDL/LDL) ratio, and decreased white adipose tissue/body weight ratio, all parameters to suggest that HNF4A-saRNA treatment induced a favorable metabolic profile. Proteomic analysis showed significant regulation of genes involved in sphingolipid metabolism, fatty acid β-oxidation, ketogenesis, detoxification of reactive oxygen species, and lipid transport. We demonstrate that HNF4A activation by oligonucleotide therapy may represent a novel single agent for the treatment of NAFLD and insulin resistance.

Human iPSCs-Derived Endothelial Cells with Mutation in HNF1A as a Model of Maturity-Onset Diabetes of the Young

Patients with HNF1A-maturity-onset diabetes of the young (MODY) often develop endothelial dysfunction and related microvascular complications, like retinopathy. As the clinical phenotype of HNF1A-MODY diabetes varies considerably, we used human induced pluripotent stem cells (hiPSCs) from two healthy individuals (control) to generate isogenic lines with mutation in HNF1A gene. Subsequently, control hiPSCs and their respective HNF1A clones were differentiated toward endothelial cells (hiPSC-ECs) and different markers/functions were compared. Human iPSC-ECs from all cell lines showed similar expression of CD31 and Tie-2. VE-cadherin expression was lower in HNF1A-mutated isogenic lines, but only in clones derived from one control hiPSCs. In the other isogenic set and cells derived from HNF1A-MODY patients, no difference in VE-cadherin expression was observed, suggesting the impact of the genetic background on this endothelial marker. All tested hiPSC-ECs showed an expected angiogenic response regardless of the mutation introduced. Isogenic hiPSC-ECs responded similarly to stimulation with pro-inflammatory cytokine TNF-α with the increase in ICAM-1 and permeability, however, HNF1A mutated hiPSC-ECs showed higher permeability in comparison to the control cells. Summarizing, both mono- and biallelic mutations of HNF1A in hiPSC-ECs lead to increased permeability in response to TNF-α in normal glycemic conditions, which may have relevance to HNF1A-MODY microvascular complications.

Knockdown of HNF4A Gene Increases Fetal Hemoglobin Synthesis in Hudep-2

Sickle cell anemia is a recessive inherited disease caused by a single nucleotide polymorphism in the β-globin gene the resulting substitution of glutamic acid by valine causes red blood cell sickling when deoxygenated. Some hypomethylating agents are able to induce the expression of γ-globin by inhibiting DNA methylation at the gene promoter. However, it is not completely understood how this regulation occurs and which genes are involved in this process. To understand fetal hemoglobin (HbF) regulation, CD34+ cells were treated with 1µM of decitabine on the 9th day of culture to induce HbF production. The expression levels of transcription factors and chromatin modifiers were evaluated through the PCR Array platform (Qiagen™ Germany). The transcription factor, HNF4A (Hepatocyte Nuclear Factor 4 Alpha), was highly upregulated in cells treated with decitabine, compared to the control cells, and was chosen as a candidate for CRISPR/Cas9 knockout in HUDEP-2 cells (immortalized human erythroid progenitor cells). The HNF4A gene has been reported as a transcription factor, which regulates the expression of several hepatic genes, and is able to play a role in the development of the liver, kidney, and intestines. Moreover, HNF4A is expressed in the hematopoietic tissue. To the best of our knowledge, the association between HNF4A and gamma globin gene synthesis has not been previously described. HUDEP-2 cells were cultured and then treated with 50nM decitabine. After 72 hours, HbF levels were measured with anti-HbF antibody by flow cytometry in three biological replicates. The percentage of cells positive for HbF in decitabine-treated HUDEP-2 were 12.27 ± 0.7%, N=3, while in control cells the percentage was 1.0 ± 0.06%, N=3 (p&amp;lt;0.0001). These results corroborate the increased expression measured in CD34+ cells. To knock out HNF4A in HUDEP-2 cells, we used the CRISPR/Cas9 system. We generated INDELs in heterozygosity for HNF4A. Briefly, HUDEP-2 cells were nucleofected with Cas9 high fidelity ribonucleoprotein (104 pmol), crRNA:tracrRNA (120 pmol) complex and 1µM of gRNA HNF4A using a CD34+ human cell kit and the E-001 program in an AMAXA Nucleofector 4D-device (Lonza). Two days after nucleofection, edited HUDEP-2 cells were submitted to clonal selection and expanded for approximately 28 days. Genomic DNA from clones was analyzed by a Sanger Sequencer, and four edited HNF4A-HUDEP-2 clones were selected with INDELs in the fourth exon of HNF4A gene. These clones were expanded in culture with controls, and the HbF levels were quantified by flow cytometry. HbF levels in these four clones were 8.2 ± 2.4%, while in the wild type HUDEP-2, HbF was 0.9 ± 0.02% (p&amp;lt; 0.05). The edited clones expressed significantly more HbF than the controls, although this expression was not homogeneous. Western blotting of edited HNF4A-HUDEP-2 clones demonstrated decreased HNF4A at the protein level (0.35 ± 0.9 AU N=8), compared to controls (2.02± 1.1 AU N=3, p&amp;lt; 0.05). Results suggest that HNF4A may play a role in the gamma globin gene transcription in HUPED-2 cells. The mechanism of how HNF4A may regulate gamma globin gene expression remains to be clarified. Disclosures No relevant conflicts of interest to declare.

Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy.

Maturity Onset Diabetes of the Young (MODY) constitutes a genetically and clinically heterogeneous type of monogenic diabetes. It is characterized by early onset, autosomal dominant inheritance and a defect in pancreatic β-cell insulin secretion. To date, various MODY subtypes have been reported, each one of a distinct genetic etiology. The aim of this study was to identify the molecular defects of 50 patients with MODY employing the methodology of next generation sequencing (NGS) targeted gene panel. A panel of seven MODY genes was designed and employed to screen 50 patients fulfilling the MODY diagnostic criteria. Patients with no pathogenic, likely pathogenic or uncertain significance variants detected, were further tested by multiplex ligation-dependent probe amplification (MLPA) for copy number variations (CNVs). Eight different pathogenic or likely pathogenic variants were identified in eight MODY patients (diagnostic rate 16%). Five variants of uncertain significance were also detected in seven MODY patients. Five novel pathogenic and likely pathogenic variants were detected in the genes GCK; p.Cys371X, HNF1A; p.Asn402Tyr, HNF4A; p.Glu285Lys, and ABCC8; p.Met1514Thr and p.Ser1386Phe. Two de novo heterozygous deletions of the entire HNF1B gene were detected in two patients, raising the diagnostic rate to 20%. Although many MODY patients still remain without exact MODY type identification, the application of NGS methodology provided rapid results, increased diagnostic accuracy, and was cost-effective compared to Sanger sequencing. Accurate genetic diagnosis of the MODY subtype is important for treatment selection, disease prognosis, and family counseling.

Association of Common Variants in HNF1A Gene with Serum AFP Level in Healthy Chinese Individuals and HCC Patients.

Although alpha-fetoprotein (AFP) is a widely used tumor marker in hepatocellular carcinoma (HCC), 40% of newly diagnosed patients do not have an elevated AFP level. Research has revealed that mutations in the HNF1A binding site of the AFP gene promoter cause significantly elevated serum AFP levels in patients with hereditary persistence of AFP. This study investigated the relationship between HNF1A genetic variants and serum AFP levels. We examined the association between the HNF1A-rs1169288 (A/C), rs2464196 (G/A), and rs1169310 (C/T) polymorphisms and AFP levels in a healthy Chinese population (n = 1010) and HCC patients (n = 185). Single nucleotide polymorphisms were genotyped by the amplification refractory mutation system combined with TaqMan probe in real-time PCR. The serum AFP concentrations were measured using the Architect i2000 immunochemistry analyzer. In healthy individuals, serum AFP levels were significantly lower with the rs2464196-AA and rs1169310-TT genotypes. Similar significant differences were observed in HCC patients. Moreover, in HCC patients, the distribution frequencies of rs2464196-AA+AG and rs1169310-TT+TC among those with AFP ≤ 20 ng/ml or ≤400 ng/ml were significantly lower than those in patients with AFP > 20 ng/ml or >400 ng/ml. Among all subjects, those carrying the HNF1A-rs2464196-A or rs1169310-T allele tended to have low levels of AFP. However, the HNF1A-rs1169288 polymorphism showed no significant association with the serum AFP level. These findings provide new insight into the genetic determinants of serum AFP level and can aid the differential diagnosis of HCC patients with low serum AFP.

Ultrasonic predictors of macrosomia in gestational diabetes mellitus

BACKGROUND: The basis of early ultrasound (US) diagnosis of diabetic fetopathy (DF) in pregnant with gestational diabetes mellitus (GDM) is the forehanded detection of macrosomia, especially its asymmetric forms. In pregnant with GDM on a diet therapy, the detection of macrosomia may be an indication for starting the insulin therapy. In pregnant with hyperglycemia due to mutation in the glucokinase gene (GCK), US fetal growth dynamics helps to assume the fetal genotype, as well as to stratify the risks of insulin therapy.&#x0D; AIM: To determine the prognostic significance of asymmetric form of macrosomia and the value of the coefficients of proportionality for the diagnosis of DF in pregnant with GDM, including hyperglycemia due to mutation in the GCK gene.&#x0D; MATERIALS AND METHODS: US fetometry was performed in 95 pregnant with GDM (including 22 pregnant with hyperglycemia caused by mutation in the GCK gene) (main group) and 427 healthy pregnant women (control group). Estimated fetal weight, standard fetometric indicators and coefficients of proportionality were evaluated. Retrospective analysis of US predictors of macrosomia was carried out after evaluating the weight of the newborn and clarifying the signs of DF.&#x0D; RESULTS: In the group with GDM, 51 (53.7%) pregnant had children with phenotypic symptoms of DF, including macrosomia 66,7% (34 children). We found statistically significant differences in fetal weight between the control group and the main group who gave birth to children with DF starting from 32 weeks. The coefficients of proportionality (femur length/abdominal circumference and the head circumference/abdominal circumference), characterizing the formation of the asymmetric macrosomia were significantly from 34 weeks (Р0,05).&#x0D; CONCLUSION: The most effective predictive fetometric indicators for the diagnosis of fetal macrosomia are the dimensions of fetal abdomen and fetal weight 90 percentile for gestational age. A specific sign of DF in pregnant with GDM is the asymmetric macrosomia. In pregnant with a mutation in the GCK gene, the tendency to macrosomia was revealed only in the absence of a mutation in the fetus, but insulin therapy in the presence of a similar mutation in fetus did not lead to a significant decrease in its percentile ranges.

Erratum: a synonymous variant in GCK gene as a cause of gestational diabetes mellitus (diabetes mellitus. 2019;22(2). Doi: 10.14341/dm9938)

An erratum on A synonymous variant in GCK gene as a cause of gestational diabetes mellitus by Natalya A. Zubkova, Petr M. Rubtsov, Liudmila I. Ibragimova, Nina A. Makretskaya, Evgeny V. Vasiliev, Vasily M. Petrov, Anatoly N. Tiulpakov (2019). Diabetes mellitus. 22(2). doi: 10.14341/DM9938An error was made in the list of authors: Fatima F. Burumkulova was not indicated as author of this article. The correct list of authors: Natalya A. Zubkova, Petr M. Rubtsov, Fatima F. Burumkulova, Liudmila I. Ibragimova, Nina A. Makretskaya, Evgeny V. Vasiliev, Vasily M. Petrov, Anatoly N. Tiulpakov.The editorial board apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.

Association between CPR-related genetic variants and risk of ischemic stroke: a nested case-control study

ABSTRACTBackground: Serum C-reactive protein (CRP) has been reported to be associated with risk of ischemic vascular disease including ischemic stroke. Genome-wide association studies have revealed several gene variants related to CRP concentration.Methods: We investigated genetic variants in CRP-related genes associated with ischemic stroke in a nested case-control study with 138 ischemic stroke cases and 276 controls. We sequenced the whole coding region of six CPR-related genes and selected eligible SNPs. Three genetic models (additive, dominant and recessive) were calculated by a multivariable conditional logistic regression to estimate the association between SNPs and risk of ischemic stroke. We also calculated gene–environment interactions by using a crossover analysis.Results: Three out of 10 eligible SNPs were shown to be associated with risk of ischemic stroke. rs1800947 in CRP gene (additive model: OR = 2.08, 95% CI: 1.00–4.23) and rs1169288 in HNF1A gene (additive model: OR = 1.45, 95% CI: 1.03–2.06) were associated with an increased risk of ischemic stroke. rs440446 in APOE gene (additive model: OR = 0.63, 95%CI: 0.44–0.88) was associated with a decreased risk of ischemic stroke. Genetic risk scores models including SC-GRS and OR-GRS both showed a significant association with risk of ischemic stroke. These three SNPs interacted with smoking and red meat intake.Conclusions: Our study showed genetic variants of CRP-related genes were associated with risk of ischemic stroke. Our findings could provide useful data for the etiology of ischemic stroke.

Association between HNF4A mutations and bleeding complications in patients with stable international normalized ratio.

This study aimed to determine the association between hepatocyte nuclear factor 4 alpha (HNF4A) polymorphisms and bleeding complications in patients on warfarin with international normalized ratios between 2.0 and 3.0 after cardiac valve replacement. Nineteen single nucleotide polymorphisms of HNF4A in addition to VKORC1 rs9934438 and CYP2C9 rs1057910 were analyzed. Univariate and multivariate analyses were conducted to evaluate associations between genetic polymorphisms and bleeding risk. Attributable risk and number needed to genotype (NNG) were calculated to assess clinical value of genotyping. Of 142 patients, 21 experienced bleeding complications. Multivariate logistic regression analysis was conducted using factors with P <0.1 in univariate analysis. Multivariate analysis showed that patients with the CC genotype of rs6130615 had an 8.4-fold increased risk of bleeding, compared with patients with the T allele. Attributable risk and NNG were 88.1% and 32.2, respectively. Patients with the TT genotype of rs3212191 had a 3.8-fold increased risk of bleeding, compared with C allele carriers, while patients with variant-type homozygotes for rs1884613 showed an 8.7-fold higher bleeding complication than C allele carriers. The attributable risk/NNG of rs3212191 and rs1884613 were 73.4%/17.6 and 88.5%/22.8, respectively. Among comorbidities, atrial fibrillation was the only significant risk factor for bleeding complications. Bleeding complications during warfarin therapy in patients with mechanical heart valves were associated with HNF4A polymorphisms and atrial fibrillation.