Study of The Molecular Nature of Congenital Cataracts in Patients from The Volga-Ural Region.

Hereditary cataracts are characterized by significant clinical and genetic heterogeneity, which can pose challenges for early DNA diagnosis. To comprehensively address this problem, it is essential to investigate the epidemiology of the disease, perform population studies to determine the spectrum and frequencies of mutations in the responsible genes, and examine clinical and genetic correlations. Based on modern concepts, non-syndromic hereditary cataracts are predominantly caused by genetic disease forms associated with mutations in crystallin and connexin genes. Therefore, a comprehensive approach to studying hereditary cataracts is necessary for early diagnosis and improved treatment outcomes. The crystallin (CRYAA, CRYAB, CRYGC, CRYGD, and CRYBA1) and connexin (GJA8, GJA3) genes were analyzed in 45 unrelated families from the Volga-Ural Region (VUR) with hereditary congenital cataracts. Pathogenic and probably pathogenic nucleotide variants were identified in ten unrelated families, nine of which had cataracts in an autosomal dominant pattern of inheritance. Two previously undescribed likely pathogenic missense variants were identified in the CRYAA gene: c.253C > T (p.L85F) in one family and c.291C > G (p.H97Q) in two families. The known mutation c.272_274delGAG (p.G91del) was found in the CRYBA1 gene in one family, while no pathogenic variants were found in the CRYAB, CRYGC, or CRYGD genes in the examined patients. In the GJA8 gene, the known mutation c.68G > C (p.R23T) was found in two families, and previously undescribed variants were identified in two other families: a c.133_142del deletion (p.W45Sfs*72) and a missense variant, c.179G > A (p.G60D). In one patient with a recessive form of cataract, two compound-heterozygous variants were identified-a previously undescribed likely pathogenic missense variant, c.143A > G (p.E48G), and a known variant with uncertain pathogenetic significance, c.741T > G (p.I24M). Additionally, a previously undescribed deletion, c.del1126_1139 (p.D376Qfs*69), was identified in the GJA3 gene in one family. In all families where mutations were identified, cataracts were diagnosed either immediately after birth or during the first year of life. The clinical presentation of the cataracts varied depending on the type of lens opacity, resulting in various clinical forms. This information emphasizes the importance of early diagnosis and genetic testing for hereditary congenital cataracts to guide appropriate management and improve outcomes.

MicroRNA Expression Signatures in Clear Cell Renal Cell Carcinoma: High-Throughput Searching for Key miRNA Markers in Patients from the Volga-Ural Region of Eurasian Continent.

Clear cell renal cell carcinoma (ccRCC) is characterized by high molecular genetic heterogeneity, metastatic activity and unfavorable prognosis. MicroRNAs (miRNA) are 22-nucleotide noncoding RNAs that are aberrantly expressed in cancer cells and have gained serious consideration as non-invasive cancer biomarkers. We investigated possible differential miRNA signatures that may differentiate high-grade ccRCC from primary disease stages. High-throughput miRNAs expression profiling, using TaqMan OpenArray Human MicroRNA panel, was performed in a group of 21 ccRCC patients. The obtained data was validated in 47 ccRCC patients. We identified nine dysregulated miRNAs (miRNA-210, -642, -18a, -483-5p, -455-3p, -487b, -582-3p, -199b and -200c) in tumor ccRCC tissue compared to normal renal parenchyma. Our results show that the combination of miRNA-210, miRNA-483-5p, miRNA-455 and miRNA-200c is able to distinguish low and high TNM ccRCC stages. Additionally, miRNA-18a, -210, -483-5p and -642 showed statistically significant differences between the low stage tumor ccRCC tissue and normal renal tissue. Contrariwise, the high stages of the tumor process were accompanied by alteration in the expression levels of miRNA-200c, -455-3p and -582-3p. Although the biological roles of these miRNAs in ccRCC are not totally clear, our findings need additional investigations into their involvement in the pathogenesis of ccRCC. Prospective studies with large study cohorts of ccRCC patients are important to further establish the clinical validity of our miRNA markers to predict ccRCC.

Association of Gasdermin B Gene GSDMB Polymorphisms with Risk of Allergic Diseases.

The GSDMB gene encodes gasdermin B from the family of gasdermin domain-containing proteins involved in various cellular processes related to tumor development and progression, such as differentiation, cell cycle control and apoptosis. Previously, we conducted GWAS on asthma in the Volga-Ural region of Russia and found SNPs associated with asthma with genome-wide significance (rs9303277, rs8067378, rs2290400, rs7216389, rs4795405) and located in the chromosomal region 17q12-q21, which contains IKZF3 (IKAROS family zinc finger 3), ZPBP2 (zona pellucida binding protein-like), GSDMB (gasdermin B), ORMDL3 (orosomucoid 1-like 3) and LRRC3C (leucine-rich repeat-containing 3C) genes. In the present study, we investigated the association of SNPs of the GSDMB gene with the development of various allergic diseases and their combined manifestations in individuals of Russian, Tatar and Bashkir ethnic origin. Our results revealed that polymorphic variants rs7216389, rs2290400 and rs2305480 are associated with the development of allergic diseases as well as with asthma and asthma combined with allergic rhinitis. We did not reveal the association of rs7216389 and rs2290400 with the development of allergic rhinitis and atopic dermatitis in the groups of patients without asthma symptoms. This may reflect a more important role of these SNPs in the development of asthma.

Identification of a new locus at 16q12 associated with time to asthma onset.

BACKGROUND: Asthma is a heterogeneous disease in which age of onset plays an important role. OBJECTIVE: We sought to identify the genetic variants associated with time to asthma onset (TAO). METHODS: We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques. RESULTS: We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 × 10-8). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD]) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor-like 1 [IL1RL1]), 6p21 (HLA-DQA1), 9p24 (IL33), and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2]-gasdermin A [GSDMA]). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33) and 17q12-q21 (near ZPBP2 and within GSDMA). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset (P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10-4). CONCLUSION: The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2), 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.

Host Genetic Variants Linked to COVID-19 Neurological Complications and Susceptibility in Young Adults-A Preliminary Analysis.

To date, multiple efforts have been made to use genome-wide association studies (GWAS) to untangle the genetic basis for SARS-CoV-2 infection susceptibility and severe COVID-19. However, data on the genetic-related effects of SARS-CoV-2 infection on the presence of accompanying and long-term post-COVID-19 neurological symptoms in younger individuals remain absent. We aimed to examine the possible association between SNPs found in a GWAS of COVID-19 outcomes and three phenotypes: SARS-CoV-2 infection, neurological complications during disease progression, and long-term neurological complications in young adults with a mild-to-moderate disease course. University students (N = 336, age 18-25 years, European ancestry) with or without COVID-19 and neurological symptoms in anamnesis comprised the study sample. Logistic regression was performed with COVID-19-related phenotypes as outcomes, and the top 25 SNPs from GWAS meta-analyses and an MR study linking COVID-19 and cognitive deficits were found. We replicated previously reported associations of the FURIN and SLC6A20 gene variants (OR = 2.36, 95% CI 1.31-4.24) and OR = 1.94, 95% CI 1.08-3.49, respectively) and remaining neurological complications (OR = 2.12, 95% CI 1.10-4.35 for SLC6A20), while NR1H2 (OR = 2.99, 95% CI 1.39-6.69) and TMPRSS2 (OR = 2.03, 95% CI 1.19-3.50) SNPs were associated with neurological symptoms accompanying COVID-19. Our findings indicate that genetic variants related to a severe COVID-19 course in adults may contribute to the occurrence of neurological repercussions in individuals at a young age.

COVID-19: Mechanisms, risk factors, genetics, non-coding RNAs and neurologic impairments.

The novel coronavirus infection (COVID-19) causes a severe acute illness with the development of respiratory distress syndrome in some cases. COVID-19 is a global problem of mankind to this day. Among its most important aspects that require in-depth study are pathogenesis and molecular changes in severe forms of the disease. A lot of literature data is devoted to the pathogenetic mechanisms of COVID-19. Without dwelling in detail on some paths of pathogenesis discussed, we note that at present there are many factors of development and progression. Among them, this is the direct role of both viral non-coding RNAs (ncRNAs) and host ncRNAs. One such class of ncRNAs that has been extensively studied in COVID-19 is microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Moreover, Initially, it was believed that this COVID-19 was limited to damage to the respiratory system. It has now become clear that COVID-19 affects not only the liver and kidneys, but also the nervous system. In this review, we summarized the current knowledge of mechanisms, risk factors, genetics and neurologic impairments in COVID-19. In addition, we discuss and evaluate evidence demonstrating the involvement of miRNAs and lnRNAs in COVID-19 and use this information to propose hypotheses for future research directions.

MicroRNA Processing Pathway-Based Polygenic Score for Clear Cell Renal Cell Carcinoma in the Volga-Ural Region Populations of Eurasian Continent.

The polygenic scores (PGSs) are developed to help clinicians in distinguishing individuals at high risk of developing disease outcomes from the general population. Clear cell renal cell carcinoma (ccRCC) is a complex disorder that involves numerous biological pathways, one of the most important of which is responsible for the microRNA biogenesis machinery. Here, we defined the biological-pathway-specific PGS in a case-control study of ccRCC in the Volga-Ural region of the Eurasia continent. We evaluated 28 DNA SNP variants, located in microRNA biogenesis genes, in 464 individuals with clinically diagnosed ccRCC and 1042 individuals without the disease. Individual genetic risks were defined using the SNP-variant effects derived from the ccRCC association analysis. The final weighted and unweighted PGS models were based on 21 SNPs, and 7 SNPs were excluded due to high LD. In our dataset, microRNA-machinery-weighted PGS revealed 1.69-fold higher odds (95% CI [1.51-1.91]) for ccRCC risk in individuals with ccRCC compared with controls with a p-value of 2.0 × 10-16. The microRNA biogenesis pathway weighted PGS predicted the risk of ccRCC with an area under the curve (AUC) = 0.642 (95%nCI [0.61-0.67]). Our findings indicate that DNA variants of microRNA machinery genes modulate the risk of ccRCC in Volga-Ural populations. Moreover, larger powerful genome-wide association studies are needed to reveal a wider range of genetic variants affecting microRNA processing. Biological-pathway-based PGSs will advance the development of innovative screening systems for future stratified medicine approaches in ccRCC.

The study of filaggrin gene mutations and copy number variation in atopic dermatitis patients from Volga-Ural region of Russia.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by age-specific localization, dryness, itch and hypersensitivity to allergens. In our study, we investigated FLG gene mutations and CNVs in AD patients and control subjects of different ethnic origin from Volga-Ural region. AD group included 303 patients (177 Russians, 126 Tatars). Control group consisted of 261 healthy individuals (152 Russians, 109 Tatars). The study revealed 66 FLG mutation carriers and demonstrated an association between c.2282del4 deletion and AD development in Russians and Tatars of Volga-Ural region of Russia. In the analysis of the FLG gene CNVs, the most common was 10-repeat allele in both Russian and Tatar patients and controls. We were unable to find any significant difference in CNV repeats count between AD patients and control individuals.