Vera V. Erdman

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.

To assess the contribution to survival of Alu insertions in the ACE, PLAT, COL13A1, LAMA2, CDH4, SEMA6A, PKHD1L1, STK38L, HECW1, and TEAD1 genes, which are candidates of aging and longevity, amid the senile physiological and pathological phenotype, an analysis of association with life expectancy was carried out. Survival and mortality data were obtained for 1382 elderly people who were selected from the sample of Tatars residing in the Republic of Bashkortostan (total 1790 people from 18 to 109 years). Mortality risk was higher among carriers of the STK38L Alu-insertion genotype (Ya5ac2145*II, HR = 2.07, P = 0.022). Alu insertion in the HECW1 and TEAD1 genes has demonstrated a survival protection effect (Ya5NBC182*II, HR = 0.71, P = 0.038 and Ya5ac2013*II, HR = 0.74, P = 0.035 respectively). The survival amid the persons with various clinical phenotypes was associated with the Alu polymorphism of the SEMA6A (Yb8NBC597*ID, HR = 0.54, P = 0.016 for the cerebrovascular diseases), TEAD1 (Ya5ac2013*II, HR = 0.57, P = 0.016 for the cardiovascular pathologies), and LAMA2 (Ya5-MLS19*ID, HR = 0.36, P = 0.03 for multimorbidity status) genes. Thus, the genes involved in the regulation of autophagy and apoptosis were associated with survival and longevity.

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).

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.

Nowadays over the world absolute and relative number of aging population dramatically increases with life expectancy up and birth rate down. Aging and senescence assessment are assumed to reflect current changes, internal degeneration and various stressors respond ability (i.e. genetic, environmental and occupational factors) of human organism. Occupational experience time is leading risk factor and indicator for accelerated aging. Last years, many reports concerning aging rate dependence on physical and chemical occupational hazardous factors were published. Summarizing this exposures and their effects on aging reviews are almost absent despite many provided studies. Overview of main occupational neuropsychiatric, physical and chemical risk factors, that causes human aging acceleration presented here. Circadian rhythm disorders, allostatic load, heat stress, local vibration, chemical effects and suspended nanoparticles (fine dust) influences on aging and such signs as Alzheimer’s disease risk increase, telomere length decrease and epigenetic changes and possible interactions between them are also briefly presented. Agricultural, industrial workers, teachers and police officers aging acceleration is detected in results of analysis of biological age markers.

Objective. To investigate the molecular mechanism underlying genetic susceptibility to essential hypertension (EH) using polygenic analysis of renin-angiotensin-aldosterone system (RAAS).Design and methods.Genotyping of renin (REN, rs2368564), angiotensinogen (AGT, rs4762), angiotensin II receptor type 1 (AGTR1, rs5186), chymase 1 (CMA1, rs1800875) and angiotensin-converting enzyme (ACE, rs1799752) polymorphic variants was performed in 346 patients with EH and 377 controls, Russians and Tatars by ethnic origin.Results. ACE rs1799752polymorphism was significantly associated with EH risk in Tatars (P_Bonf= 0,003) and in the total study group (P_Bonf= 4,09 x 10^–5). Polygenic approach identified 12 genotypes and/or alleles combinations of RAAS genes polymorphisms, significantly associated with EH in the Tatars, and 6 patterns associated with EH in the total study group. The highest risk of disease in Tatar men was associated with REN rs2368564*T + AGTR1 rs5186*C/A + ACE rs1799752*D combination (OR = 16,64, P_Bonf= 0,001), in the total group — with REN rs2368564*T/C + CMA1 rs1800875*G combination (OR = 2,37, P_Bonf= 0,045).Conclusions. Our findings indicate that EH risk in men of Russian and Tatar ethnicity is significantly associated with ACE rs1799752 polymorphism, and the results of polygenic analysis demonstrate an association of the disease risk with genotype/allele combinations of polymorphic variants in REN (rs2368564), AGTR1 (rs5186), ACE (rs1799752), and CMA1 (rs1800875) genes.