Aim. To evaluate the effectiveness of automated Sanger sequencing of the UGT1A1 gene to search for pathogenic mutations in individuals with the Gilbert syndrome phenotype. Materials and methods. Automated Sanger sequencing of exons and part of the promoter in the UGT1A1 gene was carried out for 24 people with unconjugated hyperbilirubinemia, in whom all other causes except for genetic ones were excluded and DNA analysis was performed to determine the number of TA repeats in the promoter of the UGT1A1 gene (rs3064744). Distribution of rs3064744 genotypes in the group was the following: 5 people – 7TA/7TA genotype, 5 people – 6TA/6TA genotype, 12 people – 6TA/7TA genotype, 1 person – 5TA/7TA genotype, 1 person – 6TA/8TA genotype. DNA was isolated using phenol – chloroform extraction or express methods. The sequencing was performed by capillary electrophoresis on the Hitachi 3500 Genetic Analyzer (Applied Biosystems, USA). Results. Single nucleotide variants of uncertain significance were identified: rs3755319 (in 21 people) and rs28899472 (in three people with the 7TA/7TA genotype of rs3064744) in the promoter of the UGT1A1 gene, rs2125984650 in the first exon of the UGT1A1 gene (in one person with the 5TA/7TA genotype of rs3064744). In two individuals with the 6TA/7TA genotype of rs3064744, gene variants were identified that were pathogenic or likely pathogenic for the Gilbert syndrome according to some sources (rs4148323, rs1273237448). Conclusion. According to the results of the study, automated Sanger sequencing of the UGT1A1 gene may be the next stage of DNA analysis after determining the rs3064744 genotype for individuals with 6TA/6TA, 6TA/7TA rs3064744 genotypes and suspected Gilbert syndrome.

Background: Benign unconjugated hyperbilirubinemia, also known as Gilbert's syndrome, is a common in the population moderate increase in total and unconjugated bilirubin concentrations in individuals without liver disease or hemolysis. Aim: To identify associations of rs3755319, rs4148325 of the UGT1A1 gene, rs2328136 of the NUP153-AS gene, and rs16928809 of the SLC22A18 gene with benign unconjugated hyperbilirubinemia. Methods: This case-control study included a group of individuals with benign unconjugated hyperbilirubinemia (n = 414, mean age 36.7 ± 15.9 years, 49.8% men) and a control group (n = 381, mean age 39.1 ± 15.9 years, 52.5% men). The sample was randomly selected from the participants of the MONICA project, screening of young people aged 25–44 years and a cross-sectional study of schoolchildren in Novosibirsk. DNA was isolated from venous blood by phenol-chloroform extraction or an express assay (PROBA-RAPID-GENETICS, DNA-Technology, Russia). Genotyping of the groups by rs3755319, rs4148325 of the UGT1A1 gene, rs2328136 of the NUP153-AS gene, and rs16928809 of the SLC22A18 gene was performed by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results: No significant differences were found between the individuals with benign unconjugated hyperbilirubinemia and the control group by the genotypes and alleles of the nucleotide sequence variants of rs16928809 of the SLC22A18 gene (p 0.05). The CC genotype and the C allele of rs3755319 of the UGT1A1 gene were more common in the individuals with benign unconjugated hyperbilirubinemia, than in the control group (CC vs AC + AA: odds ratio (OR) = 21.1, 95% confidence interval (CI) 14.7–30.4, p 0.001; C vs A: OR = 12.4, 95% CI 9.4–16.4, p 0.001). The concentrations of total and unconjugated bilirubin were higher in the carriers of the CC genotype of rs3755319, compared to the carriers of the other two genotypes (p 0.05). rs4148325 of the UGT1A1 gene was in the linkage disequilibrium with the rs3064744 UGT1A1 variant. The GG genotype and the G allele rs2328136 of the NUP153-AS gene were more common in the individuals with benign unconjugated hyperbilirubinemia than in the control group (GG vs AG + AA: OR = 1.361, 95% CI 1.002–1.848, p = 0.048; G vs A: OR = 1.33, 95% CI 1.02–1.73, p = 0.034). Conclusion: The CC genotype and the C allele of rs3755319 of the UGT1A1 gene, the GG genotype and the G allele of rs2328136 of the NUP153-AS gene are the genotypes and alleles of risk for benign unconjugated hyperbilirubinemia. The rs16928809 of the SLC22A18 gene is not associated with benign unconjugated hyperbilirubinemia.

BACKGROUND: Obesity is a widespread disease associated with serious complications. Obesity is a risk factor for many chronic diseases. The most common type of obesity is polygenic obesity, the pathogenesis of which involves external and internal factors, including genetic ones.AIM: Search and study of the association of variants of the nucleotide sequence rs9939609 of the FTO gene, rs7903146 of the TCF7L2 gene, rs1799883 of the FABP2 gene, rs1800497 of the DRD2 gene, rs17782313 of the MC4R gene with morbid obesity in women.MATERIALS AND METHODS: Study design is case-control study. The morbid obesity group and the control group were formed from the DNA bank of participants of the international project HAPIEE. Genotyping was performed by PCR-RFLP and real-time PCR (TaqMan probes, Applied Biosystems, USA). Statistical analysis was performed in SPSS software using Pearson’s chi-square test, Fisher’s exact two-tailed test with Yates’ correction for continuity. The significance level was used p<0.05.RESULTS: Morbid obesity group included 192 women (mean age 57.02± .16 years) with BMI over 40 kg/m2, control group included 450 women (mean age 55.44±7.41 years) with normal BMI (18.5-24.9 kg/m2). There were no statistically significant differences between the groups in the frequencies of genotypes and alleles rs7903146 of the TCF7L2 gene, rs1799883 of the FABP2 gene, rs1800497 of the DRD2 gene (p>0.05). In the group of morbid obesity, the proportion of carriers of the TT genotype rs9939609 of the FTO gene was statistically significantly lower, and the AT genotype was significantly higher than in the control group (OR=0.579, 95% CI 0.399-0.840, p=0.004; OR=1.408, 95% CI 1.003- 1.976, p=0.047, respectively). The heterozygous TC genotype rs17782313 of the MC4R gene is statistically significantly more common (OR=1.825, 95% CI 1.257-2.652, p=0.002), while the homozygous TT genotype is less common (OR=0.500, 95% CI 0.346-0.723, p<0.001) in group of morbid obesity compared with the control group.CONCLUSION: Heterozygous genotypes of the rs9939609 of the FTO gene (AT) and rs17782313 of the MC4R gene (TC) are risk genotypes; the homozygous genotype TT of the variants is protective for morbid obesity in women. Single nucleotide variants rs7903146 of the TCF7L2 gene, rs1799883 of the FABP2 gene, and rs1800497 of the DRD2 gene are not associated with morbid obesity in women.

We explored the relationship between the copy number of mitochondrial DNA (mtDNA-CN) and all-cause natural mortality. We examined a random population sample in 2003/2005 (n = 9360, men/women, 45-69, the HAPIEE project) and followed up for 15 years. Using a nested case-control design, we selected non-external deaths among those free from baseline cardiovascular diseases (CVD) and cancer (n = 371), and a sex- and age-stratified control (n = 785). The odds ratios (ORs) of death were 1.06 (95%CI 1.01-1.11) per one-decile decrease in mtDNA-CN independent of age, sex, metabolic factors, smoking, alcohol intake and education. The age-sex-adjusted ORs of death in the second and first tertiles of mtDNA-CN vs. the top tertile were 2.35 (95% CI 1.70-3.26) and 1.59 (1.16-2.17); an increased risk was confined to the second tertile after controlling for smoking and metabolic factors. The multivariable-adjusted OR of CVD death was 1.92 (95% CI 1.18-3.15) in tertile 2 vs. the top tertile of mtDNA-CN, and for cancer-related death the ORs were 3.66 (95% CI 2.21-6.05) and 2.29 (95% CI 1.43-3.68) in tertiles 2 and 1 vs. the top tertile. In the Siberian population cohort, the mtDNA-CN was an inverse predictor of the 15-year risk of natural mortality, due to the greatest impact of CVD and cancer-related death. The findings merit attention for exploring further the role of mtDNA in human ageing and the diversity of mortality.

Aim . To study new molecular genetic markers of Gilbert’s syndrome (GS). Materials and methods . It was a case – control study. The GS group included 125 people (mean age 38.5 ± 11.9 years, 58.9% were men) with unconjugated hyperbilirubinemia; known causes of unconjugated hyperbilirubinemia were excluded. The control group (n = 323, mean age 48.9 ± 11.9 years, 53.2% were men) was a random sample of individuals from the DNA bank of participants of the HAPIEE and MONICA projects. DNA was isolated by phenol – chloroform extraction from venous blood. Genotyping of groups by rs3064744, rs34993780, rs56059937, rs4148323, and rs4124874 single nucleotide polymorphisms (SNPs) in the UGT1A1 gene was performed by polymerase chain reaction followed by the polyacrylamide gel analysis according to the author’s protocols. Results . For rs34993780 and rs56059937, no carriers of a rare allele were found in the GS group and the control group. In the GS group, two carriers of a heterozygous mutation rs4148323 were found. Statistically significant differences between the groups were found in the frequencies of rs4124874: homozygous GG was statistically significantly more common in the GS group than in the control group (odds ratio (OR) = 11.8, 95% confidence interval (CI) 6.9–20.3, p < 0.001). Conclusion . The GG genotype of rs4124874 in the UGT1A1 gene is associated with an increased risk of GS. Carriers of the rare heterozygous mutation rs4148323 were found in the GS group.

В одной трети случаев причина внезапной смерти остается необъясненной после проведения стандартного судебно-медицинского исследования. При отрицательной аутопсии во многих странах рекомендовано проведение посмертного молекулярно-генетического исследования. Цель исследования – оценить диагностическую значимость молекулярной аутопсии методом экзомного секвенирования для мужчин молодого возраста, умерших внезапной сердечной смертью (ВСС). Материал и методы . Выполнено экзомное секвенирование ДНК группы молодых мужчин (37 человек), умерших ВСС в возрасте до 45 лет (средний возраст 32,4 ± 6,4 года). ДНК выделена методом фенол-хлороформной экстракции из ткани миокарда. Экзомный анализ выполнен на платформе Illumina. Для некоторых из выявленных вариантов проведено подтверждающее прямое автоматическое секвенирование по Сэнгеру. Результаты . Из 37 образцов ДНК при анализе результатов секвенирования 205 генов обнаружено более 30 вариантов в 17 образцах (46 %), вероятно имеющих отношение к фенотипу ВСС. Найденные мутации локализованы в генах, ассоциированных с фенотипами, приводящими к развитию ВСС ( дилатационная или гипертрофическая кардиомиопатия, нарушения ритма сердца). Заключение. Впервые в России проведено экзомное секвенирование образцов ДНК мужчин, умерших ВСС в возрасте до 45 лет. Молекулярная аутопсия методом экзомного секвенирования – эффективный метод поиска причинных вариантов нуклеотидной последовательности при ВСС.

The immune system is responsible for control of the antigenic continuity, ensuring the friend-orfoe identification and the formation of appropriate responses by the organism, aimed either at destruction (in case of infection with infectious pathogens and transplantation of an alien graft), or protection of the "foe" to be incorporated by the host organism (under physiological pregnancy, or in case of pathology under malignant growth).

Single nucleotide polymorphisms rs1008832 of the CACNA1C gene, rs4027402 of the SYNE2 gene, rs2340917 of the TMEM43 gene, rs58225473 of the CACNB2 gene were found by sequencing the clinical exome of a group of men who died of sudden cardiac death (SCD) at the age of 45 years. The aim of the study is to study the association of single nucleotide polymorphisms rs1008832 of the CACNA1C gene, rs4027402 of the SYNE2 gene, rs2340917 of the TMEM43 gene, rs58225473 of the CACNB2 gene with SCD in a case-control study using routine molecular genetic analysis. Material and methods. SCD group (n = 400, mean age 53.2 ± 8.7 years, 70.9 % men, 29.1 % women) was formed using the SCD criteria of the European Society of Cardiology from the anonymous DNA bank of the deceased sudden death (1999–2019). The control group (n = 400, mean age 53.1 ± 8.3 years, 68.3 % men, 31.7 % women) was matched by sex and age to the SCD group from DNA banks of international projects MONICA and HAPIEE of living at the time of researches participants. Genotyping was carried out using the polymerase chain reaction followed by analysis of restriction fragment length polymorphism. Results. There were no statistically significant differences in the frequencies of genotypes and alleles of single nucleotide polymorphisms rs1008832 of the CACNA1C gene, rs4027402 of the SYNE2 gene, rs2340917 of the TMEM43 gene, rs58225473 of the CACNB2 gene between the SCD group and the control group (p > 0.05). Conclusions. The association of single nucleotide rs1008832 of the CACNA1C gene, rs4027402 of the SYNE2 gene, rs2340917 of the TMEM43 gene, rs58225473 of the CACNB2 gene with SCD has not been confirmed.

Aim . To investigate polymorphisms of 18 genes as possible molecular genetic markers of predisposition or resistance to development of non-infective (NE) or infective endocarditis (IE). Materials and methods . The study encompassed 81 patients with NE and 94 patients with IE. The control group included 225 conditionally healthy people. Polymorphisms of 18 genes were tested using polymerase chain reaction (PCR). Results . For the first time, a statistically significant relationship was identified between gene polymorphisms and valvular vegetations: for genes in the hemostatic system – rs6025 (1691 G > A) of the F5 gene (AG genotype), rs1126643 (807 C > T) of the ITGA2 gene (TT genotype); for folate pathway genes – rs1805087 (2756 A > G) of the MTR gene (AG genotype) and rs11697325 (–8202 A/G) of the MMP9 gene (AA genotype) and rs2476601 (C1858T) of the PTPN22 gene (TT genotype). The protective effect of gene polymorphisms was revealed: for the NOS3 gene (4b / 4b genotype) and G (–572) C of the IL6 gene (CC genotype). For two polymorphisms, an association with thromboembolic complications in NE was revealed: rs1126643 (807 C > T) of the ITGA2 gene and rs1799889 (–675 5G > 4G) of the PAI (SERPINE1) gene. In IE, such an association was detected for the polymorphism rs11697325 (–8202 A/G) of the MMP- 9 gene. Conclusion . The polymorphisms of candidate genes were revealed, that are associated with the clinical and hemostasiological characteristics of IE and NE. In NE, for the first time, the association with thromboembolic complications was identified for two polymorphisms: rs1126643 (807 C > T) of the ITGA2 gene and rs1799889 (– 675 5G > 4G) of the PAI-1 (SERPINE1) gene. In IE, such a relationship was detected for one polymorphism – rs11697325 (8202 A/G) of the MMP-9 gene.

Introduction. The study of the contribution of molecular genetic markers to the formation of occupational diseases is currently an urgent direction in occupational health. It is considered proven that the development and course of occupational diseases depends not only on the occupational risk, but also on the individual characteristics of the body of workers. The study of molecular genetic markers makes it possible to determine the risk groups of early development and unfavorable course of occupational diseases in the post-contact period. The study aims to explore the association of the ID polymorphism of the CASP8 gene with vibration disease, the timing of its development and some biochemical parameters. Materials and methods. We have examined eighty men with vibration disease. Of these: twenty three people with early stages of disease development (work experience under the influence of industrial vibration for less than fifteen years), fifty-seven people with late stages of disease development (work experience under the influence of industrial vibration for more than fifteen years). The scientists have carried DNA extraction from blood by the phenol-chloroform method. In the caspase 8 gene (CASP8) in the promoter we have checked the presence/absence of detention in 6 bp652 AGTAAG ins/del (rs3834129) using PCR.The researchers carried out the frequencies of the genotype and alleles of the I/D polymorphism of the CASP8 gene in the studied groups. Results. The authors found that the genotype ID of the rs3834129 polymorphism of the CASP8 gene is significantly more common in the group of patients with late-onset vibration disease (VD). The researchers found when studying some indicators of connective tissue metabolism, that the level of uronic acids (UC) was significantly lower in carriers of the genotype ID polymorphism of the CASP8 gene compared with carriers of other genotypes. Conclusion. The carriage of the genotype ID of the rs3834129 polymorphism of the CASP8 gene is a marker associated with resistance to the formation of VB in workers of vibration-hazardous professions, as well as with a low level of activity of fibroplastic processes. Limitations. The relatively small size of the studied groups. Ethics. The authors have conducted the study in compliance with the Ethical principles of conducting medical research with the participation of a person as a subject and the rules of clinical practice in the Russian Federation approved by Order of the Ministry of Health of the Russian Federation No. 266 of 19.06.2003. The conclusion of the Ethical Committee at the Federal State Budgetary Educational Institution of the Ministry of Health of the Russian Federation (Protocol No. 65 of 27.05.2014) and informed consent of patients was received.

Highlights. The association of single nucleotide polymorphic variants rs12143842 and rs4657139 of the NOS1AP gene with the duration of the QT interval was found in men of the Siberian population. Aim. To study the association of single nucleotide variants rs12143842 and rs4657139 of the NOS1AP gene with the duration of the QT interval. Methods. The study sample of men (1353 people) aged 25–69 years was formed from the DNA bank of participants in the international HAPIEE project and screening of young people 25–44 years old, residents of Novosibirsk. From each age subgroup (25–29, 30–34, …, 65–69 years old), about 10–15% of men with the shortest, average and longest QT interval were selected and the corresponding groups were formed. Genotyping of rs4657139 was carried out using PCR with RFLP (polymerase chain reaction followed by restriction fragment length polymorphism analysis). Genotyping rs12143842 – using RT-PCR (real-time polymerase chain reaction). Results. At the age of over 50 years, the CC genotype rs12143842 was detected in 66.1% of men in the group with a short and average QT interval and in 50.6% in the group with a long QT interval, while the TT genotype prevailed in the group with a long QT interval, 10, 8% of cases (odds ratio (OR) = 3.345, 95% confidence interval (CI) 1.149–9.739, p = 0.02). The homozygous TT genotype rs4657139 was more common in the long QT group, in 20.1% of cases, while the AA and AT genotypes predominated in the short, average QT groups (p = 0.041). A similar trend persists when separating by age in people over 50 years of age (p = 0.031) and when comparing genotype frequencies in the long and average QT groups in the model TT vs AA + AT & long QT vs short + average QT (p = 0.003). Conclusion. Single nucleotide variants rs12143842 and rs4657139 of the NOS1AP gene are associated with the duration of the QT interval in male residents of Novosibirsk.

Highlights. Probably causal mutations of QT interval prolongation in genes associated with LQTS were found in men of the Siberian population.Aim. To detect and study mutations in individuals with borderline prolongation of the QT interval in Siberian males.Methods. The study was conducted on the material of the international project HAPIEE in the period from 2003 to 2005 and screening of young people aged 25–44, performed in Novosibirsk. The total sample of men was 1353 people aged 25 to 69 years. From each age subgroup (25–29, 30–34, ..., 65–69 years old) 2–3 samples with the highest QT values were selected . The study group consisted of 30 men who subsequently underwent sequencing of a panel of genes. The search for mutations was carried out in genes associated with long QT syndrome (LQTS): KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1, SCN4B, KCNJ5, ANK2, CAV3, SNTA1, AKAP9, CALM1 and CALM2. All identified single nucleotide variants were verified by direct Sanger sequencing.Results. Three rare variants in the LQTS genes have been identified: p.P197L of the KCNQ1 gene, p.R176W, and p.D1003GfsX116 of the KCNH2 gene.Conclusion. In Caucasian men from the Novosibirsk population with borderline prolongation of the QT interval, probably causal substitutions in the LQTS genes – KCNH2 and KCNQ1, contributing to the prolongation of the QT interval, were found. To clarify the spectrum and frequency of occurrence of various mutations in genes, life-threatening arrhythmias in the population, additional studies are needed on extended samples.

ИССЛЕДОВАНИЕ АССОЦИАЦИИ RS7903146 ГЕНА TCF7L2, RS13266634 ГЕНА SLC30A8, RS1799883 ГЕНА FABP2

Background. Breast cancer (BC) is the most common female malignancy worldwide. partner and localizer of BRCA2 gene (PALB2) is directly involved in DNA damage response. germline mutation in PALB2 has been identified in breast cancer and familial pancreatic cancer cases, accounting for approximately 1–2% and 3–4%, respectively. the goal of this report was to describe new PALB2 mutation in a young Yakut breast cancer patient with family history of cancer. Material and methods. Genomic DNA were isolated from blood samples and used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOPHIA GENETICS, Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). paired-end sequencing (2 × 150 bp) was conducted using NextSeq 500 system (Illumina, USA). Results. Here we describe a case of a never-before-reported mutation in the PALB gene that led to the early onset breast cancer. We report the case of a 39-year-old breast cancer Yakut woman with a family history of pancreatic cancer. Bioinformatics analysis of the NGS data revealed the presence of the new PALB2 gene germinal frameshift deletion (NM_024675:exon1:c.47dela:p.K16fs). in accordance with dbPubMed ClinVar, new mutation is located in codon of the PALB2 gene, where the likely pathogenic donor splice site mutation (NM_024675.3:c.48+1delG) associated with hereditary cancer-predisposing syndrome has been earlier described. Conclusion. We found a new never-before-reported mutation in PALB2 gene, which probably associated with early onset breast cancer in Yakut indigenous women with a family history of pancreatic cancer.

The aim of the study was to evaluate the association of methylation of the F2RL3, CDKN2A gene with sudden cardiac death (SCD). Material and methods. Case-control study design. The SCD group included 150 deceased men (mean age 46.7 ± 9.2 years) with the main pathological diagnoses of acute circulatory failure, acute coronary insufficiency, which meets the SCD criteria of the European Society of Cardiology. The control group included 150 men who died suddenly, but not due to cardiovascular pathology (mean age 42.6 ± 1.2 years). DNA was isolated by phenol-chloroform extraction from myocardial tissue in both groups. The methylation status of the F2RL3 gene (19: 16890405-16890606, GRCh38.p13) and the CDKN2A gene (9: 21974726-21974877, GRCh38.p13) was assessed by methyl-specific polymerase chain reaction. Results. In the SCD group, 17.3 % (26/150) had the F2RL3 gene completely methylated (MM); in 6.0 % (9/150) it is completely unmethylated (UU); 76.7 % (115/150) had both methylated and unmethylated F2RL3 (MU) gene. In the control group, 16 % (24/150) had the F2RL3 gene completely methylated (MM); in 5.3 % (8/150), it is completely unmethylated (UU); 78.7 % (118/150) had both methylated and unmethylated F2RL3 (MU) gene. When comparing the groups, there were no statistically significant differences in the methylation status of the F2RL3 gene between the groups (p > 0.05). In all subjects in the SCD group and the control group, the CDKN2A gene is completely unmethylated. Conclusions. Methylation of genes F2RL3, CDKN2A is not associated with sudden cardiac death.

An effective system to diagnose predisposition to development of sudden cardiac death (SCD) is required in order to determine the risk of developing a sudden fatal outcome well in advance of the onset thereof, including in people with asymptomatic cardiovascular disease, as well as to implement early preventive measures that can result in a decrease in the population mortality from cardiovascular diseases. Thus, the search for SCD risk markers becomes a topical issue for modern health care. According to recent studies, epigenetic mechanisms of heredity, and DNA methylation above all, play an important role in development of many diseases. The review provides the results of recent foreign and Russian studies on identification of a link between DNA methylation and development of cardiovascular diseases being the basis for SCD (IHD, cardiomyopathies, heart rhythm disturbances). The major part of the review is dedicated to studying DNA methylation in IHD, which is the most epigenetically explored nosology at the moment. Attention is also paid to studies of the DNA methylation role in development of acute coronary syndrome and myocardial infarction, which have development mechanisms similar to those of SCD. There were only few studies on identification of a link between DNA methylation and cardiomyopathies and cardiac arrhythmias conducted, however, an association of specific genes methylation with the explored nosologies was revealed. The review also provides pathogenetic substantiations of the possibilities to use epigenetic markers of cardiovascular diseases as SCD markers. Thus, it has been established that study of genes the methylation of which is associated with IHD (CTH, PLCB1, PTX3, MMP9, FN1, F2RL3, ABCB1, FOXP3, GDF15, IL6, CASR), with lipid metabolism disorders and atherosclerosis (CETP, CCL2, SREBF2, TIMP1), as well as with heart rhythm disturbances (SCN5A and KCNQ1), may be most promising in relation to SCD.

1 Научно-исследовательский институт терапии и профилактической медицины – филиал Федерального государственного бюджетного научного учреждения «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук» 630089, Россия, г. Новосибирск, ул. Бориса Богаткова, 175/1 2 Федеральное государственное бюджетное образовательное учреждение высшего образования «Новосибирский государственный медицинский университет» Министерства здравоохранения Российской Федерации 630091, Россия, г. Новосибирск, Красный просп., 52 3 Государственное бюджетное учреждение здравоохранения Новосибирской области «Новосибирское областное клиническое бюро судебно-медицинской экспертизы» 630087, Россия, г. Новосибирск, ул. Немировича-Данченко, 134

Цель. Изучение ассоциации полиморфизмов rs9939609 гена FTO, rs7903146 гена TCF7L2, rs1799883 гена FABP2 с морбидным ожирением у женщин. Материалы и методы. Группа морбидного ожирения (n=192, средний возраст 57,02 ± 7,16 лет, ИМТ> 40 кг/м2) и контрольная группа (n=450, средний возраст 55,44 ± 7,41 лет, ИМТ 20 - 25 кг/м2) сформированы из банка ДНК международного исследования HAPIEE. Генотипирование выполнено методами ПЦР-ПДРФ и ПЦР в режиме реального времени с использованием TaqMan зондов (Applied Biosystems, США). Статистическая обработка полученных результатов осуществлена в программном обеспечении SPSS. Результаты. Не выявлено статистически значимых различий между группой морбидного ожирения и контрольной группой по частотам генотипов rs7903146 гена TCF7L2, rs1799883 гена FABP2 (р>0,05). В группе морбидного ожирения у женщин доля носителей генотипа ТТ полиморфизма rs9939609 гена FTO статистически значимо меньше (26,6%), а генотипа АТ значимо больше (53,6%), чем в контрольной группе (38,4%; 45,1%, соответственно), (ОШ=0,58, 95%ДИ 0,4-0,84, p=0,004; ОШ=1,41, 95%ДИ 1,003-1,98, p=0,047, соответственно). Выводы. Генотип АТ полиморфизма rs9939609 гена FTO является генотипом риска морбидного ожирения у женщин, а генотип ТТ обладает протективным эффектом в его отношении. Не обнаружено ассоциации вариантов нуклеотидной последовательности rs7903146 гена TCF7L2 и rs1799883 гена FABP2 с морбидным ожирением у женщин. Aim. Study the association of FTO rs9939609, TCF7L2 rs7903146, rs1799883 FABP2 polymorphisms on the risk of morbid obesity in women. Materials and methods. The morbid obesity group (n=192, average age 57.02 ± 7.16 years, BMI > 40 kg/m2) and the control group (n=450, average age 55.44 ± 7.41 years, BMI 20-25 kg/m2) were formed from the DNA bank of the international HAPIEE research. Genotyping was performed by PCR-RFLP and real time PCR using TaqMan (Applied Biosystems, USA). The results were statistically processed in the SPSS software. Results. There were no statistically significant differences in the genotype frequencies of TCF7L2 rs7903146, FABP2 rs1799883 (р>0.05) between the morbid obesity group and the control group. The morbid obesity group has the number of TT genotype carriers of FTO rs9939609 polymorphism less (26,6%) and AT genotype more (53,6%) than in the control group (38,4%; 45,1%, respectively), (OR=0.58, 95%CI 0.4-0.84, p=0.004; OR=1.41, 95%CI 1.003-1.98, p=0.047, respectively). Conclusion. AT genotype of FTO rs9939609 is the genotype of the risk of morbid obesity in women and TT genotype has a protective effect against it. Polymorphisms TCF7L2 rs7903146, FABP2 rs1799883 were not associated with morbid obesity in the studied group of women.

Backgraound. High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer. The prevalence of BRCA1/2 germline mutations is the highest in HGSOC. patients with germline BRCA gene mutations are more likely to respond to platinum-based chemotherapy. Clinical trials demonstrate the effectiveness of PARP inhibitors in the treatment of BRCA-associated ovarian cancer. Re-administration of PARP inhibitors after response to platinum-based chemotherapy demonstrates an increase in progression-free survival rates regardless of BRCA status. it is important for understanding the development of molecular mechanisms of resistance to platinum drugs and PARP inhibitors, as well as for developing new treatment strategies and tools to overcome resistance. Case description. This clinical case of BRCA-associated hereditary ovarian cancer demonstrates the efficacy and good tolerability of PARP inhibitor maintenance therapy following the treatment of the first relapse, as well as the efficacy of re-administration of PARP inhibitors following the treatment of the second relapse. The short-course of re-treatment with PARP inhibitors was accompanied by the development of multidrug resistance. the overall survival time was 112 months. Conclusion. The presence of mutations in BRCA1/2 genes is a promising justification for the administration of maintenance therapy with PARP inhibitors. Re-administration of PARP inhibitor maintenance therapy for relapsed ovarian cancer is currently being considered as a possible therapeutic option. deciphering the molecular mechanisms of resistance to PARP inhibitors is of paramount importance for the development of new treatment strategies and tools to overcome chemoresistance, re-sensitization of the tumor to platinum-based drugs or PARP inhibitors.