Timur R. Nasibullin

Background/Objectives: Chronic obstructive pulmonary disease (COPD) is increasingly viewed as a disorder of impaired cellular adaptation to chronic stress, involving oxidative injury, mitochondrial dysfunction, and accelerated cellular senescence. We investigated whether genetic variation in these pathways contributes to disease susceptibility, lung function impairment, and polygenic risk prediction. Methods: Thirty-three single-nucleotide variants were analysed in 747 patients with COPD and 703 controls. Associations with disease susceptibility and lung function parameters were assessed using regression models with correction for multiple testing. Weighted and unweighted polygenic scores were constructed from associated variants and evaluated using receiver operating characteristic and net reclassification improvement analyses. Results: Significant associations were identified in genes involved in antioxidant defence (NFE2L2, HMOX1, GSR), PI3K/AKT/mTOR signalling (PIK3R1, PTEN), mitochondrial function (TOMM40), cellular stress responses (FOXO3A), and long non-coding RNA regulation (MEG3, CDKN2B-AS1). The strongest association was observed for PIK3R1 rs831125 (OR = 2.31, p = 2.53 × 10⁻¹⁰). Variants in NFE2L2, PIK3R1, MEG3, MALAT1, and SIRT3 were additionally associated with pulmonary function parameters. The weighted polygenic score demonstrated good discriminative ability (AUC 68.8%, 95% CI 65.9–71.7%) and substantially improved prediction when combined with age, sex, and smoking exposure (AUC 88.1%, 95% CI 86.3–89.8%; NRI = 0.62, p = 2.21 × 10⁻²⁸). Conclusions: The identified loci converge on interconnected pathways involved in cellular stress adaptation, mitochondrial homeostasis, and senescence, supporting their contribution to chronic obstructive pulmonary disease susceptibility and functional decline.

Objective. To identify informative predictors of the development and progression of multiple sclerosis (MS) based on polygenic analysis of associations of polymorphic variants in the IL1R1, IL10, IL12B, IL2, IL2RA, and IL7R genes. Material and methods. The study included 247 patients with MS and 1271 control subjects. Associations of development and progression of MS with polymorphic variants of the IL1R1, IL10, IL12B, IL2, IL2RA, IL7, and IL7R genes were analyzed. The combinations of allelic variants associated with the disease were searched using the APSampler software, and predictive models of the development and progression of MS were developed using multifactorial logistic regression with step-by-step inclusion of variables. Results. The increased probability of MS was associated with the IL1R1 rs2287047 (recessive model, OR=2.2, pFDR=0.022), IL7R rs1494558 polymorphic variants (log additive model, OR=1.49, pFDR=0.003), and IL2RA rs12722580 *I/D genotype (codominant model, OR=1.67, pFDR=0.03). Reduced MS risk was associated with IL10 rs1800872 (recessive model, OR=0.38, pFDR=0.044), IL7R rs10624573 (dominant model, OR=0.67, pFDR=0.022), IL7R rs6897932 variants (recessive model, OR=0.21, pFDR=0.008), and IL2RA rs12722580 * D/D genotype (codominant model, OR=0.78, pFDR=0.03). Combinations (IL7R rs1494558*T+IL7R rs6897932*T, IL1R1 rs2287047*C+IL12B rs3212227*C and IL7R rs1494558*T/C+IL12B rs3212227*A) with a synergistic effect were identified, and predictive models of MS development and progression risk with a sufficiently high prognostic value were created. Conclusion. The results of the study emphasize the importance of polymorphic variants of IL7R, IL1R1, IL2RA, and IL10 in the genetic predisposition to MS. The obtained models require validation and can be supplemented with other predictors to improve accuracy; nevertheless, they demonstrate important pathogenetic patterns and directions for further study.

Objective. To identify pharmacogenetic markers of the effectiveness and safety of sertraline pharmacotherapy at polymorphic loci (−1438G>A, rs6311), (102c>T, rs6313), (1354C/T, rs6314), (rs7997012 G>A) of the HTR2A gene in patients with mixed anxiety-depressive disorder from the Republic of Bashkortostan. Material and methods. The study included 100 patients treated with sertraline. The effectiveness and safety of sertraline therapy in patients were assessed using standardized psychometric scales on the day before the start of therapy and then for 42 days. Four polymorphic loci, rs6311, rs6313, rs6314, and rs7997012, of the HTR2A gene were tested using real-time polymerase chain reaction (PCR). Results. Significant differences in the severity of depressive symptoms were found between carriers of different rs6311 genotypes of the HTR2A gene at the beginning of the study (p<0.05) and on day 42 of the study (p<0.001). More severe depressive symptoms were observed in carriers of the rs6311*A/A (p<0.05) and rs6313*T/T (p<0.001) genotypes. Statistically significant differences were observed between carriers of different rs6311 and rs6313 genotypes of the HTR2A gene in the severity of anxiety symptoms on all study days. More severe anxiety symptoms were observed in carriers of the rs6311*A/A (p<0.001) and rs6313*T/T (p<0.001) genotypes. The rs6311*A/A and rs6313*T/T genotypes can be considered markers of low effectiveness for anxiety and depressive symptoms and markers of risk of adverse reactions (ADRs) when taking sertraline. The rs6314*C/T and rs7997012*G/G genotypes can be considered markers of the ADR risk during sertraline therapy. Conclusion. The study showed that the studied polymorphic variants of the HTR2A gene can be predictors of the effectiveness and safety of sertraline in the treatment of mixed anxiety-depressive disorder.

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown pathogenesis with no effective treatment currently available. Given the regulatory roles of lncRNAs (TP53TG1, LINC00342, H19, MALAT1, DNM3OS, MEG3), miRNAs (miR-218-5p, miR-126-3p, miR-200a-3p, miR-18a-5p, miR-29a-3p), and their target protein-coding genes (PTEN, TGFB2, FOXO3, KEAP1) in the TGF-β/SMAD3, Wnt/β-catenin, focal adhesion, and PI3K/AKT signaling pathways, we investigated the expression levels of selected genes in peripheral blood mononuclear cells (PBMCs) and lung tissue from patients with IPF. Lung tissue and blood samples were collected from 33 newly diagnosed, treatment-naive patients and 70 healthy controls. Gene expression levels were analyzed by RT-qPCR. TaqMan assays and TaqMan MicroRNA assay were employed to quantify the expression of target lncRNAs, mRNAs, and miRNAs. Our study identified significant differential expression in PBMCs from IPF patients compared to healthy controls, including lncRNAs MALAT1 (Fold Change = 3.809, P = 0.0001), TP53TG1 (Fold Change = 0.4261, P = 0.0021), and LINC00342 (Fold Change = 1.837, P = 0.0448); miRNAs miR-126-3p (Fold Change = 0.102, P = 0.0028), miR-200a-3p (Fold Change = 0.442, P = 0.0055), and miR-18a-5p (Fold Change = 0.154, P = 0.0034); and mRNAs FOXO3 (Fold Change = 4.604, P = 0.0032) and PTEN (Fold Change = 2.22, P = 0.0011). In lung tissue from IPF patients, significant expression changes were observed in TP53TG1 (Fold Change = 0.2091, P = 0.0305) and DNM3OS (Fold Change = 4.759, P = 0.05). Combined analysis of PBMCs expression levels for TP53TG1, MALAT1, miRNA miR-126-3p, and PTEN distinguished IPF patients from healthy controls with an AUC = 0.971, sensitivity = 0.80, and specificity = 0.955 (P = 6 × 10^–8). These findings suggest a potential involvement of the identified ncRNAs and mRNAs in IPF pathogenesis. However, additional functional validation studies are needed to elucidate the precise molecular mechanisms by which these lncRNAs, miRNAs, and their targets contribute to PF.

Myocardial infarction (MI) is a multifactorial polygenic disease that develops as a result of a complex interaction of numerous genetic factors and the external environment. Accordingly, the contribution of each of them separately is usually not large and may significantly depend on the state of other accompanying factors. The purpose of the study was to search for informative predictors of MI risk based on polygenic analysis of polymorphic variants of (1) the antioxidant defense enzyme genes PON1 (rs662), PON2 (rs7493), CAT (rs1001179), MSRA (rs10098474) and GSTP1 (rs1695); (2) the apoptosis genes CASP8 (rs3834129), TP53 (rs1042522) and BCL2 (rs12454712); and (3) the inflammation genes CRP (rs1205), CX3CR1 (rs3732378), IL6 (rs1800795) and CCL2 (rs1024611). 591 DNA samples were used in the study (280 patients with the onset at 30 to 60 years, with an average age of 46.02 ± 6.17, and 311 control subjects aged 30 to 62, with an average age of 44.65 ± 7.07). All the participants were male and Tatars by ethnicity. The logistic regression analysis with various models demonstrated associations with MI of polymorphic variants of the genes CX3CR1 (rs3732378) (overdominant model – G/G + A/A vs A/G P = 0.0002, OR = 1.9), MSRA (rs10098474) (dominant model – T/T vs T/C + C/C P = 0.015, OR = 1.51), CCL2 (rs1024611) (recessive model – P = 0.0007 – A/A + A/G vs G/G OR = 2.63), BCL2 (rs12454712) (log-additive model – *C allele, P = 0.005, OR = 1.38). Using the Monte Carlo method and Markov chains (APSampler), combinations of alleles/ genotypes of the studied polymorphic loci associated with a high risk of MI were obtained, which, in addition to those identified during single-locus analysis, contained polymorphic variants of the genes CASP8, TP53, CAT, PON2, CRP, IL6, GSTP1. Among the combinations obtained, a pairwise analysis of possible non-linear interactions between the identified combinations of alleles/genotypes was carried out, which showed synergistic interactions of the polymorphic variants CX3CR1*A/G and CASP8*I/I, MSRA*C and CRP*C, CAT*C/T and MSRA*C, CAT*C/T and CX3CR1*A contributing to the development of MI. Based on the results obtained using multivariate logistic regression analysis, a predictive model was built to assess the risk of developing MI, the predictive ability of which reached the value AUC = 0.71 (AUC – area under the curve in ROC analysis).

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease of the respiratory system which develops as a result of a complex interaction of genetic and environmental factors closely related to lifestyle. We aimed to assess the combined effect of the PI3K/AKT/mTOR signaling pathway (PIK3R1, AKT1, MTOR, PTEN) and sirtuin (SIRT1, SIRT3, SIRT6) genes to COPD risk. SNPs of SIRT1 (rs3758391, rs3818292), SIRT3 (rs3782116, rs536715), SIRT6 (rs107251), AKT1 (rs2494732), PIK3R1 (rs10515070, rs831125, rs3730089), MTOR (rs2295080, rs2536), PTEN (rs701848, rs2735343) genes were genotyped by real-time polymerase chain reaction (PCR) among 1245 case and control samples. Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and smoking pack-years. Significant associations with COPD were identified for SIRT1 (rs3818292) (P = 0.001, OR = 1.51 for AG), SIRT3 (rs3782116) (P = 0.0055, OR = 0.69) and SIRT3 (rs536715) (P = 0.00001, OR = 0.50) under the dominant model, SIRT6 (rs107251) (P = 0.00001, OR = 0.55 for СT), PIK3R1: (rs10515070 (P = 0.0023, OR = 1.47 for AT), rs831125 (P = 0.00001, OR = 2.28 for AG), rs3730089 (P = 0.0007, OR = 1.73 for GG)), PTEN: (rs701848 (P = 0.0015, OR = 1.35 under the log-additive model), and rs2735343 (P = 0.0001, OR = 1.64 for GC)). A significant genotype-dependent variation of lung function parameters was observed for SIRT1 (rs3818292), SIRT3 (rs3782116), PIK3R1 (rs3730089), and MTOR (rs2536). Gene-gene combinations that remained significantly associated with COPD were obtained; the highest risk of COPD was conferred by a combination of G allele of the PIK3R1 (rs831125) gene and GG of SIRT3 (rs536715) (OR = 3.45). The obtained results of polygenic analysis indicate the interaction of genes encoding sirtuins SIRT3, SIRT2, SIRT6 and PI3KR1, PTEN, MTOR and confirm the functional relationship between sirtuins and the PI3K/AKT/mTOR signaling pathway.

ЦЕЛЬ ИССЛЕДОВАНИЯ Выявление комплексных генетических предикторов рассеянного склероза (РС) с использованием ранее установленных в полногеномных ассоциативных исследованиях маркеров заболевания (GWAS-маркеров) в популяции больных РС и здоровых лиц Республики Башкортостан (Российская Федерация) при помощи полигенного подхода. МАТЕРИАЛ И МЕТОДЫ Общая группа исследования составила 2048 человек (641 пациент с РС и 1407 здоровых лиц), которые постоянно проживали в Республике Башкортостан и принадлежали к башкирской (n=325), русской (n=772) или татарской (n=951) национальностям. Выполнен анализ ассоциаций с РС полиморфных вариантов, ранее ассоциированных с заболеванием по данным GWAS. Из 641 пациента с РС 247 были объектом 20-летнего проспективного клинического наблюдения. РЕЗУЛЬТАТЫ В результате проведенного анализа установлено, что аллель C6orf10 rs3129934*T наиболее значимо ассоциирована с РС в группе русских (отношение шансов (ОШ)=2,00, P=5,85·10^–5) и татар (ОШ=2,38, P=8,61·10^–7). Повышенный риск заболевания у русских также связан с аллелями EOMES rs11129295*T (ОШ=1,56, P=0,007) и IL7R rs1494558*I (ОШ=1,61, P=0,003). При проведении метаанализа была подтверждена ассоциация аллелей C6orf10 rs3129934*T, EOMES rs11129295*T и IL7R rs1494558*I с РС в исследуемой группе, а также выявлены ассоциации аллелей INAVA rs7522462*G, IL7R rs10624573*I, CD6 rs17824933*G, GPC5 rs9523762*A и GPR65 rs2119704*C с заболеванием. При помощи полигенного анализа был идентифицирован комплексный предиктор C6orf10 rs3129934*C + INAVA rs7522462*G + CD6 rs17824933*C, обладающий выраженным протективным действием в отношении РС в общей группе исследования (ОШ=0,34, P_FDR=2,65·10^–7). ЗАКЛЮЧЕНИЕ Нам удалось воспроизвести ассоциации между РС и 8 генетическими вариантами (C6orf10 rs3129934, INAVA rs7522462, IL7R rs10624573, EOMES rs11129295, GPR65 rs2119704, GPC5 rs9523762, CD6 rs17824933 и CD58 rs2300747), ранее выявленными в GWAS европейских популяций. В дальнейшем проведение полноэкзомного или полногеномного секвенирования может помочь раскрыть механизмы, лежащие в основе патогенеза РС в популяциях России.

Цель. Цель исследования состояла в поиске информативных предикторов эффективности лечения РС для использования в персонализированной терапии заболевания на основании проспективного исследования РС в Республике Башкортостан.

Longevity is a unique human phenomenon and a highly stable trait, characterized by polygenicity. The longevity phenotype occurs due to the ability to successfully withstand the age-related genomic instability triggered by Alu elements. The purpose of our cross-sectional study was to evaluate the combined contribution of ACE*Ya5ACE, CDH4*Yb8NBC516, COL13A1*Ya5ac1986, HECW1*Ya5NBC182, LAMA2*Ya5-MLS19, PLAT*TPA25, PKHD1L1*Yb8AC702, SEMA6A*Yb8NBC597, STK38L*Ya5ac2145 and TEAD1*Ya5ac2013 Alu elements to longevity. The study group included 2054 unrelated individuals aged from 18 to 113 years who are ethnic Tatars from Russia. We analyzed the dynamics of the allele and genotype frequencies of the studied Alu polymorphic loci in the age groups of young (18–44 years old), middle-aged (45–59 years old), elderly (60–74 years old), old seniors (75–89 years old) and long-livers (90–113 years old). Most significant changes in allele and genotype frequencies were observed between the long-livers and other groups. The search for polygenic predictors of longevity was performed using the APSampler program. Attaining longevity was associated with the combinations LAMA2*ID + CDH4*D (OR = 2.23, P_Bonf = 1.90 × 10⁻²) and CDH4*DD + LAMA2*ID + HECW1*D (OR = 4.58, P_Bonf = 9.00 × 10⁻³) among persons aged between 18 and 89 years, LAMA2*ID + CDH4*D + SEMA6A*I for individuals below 75 years of age (OR = 3.13, P_Bonf = 2.00 × 10⁻²), LAMA2*ID + HECW1*I for elderly people aged 60 and older (OR = 3.13, P_Bonf = 2.00 × 10⁻²) and CDH4*DD + LAMA2*D + HECW1*D (OR = 4.21, P_Bonf = 2.60 × 10⁻²) and CDH4*DD + LAMA2*D + ACE*I (OR = 3.68, P_Bonf = 1.90 × 10⁻²) among old seniors (75–89 years old). The key elements of combinations associated with longevity were the deletion alleles of CDH4 and LAMA2 genes. Our results point to the significance for human longevity of the Alu polymorphic loci in CDH4, LAMA2, HECW1, SEMA6A and ACE genes, involved in the integration systems.