GENE POLYMORPHISM ANALYSIS OF CHEMOKINES, CHEMOKINE RECEPTORS, ACUTE PHASE PROTEINS, AND CD14 IN FEMALE OBESITY DEVELOPMENT

In the present study, we have investigated frequency of genotypes and functional alleles of genes encoding chemokines (CXCL12 rs1801157, CCL2 rs1024611), chemokine receptors (CCR5 del32, CX3CR1 rs3732378), acute phase proteins SAA rs1136743, and CD14 rs2569190 polymorphisms among Tatar obese or overweight women from the Republic of Bashkortostan.The group of patients comprised unrelated women with obesity (BMI ≥ 30 kg/m2, n = 225), females with overweight (BMI 25.0-29.9 kg/m2, n = 184), and control group of women (n = 327) BMI < 25.0 kg/m2. Genotyping was performed by PCR-RFLP analysis. Patients and controls differed in such parameters as body weight (p = 0.00001), BMI level (p = 0.001) and fasting glucose level (p = 0.0001).An association was revealed between obesity and AG-AA genotypes (p = 0.007) and A allele (p = 0.003) of polymorphic locus rs3732378 of CXCR1 gene, as well as TT genotype (p = 0.027) and T allele (p = 0.021) of polymorphic locus rs1136743 of SAA gene. It has been shown that the AA genotype of polymorphic locus rs3732378 of the CX3CR1 gene is associated with increased body weight (p = 0.002) and elevated BMI (p = 0.018); the GG genotype of polymorphic locus rs1024611 of the CCL2 gene is associated with elevated fasting glucose level (p = 0.001).As based on clinical and genetic data and using logistic regression, some statistically significant differences were revealed, which allow to predict development of obesity in Tatar women

Анализ генетических факторов, вовлеченных в развитие хронической обструктивной болезни легких: оценка вклада генов биотрансформации ксенобиотиков и антиоксидантной защиты

Summary. The purpose of this study was to investigate a role of xenobiotic biotransformation and antioxidant defense gene polymorphism for development of chronic obstructive pulmonary disease (COPD). Polymorphism of these genes encoding 22 enzymes was investigated in 361 COPD patients and 585 healthy individuals at Republic of Bashkortostan. Our results indicate that CYP1А1 (2455A>G, 3801T>C), CYP1А2 (–163С>А), CYP2F1 (c.14_15insC), CYP2J2 (–76G>T), CYP2S1 (13106C>T, 13255A>G), GSTM1 (Del), GSTT1 (Del), CAT (–1167C>T), GPX1 (Pro197Leu), NQO1 (609C>T) genotypes and allele frequencies were similar in COPD and healthy control groups. A significant association have been determined between CYP1А2 (–2464delT), CYP1B1 (4326C>G), CYP2A6 (deletion), GSTP1 (Ile105Val, Ala114Val), CAT (–262 C>T), NQO1 (465C>T), SOD1 (c.239+34A>C), SOD3 (Arg213Gly), UGT2B7 (802C>T) gene loci and COPD.Oxidative stress is the crucial pathogenic factor of COPD. An increased risk of oxidative stress is associated with certain alleles of genes encoding cytochrome P450, glutathione S–transferase, superoxide dismutase, catalase, and others. We demonstrated that polymorphism of xenobiotic biotransformation and antioxidant defense genes significantly influences the individual response to toxic components of tobacco smoke and is associated with COPD in residents of Bashkortostan

Ассоциация полиморфных вариантов генов ферментов матриксных металлопротеаз и антипротеаз с развитием и тяжестью течения хронической обструктивной болезни легких

To evaluate a role of polymorphic variants of metalloproteinase and protease genes for hereditary susceptibility to COPD and its severity, we analyzed polymorphic loci of MMP1, MMP9, MMP12, PI, and AACT genes in COPD patients (n = 318) and healthy persons (n = 319) living at the Bashkortostan Republic. Results showed that frequency of genotypes and alleles of G(-1607)GG gene MMP1, С(-1562)T gene MMP9, A(-82)G gene MMP12, and Ala 15 Thr gene ААСТ did not differ in COPD patients and healthy subjects. The Zand S-mutations of the PI gene were also similar in both the groups. The heterozygous GA genotype of G1237A locus in the 3'-non-translated region of PI gene was associated with COPD occurrence (OR = 2.09; 95 % CI: 1.15–3.81). To determine polymorphic variants associated with severity of clinical course and age of the disease manifestation, a comparative analysis of rates of genotypes and alleles was performed in patients with different COPD stages and of different age. The stage IV COPD patients significantly more often carried rare T allele in С(-1562)T locus of the MMP9 gene (15.89 % vs 8.38 %; χ2 = 7.804; df = 1; p = 0.005; OR = 2.06; 95 % CI: 1.22–3.49). Individuals with rare TT genotype of MMP9 gene were found only among the stage IV COPD patients (3.97 % vs 0 %; χ2 = 4.78; p = 0.029; pcor = 0.058). Moreover, analysis of this locus in patients with early manifestation of COPD (younger the 55 yrs) revealed significantly more frequent rate of T allele in patients with stage IV COPD compared to patients of the same age but less severe COPD (χ2 = 5.26; df = 1; p = 0.022).С целью оценки роли полиморфных вариантов генов матриксных металлопротеаз и антипротеаз в формировании наследственной предрасположенности к развитию ХОБЛ и тяжести течения заболевания был проведен анализ полиморфных локусов генов MMP1, MMP9, MMP12, PI и AACT в группах больных ХОБЛ (n = 318) и здоровых индивидов (n = 319), проживающих в Республике Башкортостан. Анализ полученных результатов показал, что частоты генотипов и аллелей локусов G(-1607)GG гена MMP1, С(-1562)T гена MMP9, A(-82)G гена MMP12, Ala 15 Thr гена ААСТ статистически достоверно не различаются в группах больных ХОБЛ и здоровых индивидов. Частоты Z и S мутаций гена PI также сходны в обеих группах. Выявлена ассоциация гетерозиготного генотипа GA локуса G1237A в 3'-нетранслируемой области гена PI с развитием ХОБЛ (отношение риска (ОР) = 2,09, 95%-ный доверительный интервал (ДИ) – 1,15–3,81). С целью выявления полиморфных вариантов, ассоциированных с тяжестью клинического течения и возрастом манифестации заболевания был проведен сравнительный анализ частот генотипов и аллелей изученных локусов у больных с разными стадиями ХОБЛ и в разных возрастных группах. Показано, что среди больных с 4-й стадией ХОБЛ достоверно чаще встречаются носители редкого аллеля T локуса С(-1562)T гена MMP9 (15,89 % против 8,38 %; χ2 = 7,804; df = 1; p = 0,005; ОР = 2,06; 95%-ный ДИ – 1,22–3,49). Только среди больных с 4-й стадией ХОБЛ были выявлены индивиды с редким генотипом TT гена MMP9 (3,97 % против 0 %; χ2 = 4,78; p = 0,029; pcor = 0,058). Кроме того, анализ данного локуса у больных с ранней манифестацией ХОБЛ (до 55 лет) показал статистически достоверное увеличение частоты аллеля T в группе пациентов с тяжелой 4-й стадией ХОБЛ по сравнению с больными в той же возрастной группе, но с более легкими стадиями ХОБЛ (χ2 = 5,26; df = 1; p = 0,022)

Role of PI3K/AKT/mTOR signaling pathway and sirtuin genes in chronic obstructive pulmonary disease development

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

Профессиональный хронический бронхит: роль полиморфных вариантов генов ферментов-антиоксидантов в формировании предрасположенности к заболеванию

Distributions of alleles and genotypes of GSTP1Ile105Val and Ala114Val, CAT С(-262)T and C1167T, NQO1 C609T and C465T, GPX1Pro197Leu, GSTM1, GSTT1 polymorphic loci have been studied in patients with occupational chronic bronchitis and in healthy workers. No statistically significant difference was determined in distribution of alleles and genotypes of GSTP1 Ala114Val, CAT С(-262)T and C1167T, NQO1 C609T, GPX1Pro197Leu, GSTM1, GSTT1 polymorphisms between these groups. Polymorphic marker NQO1 C465T was associated with higher risk of occupational chronic bronchitis (OR = 3.68; CI 95 %: 1.68-8.31) suggesting involvement of this gene in development of this pathology.Изучено распределение аллелей и генотипов полиморфных локусов Ile105Val и Ala114Val гена GSTP1, С(-262)T и C1167T гена CAT, C609T и C465T гена NQO1, Pro197Leu гена GPX1 и делеционных локусов генов GSTM1, GSTT1 в группе больных профессиональным хроническим бронхитом и в группе здоровых рабочих. Нами не выявлены статистически значимые различия в распределении аллелей и генотипов полиморфизмов Ala114Val гена GSTP1, С(-262)T и C1167T гена CAT, C609T гена NQO1, Pro197Leu гена GPX1 и делеций генов GSTM1, GSTT1 между исследуемыми группами. Обнаружена ассоциация полиморфного маркера С465Т гена NQO1 с повышенным риском развития профессионального хронического бронхита (отношение шансов – 3,68, 95%-ный доверительный интервал – 1,688,31), что свидетельствует о вовлеченности данного гена и его белкового продукта в патогенез заболевания

ГЕНЕТИЧЕСКИЕ МАРКЕРЫ РИСКА РАЗВИТИЯ ПОВЕРХНОСТНОГО И ИНВАЗИВНОГО РАКА МОЧЕВОГО ПУЗЫРЯ

To reveal possible associations of the polymorphic variants of the cytochrome P450 and enzymes glutathione-S-transferase genes with the risk for bladder cancer (BC), the authors analyzed the frequency of genotypes and alleles at the polymorphic loci of the CYP1A1 (A2454G), GSTM1 (del), and GSTP1 (A313G) genes in 208 patients diagnosed as having BC (104 patients with invasive BC and 104 with superficial BC) and in 367 patients without identified oncopathology. The *1A*2C (OR = 3.42) and *2C*2С (OR = 6.98) genotypes, *2C (OR = 3.73) allele of the CYP1A1 gene and the GG (OR = 2.53) genotype of the GSTP1 gene were ascertained to be genetic markers for a risk for BC. The presence of the *2C (OR = 1.69) allele of the CYP1A1 gene, the G (OR = 2.40) allele and the AG genotype (OR = 2.40) of the GSTP1 gene was associated with the invasive forms of BC. There were no substantial differences in the distribution of the frequency of genotypes of the GSTM1 gene between the samples of patients and healthy individuals.С целью выявления возможных ассоциаций полиморфных вариантов генов цитохрома P450 и ферментов глутатион-S-трансферазы с риском развития рака мочевого пузыря (РМП) нами проведен анализ частот встречаемости генотипов и аллелей полиморфных локусов генов CYP1A1 (A2454G), GSTM1 (del), GSTP1 (A313G) у 208 больных с диагнозом РМП (104 пациента с инвазивным и 104 – с поверхностным раком) и у 367 пациентов без выявленной онкопатологии. Установлено, что генетическими маркерами риска развития РМП являются генотипы *1A*2C (ОP 3,42) и *2C*2С (ОР 6,98), аллель *2C (ОР 3,73) гена CYP1A1, генотип GG (ОР 2,53) гена GSTP1. Наличие аллеля *2C (ОР 1,69) гена CYP1A1, аллеля G (ОР 2,40) и генотипа AG (ОР 2,40) гена GSTP1 ассоциировано с инвазивными формами РМП. Существенных различий в распределении частот встречаемости генотипов гена GSTM1 между выборками больных и здоровых не выявлено

МОЛЕКУЛЯРНЫЕ МАРКЕРЫ ПРОГНОЗА ПРИ РАКЕ МОЧЕВОГО ПУЗЫРЯ

Bladder cancer (BC) remains a current problem in oncourology. Despite that bladder cancer risk factors have been studied and described in the literature, new molecular and genetic mechanisms have been identified that predisposes to the disease development. There are numerous cellular processes involve in BC pathogenesis. The less-aggressive, non-invasive slow progressing bladder cancer types are defined by Ras-MAPK system activation. Tumors that are more aggressive and have low cancer-specific survival rate are characterized by changes in retinoblastoma genes and p53. Attempts are made to develop prognostic tests to predict tumor behavior, targeted treatment. perspectively, BC patients will be treated using molecular genetic markers allowing the accurate prediction of the patient’s tumor behavior and fitting the treatment tactics on the individual basis.Рак мочевого пузыря (РМП) остается актуальной проблемой онкоурологии. Несмотря на то, что факторы риска РМП изучены и описаны в литературе, выявляются новые молекулярно-генетические механизмы, предрасполагающие к развитию заболевания. В патогенез РМП вовлечено множество клеточных процессов. Менее агрессивные, неинвазивные, медленно прогрессирующие формы РМП характеризуются активацией системы Ras-mitogen-activated protein kinase (Ras-MAPK). Более агрессивные опухоли с низкой раковоспецифической выживаемостью, характеризуются изменениями в генах ретинобластомы и p53. Предпринимаются попытки разработать прогностические тесты, предсказывающие развитие опухоли, выбор тактики лечения. В перспективе в лечении пациентов РМП будут использоваться молекулярно-генетические маркеры, позволяющие достоверно предсказать поведение опухоли у пациента и выбрать индивидуальную тактику лечения

The promoter polymorphism -1562C/T in matrix metalloproteinase-9 and COPD severity

Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous respiratory disease. COPD is characterized by a progressive irreversible airflow limitation that is due to a loss of lung elasticity resulting from peripheral airflow obstruction (chronic bronchitis) and parenchymal destruction (emphysema). Matrix metalloproteinases (MMP) are a major group of proteases known to regulate extracellular matrix turnover. They have been suggested to be important in the process of lung diseases associated with tissue remodeling. Polymorphisms in MMPs which known to upregulate their activity may result in the degradation of a lung matrix. A case-control study was performed to investigate the association of polymorphisms of MMP type 1 (-1607G/GG), 9 (-1562C/T) and 12 (-82A/G) genes with COPD and disease severity. A total of 309 COPD patients admitted to departments of respiratory medicine have been recruited in Ufa city hospitals (## 13, 21, and 22). COPD patients have been undergone a spirometry and a physical examination by a chest physician to refer the GOLD II-IV stages. The control group comprised of 305 healthy subjects without evidence of chronic diseases (Table Basic characteristic of study groups)

GENETIC RISK MARKERS FOR SUPERFICIAL AND INVASIVE BLADDER CANCER

<p>To reveal possible associations of the polymorphic variants of the cytochrome P450 and enzymes glutathione-S-transferase genes with the risk for bladder cancer (BC), the authors analyzed the frequency of genotypes and alleles at the polymorphic loci of the CYP1A1 (A2454G), GSTM1 (del), and GSTP1 (A313G) genes in 208 patients diagnosed as having BC (104 patients with invasive BC and 104 with superficial BC) and in 367 patients without identified oncopathology. The *1A*2C (OR = 3.42) and *2C*2С (OR = 6.98) genotypes, *2C (OR = 3.73) allele of the CYP1A1 gene and the GG (OR = 2.53) genotype of the GSTP1 gene were ascertained to be genetic markers for a risk for BC. The presence of the *2C (OR = 1.69) allele of the CYP1A1 gene, the G (OR = 2.40) allele and the AG genotype (OR = 2.40) of the GSTP1 gene was associated with the invasive forms of BC. There were no substantial differences in the distribution of the frequency of genotypes of the GSTM1 gene between the samples of patients and healthy individuals.</p

MOLECULAR PROGNOSTIC MARKERS OF URINE BLADDER CANCER

Bladder cancer (BC) remains a current problem in oncourology. Despite that bladder cancer risk factors have been studied and described in the literature, new molecular and genetic mechanisms have been identified that predisposes to the disease development. There are numerous cellular processes involve in BC pathogenesis. The less-aggressive, non-invasive slow progressing bladder cancer types are defined by Ras-MAPK system activation. Tumors that are more aggressive and have low cancer-specific survival rate are characterized by changes in retinoblastoma genes and p53. Attempts are made to develop prognostic tests to predict tumor behavior, targeted treatment. perspectively, BC patients will be treated using molecular genetic markers allowing the accurate prediction of the patient’s tumor behavior and fitting the treatment tactics on the individual basis.</p