Olga Yurievna Bushueva

1. Cellular proteostasis fully depends on the protein quality-control system, which includes three different mechanisms: protein refolding by molecular chaperones, removal by energy-dependent prote...

Heat shock protein 70 (HSP70) family members and co-chaperones participate in cellular stress responses, proteostasis, apoptosis, inflammation, and mitochondrial function implicated in ischemic stroke (IS). We investigated associations between genetic variants in HSP70 family genes and BAG co-chaperones and IS susceptibility, clinical characteristics, and gene expression. Twenty-three single-nucleotide polymorphisms were analyzed in 768 patients with IS and 794 controls. Functional annotation included eQTL resources, protein–protein interaction analyses, and targeted genotype–expression analysis of paired peripheral-blood transcriptomes from 19 patients during acute IS and on day 7. In the overall cohort, the variants rs2227956 in HSPA1L and rs7749960 variant in the BAG2 gene were associated with reduced IS risk. The variants rs2227956 and rs2075799 in HSPA1L, rs753856 in HSPA6, rs706121 in BAG1, rs7749960 in BAG2, and rs196329 in BAG3 were linked to IS risk, associations specific to certain subgroups. Additional variants were associated with age at IS onset, lipid levels, coagulation parameters, body mass index, and number of IS episodes. Functional analyses linked associated loci to pathways relevant to atherosclerosis, inflammation, apoptosis, oxidative stress, autophagy, mitochondrial dysfunction, and angiogenesis. Transcriptomic analysis identified associations of rs1043618 HSPA1A with C4B expression during acute IS and DDR1 expression on day 7, while rs1042665 HSPA9 was associated with genotype-dependent changes in HSPA9 expression. These findings support a role for HSP70-related genetic variation in IS susceptibility, clinical heterogeneity, and phase-specific gene-expression differences.

A common feature of severe COVID-19 and two common metabolic comorbidities, type 2 diabetes mellitus (T2DM) and obesity, is a persistent inflammatory response. Heat shock proteins (HSPs) are key regulators of cell proteostasis under stressful conditions, including inflammation, oxidative stress, hyperglycemia, and hyperlipidemia. The aim of the present study was to investigate associations between polymorphic variants in genes encoding HSPs and T2DM or obesity among patients with severe or critical COVID-19.

Uterine fibroids (UF) are among the most common benign tumors in women, yet their genetic underpinnings remain largely unexplored. Given the importance of genetic predisposition and the significance of GWAS-identified loci in UF, we aimed to investigate how family history of UF influences the association between these loci and the disease risk. DNA samples from 241 women with a family history of UF and 947 women without were genotyped for seven GWAS SNPs using probe-based PCR. In patients without a family history of UF, rs547025 SIRT3 was associated with a reduced risk (effect allele C, OR = 0.59, 95 % CI = 0.41–0.83, p = 0.002). Conversely, rs7986407 FOXO1 was linked to an increased risk of UF in those with a family history (effect allele G, OR = 1.94, 95 % CI = 1.03–3.68, p = 0.03). The most significant gene-environment interactions in patients with a family history were observed with pelvic inflammatory disease and GWAS SNPs, while in those without a family history, interactions additionally involved medical abortions. Our bioinformatic analysis uncovered the SNPs’ molecular mechanisms, contributing to UF development.

Heat shock proteins of the HSP70 family and their BAG co-chaperones regulate responses to oxidative stress, inflammation, apoptosis, and ischemia, all central to coronary artery disease (CAD) pathogenesis. The contribution of genetic variants within HSP70-family and BAG co-chaperone genes to CAD susceptibility remains unclear. Thus, we sought to evaluate associations of HSP70- and BAG-related SNPs with CAD risk and to characterize their potential regulatory effects using comprehensive bioinformatic analyses. A case–control cohort of 834 CAD patients and 1328 controls of Russian ethnicity was genotyped for 13 SNPs. Associations with CAD susceptibility and traits were tested using log-additive regression with adaptive permutation. Loci underwent functional annotation. The C allele of BAG1 rs706121 was associated with increased CAD risk overall (OR = 1.24, p_perm = 0.019), in males (OR = 1.39, p_perm = 0.002), and in smokers (OR = 1.39, p_perm = 0.020). BAG3 rs196329 was associated with lower risk in males (A allele: OR = 0.82, p_perm = 0.040), whereas HSPA6 rs753856 was associated with reduced risk in physically active individuals (G allele: OR = 0.61, p_perm = 0.008). Additional associations involved clinical or biochemical traits. Functional annotation identified potential regulatory effects, including eQTL associations, overlap with histone marks, and allele-dependent changes in transcription factor binding. HSP70 and BAG variants may contribute to CAD susceptibility and support sex- and lifestyle-informed risk assessment.

Proteins with chaperone-like activity can play a key role in the development of age-related macular degeneration (AMD) through the regulation of oxidative stress, apoptosis, and inflammation. Recently, a new class of chaperones (heat-resistant obscure proteins (Hero)) has been identified; these proteins exhibit properties similar to other molecular chaperones. The aim of this study is to investigate the association between the genes encoding the Hero9 (BBLN) and Hero7 (SERF2) proteins and the risk of developing AMD. The case–control study included 1845 unrelated individuals from Central Russia (300 patients with AMD, 1545 controls). Genotyping of the rs2 900 262 BBLN and rs4 644 832 SERF2 was performed by the real-time PCR method using allele-specific probes. The rs2 900 262 BBLN SNP was associated with an increased risk of AMD in patients with the dry form of the disease (effect allele T, OR = 2.08, 95% CI = 1.11–3.88, p_perm = 0.02, p_bonf = 0.04). The rs4 644 832 SERF2 SNP (protective allele G) was associated with a later age of AMD manifestation and later involvement of the second eye in the pathology. Both studied SNPs are characterized by strong eQTL effects that influence the expression of the genes pathogenetically significant for AMD (CIZ1, MAP1A, PDIA3, CKMT1A/B, STRC) in the blood, vessels, and nervous system tissues. They also influence the transcription factor binding sites involved in the interleukin 9 signaling, epithelial morphogenesis, and cellular response to oxygen level.

Background: Despite significant advances in identifying susceptibility genes for bronchial asthma (BA), the immunogenetic and other molecular mechanisms underlying disease risk and progression remain incompletely understood. This study aimed to investigate the association between two common single-nucleotide polymorphisms (SNPs), rs17293632 and rs2033784, located within the SMAD3 (SMAD family member 3) gene—previously identified in genome-wide association studies—and susceptibility to atopic asthma and allergen sensitivity in Russian children. Methods: This study included DNA samples from 999 unrelated children from the Kursk region, comprising 526 patients with BA (316 boys and 210 girls) and 473 healthy children. SNP genotyping was performed using the MassARRAY-4 system. Results: Both SNPs were associated with an increased risk of BA under the additive genetic model (p ≤ 0.001). In the sex-stratified analysis, the rs17293632 (odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.15–2.77; p = 9.0 × 10-4) and rs2033784 (OR = 1.80, 95% CI: 1.28–2.52; p = 6.0 × 10-4) variants were exclusively associated with asthma risk among girls, whereas no significant associations were observed in boys. The rs17293632T-rs2033784G haplotype was associated with an increased risk of asthma in girls (OR = 2.01, 95% CI: 1.38–2.92, p = 3.0 × 10-4). Notably, SMAD3 gene polymorphisms were associated with an increased risk of asthma exclusively among children living in urban environments (p ≤ 0.0001). Polymorphisms in the SMAD3 gene have also been linked to specific allergies, including those to horsehair, chicken eggs, beef, wheat, oatmeal, barley, and foxtail. Conclusions: The present study of Russian children confirmed that the rs17293632 and rs2033784 polymorphisms of the SMAD3 gene are significant genetic markers associated with BA and allergies. However, an association between these SMAD3 variants and asthma was observed only among girls, marking the first time this association has been reported. Further research is necessary to determine whether the SMAD3 gene constitutes a viable therapeutic target for treating asthma and allergic diseases.

Serum gamma-glutamyltransferase (GGT) is a biomarker for cardiovascular disease, but the role of its encoding gene family in ischemic stroke (IS) is unknown. This pilot study of 1288 individuals (600 cases and 688 controls) investigated GGT1, GGT5, GGT6, and GGT7 polymorphisms using the MassARRAY-4 system. Conventional single-variant, haplotype, and diplotype analyses were complemented by Model-Based Multifactor Dimensionality Reduction (MB-MDR) with stability assessment and model prioritization. Conventional analysis identified female-specific associations for three GGT5 variants (rs8140505, rs2275984, and rs2267073; P_perm < 0.05). A common GGT5 haplotype was protective in females (P_perm = 0.02). Diplotype analysis revealed joint effects of GGT genotypes on IS risk in females (FDR < 0.05). MB-MDR uncovered complex higher-order interactions (P_perm < 0.0001): in women, 12 models represented second-order interactions between smoking and individual GGT variants. In men, 8 models centered on GGT1 rs5751909 spanning second- to fourth-order interactions with alcohol, smoking, and other GGT family members. All prioritized models passed FDR correction (q < 0.05) and achieved higher weighted composite scores. eQTL data linked these variants to regulatory networks controlling glutathione metabolism, oxidative stress, and inflammation. This study supports a novel hypothesis on the combined involvement of GGT gene family polymorphisms and pro-oxidant environmental factors in ischemic stroke predisposition, demonstrating that disease risk is shaped by sex-specific gene–environment interactions. The pronounced sexual dimorphism highlights the need for sex-specific personalized approaches: smoking cessation may be particularly impactful in women carrying GGT5 risk variants, while alcohol moderation could be prioritized in men with GGT1 risk variants.

Current experimental data indicate the leading role of cytokines in the formation of manifestations of bronchial asthma (BA), thus supporting the so-called anti-cytokine approach to the therapy of this disease. The aim of this study was to evaluate possible association of rs10455025 TSLP gene variant and rs11811856 polymorphism of TNFSF4 gene with the risk of developing BA among children from Kursk population. The study included 999 unrelated individuals, including 526 patients with BA and 473 control persons. These functional gene polymorphisms (SNPs) were genotyped using the MassArray-4 genomic mass spectrometer. We have found that the alleles rs11811856G TNFSF4 and rs10455025C TSLP , as well as the genotypes rs11811856G/G and rs10455025-C/C are associated with an increased risk of developing BA in children. The association of rs11811856 TNFSF4 with an increased risk of developing BA was revealed in both boys and girls. Meawhile, the rs10455025 polymorphism of TSLP gene did not show any associations in the stratified analysis by gender. Upon analysis of gene-environment interactions in general group, a relationship was established with the risk of asthma depending on exposure to tobacco smoke and the place of residence of children. We have found a relationship between the SNP status and the risk of concomitant allergopathology in children with BA, and the influence of the studied polymorphisms on laboratory indices of rhinocytogram and spirometry. The results of this study have shown that the studied SNPs (rs10455025 TSLP and rs11811856 TNFSF4 ) in children with BA are associated with increased risk of developing food sensitization to banana, rice, duck, and a number of pollen (foxtail, common horsetail, bluegrass, ryegrass, fireweed, ash, barley), and epidermal (human hair) allergens. It has also been found that the studied SNPs reduce the risk of sensitization to house dust, cat hair, rabbit hair, and quinoa pollen. The present study showed that the polymorphic gene variants (rs10455025 TSLP and rs11811856 TNFSF4 ) are significantly associated with the risk and clinical features of developing BA.