Сахарный диабет 2-го типа (СД2) является независимым фактором риска сердечно-сосудистых заболеваний, наличие которых значимо повышает сердечно-сосудистый риск. К основным факторам риска развития СД2 относят ожирение, неправильное питание, сниженную физическую активность и генетическую предрасположенность. Наследуемость СД2, по данным близнецовых исследований, достигает 72%. В настоящее время наиболее эффективным методом поиска генетических факторов комплексных заболеваний является полногеномный поиск ассоциаций, на основе результатов которого для выявления лиц с высоким риском развития СД2 могут быть созданы шкалы генетического риска. Данные, полученные в ходе исследований генетических факторов СД2, могут быть использованы для скрининга, профилактики и разработки новой таргетной фармакотерапии с возможным индивидуально оптимизированным лечением. Целью обзора являются представление актуальных данных по вкладу наследственности в развитие СД2 и оценка генетического риска его развития.

The aim of the study was to develop a panel for detecting heterozygous carriage of frequent mutations associated with phenylketonuria (PKU), and to determine their allelic frequencies in one of the regions of Russia. PKU is one of the most common monogenic diseases with autosomal recessive inheritance. Carrier screening leads to a reduction in the number of children born with PKU. The diagnostic panel included 23 pathogenic variants of the PAH gene nucleotide sequence. Participants of the study (n = 642) were randomly selected from an ESSE-Vologda population-based study. Genotyping was performed using real-time polymerase chain reaction on a QuantStudio 12K Flex Real-Time PCR System (Thermo Fisher Scientific, United States). The data were analyzed using the TaqMan Genotyper Software (Thermo Fisher Scientific, United States). Seventeen heterozygous carriers of six variants of the nucleotide sequence associated with the development of PKU were identified: R408W (rs5030858), A403V (rs5030857), I306V (rs62642934), L48S (rs5030841), IVS12+1G>A (rs5030861), R261Q (rs5030849_C_T). The frequency of heterogyzotes in the Russian population was 2.65% (95% CI 1.55–4.21), or 1 : 38. The data obtained indicate the prospects of mass screening for the carriage of frequent mutations associated with PKU in people with an uncomplicated family history. The developed diagnostic panel allows one to rapidly obtain the result of genetic analysis and can be used for PKU carrier screening.

The article presents the results of clinical, instrumental and molecular genetic tests of three generations of a family with inherited cardiomyopathy caused by a new variant in the MYBPC3 gene. A specific feature of this case is the phenotypic heterogeneity of the mutation — a combination of hypertrophic cardiomyopathy and left ventricular non-compaction in family members. Attention is drawn to the various severity of clinical manifestations in relatives of carriers of mutation: from asymptomatic to severe heart failure and acute cerebrovascular accident.

Progress in genetics and molecular research enabled discovery of mutations in BRCA1 and BRCA2, leading to the development of hereditary breast (BC) and ovarian (OC) cancer. Genetic testing contributes to early diagnosis and targeted prevention of these cancers. Objective: To investigate the prevalence of pathogenic variants in BRCA1 and BRCA2 genes in patients with BC/OC and in a population-based sample without oncological diseases. Methods: 156 patients with diagnosed BC/OC were included in the study consecutively. In addition to it, 359 women from a population-based sample ESSE-Vologda were recruited in the study. Variants of BRCA1 and BRCA2 were detected using a custom panel. Results: Among cancer patients there were 5 carriers (3.21%) of mutations in BRCA1 (4 - rs80357906, 2.56%; 1 - rs80357711, 0.64%) and 1 carrier (0.64%) of rs80359550 in BRCA2. In a population-based sample no mutations were identified. The presence of BRCA1 (rs80357906, rs80357711) or BRCA2 (rs80359550) variants increases the risk of BC/OC at least 2.63 times (р=0.0009). Conclusion: Detection of pathogenic variants in BRCA1 and BRCA2 could facilitate early diagnosis and timely prevention of BC and OC.

Некомпактный миокард левого желудочка (НМЛЖ) характеризуется развитием ряда осложнений, что в сочетании с сопутствующими заболеваниями обычно приводит к полипрагмазии. Фармакогенетическое тестирование (ФГТ), направленное на выявление вариантов генов, ассоциированных с метаболизмом лекарственных препаратов (ЛП), может позволить подобрать наиболее эффективную и безопасную лекарственную терапию в каждом конкретном случае. В исследование было включено 16 больных с НМЛЖ, его осложнениями и другими заболеваниями. Всем пациентам проводилась оценка 60 однонуклеотидных полиморфизмов (SNP) с помощью полимеразной цепной реакции в реальном времени в амплификаторе QuantStudio 12KFlexReal-TimePCRSystem (ThermoFisherScientific, США). По результатам ФГТ выявлено 62,5% пациентов с НМЛЖ, генотипы которых ассоциированы с изменением метаболизма ЛП. У 12,5% пациентов в анамнезе прием ЛП, требующих коррекции дозы или замены на другой ЛП с учетом результатов ФГТ. A left ventricular non-compaction cardiomyopathy (LVNC) is characterized by the development of a number of complications, which in combination with concomitant diseases usually leads to polypharmacy. Pharmacogenetic testing (PGT), aimed at identifying variants of genes associated with the metabolism of drugs, allows to choose the most effective and safe drug therapy in each case. The study includes 16 patients with LVNC, its complications and other diseases. All patients were assessed for 60 single nucleotide polymorphisms (SNPs) using real-time polymerase chain reaction in a QuantStudio 12KFlexReal-TimePCRSystem thermocycler (ThermoFisher Scientific, USA). According to the results of PGT 62.5% of the patients with LVNC and genotypes associated with a change in the metabolism of drugs were revealed. 12.5% of the patients had a history of taking drugs that required dose adjustment or replacement with another drug, taking into account the results of PGT.

Целью работы было создание панели для скрининга носительства мутаций, связанных с развитием муковисцидоза (МВ), и апробация панели в популяционной выборке ЭССЕ-Вологда. В исследование вошли 642 участника из популяционной выборки региона Вологды. Детекцию мутаций осуществляли с помощью системы QuantStudio 12K Flex Real-Time PCR. Создана скрининговая панель, включающая 60 мутаций гена CFTR. Среди 642 участников исследования выявлено 23 гетерозиготных носителя 6 мутаций, связанных с развитием МВ, частота носительства составила 3,58% (ДИ 95%: 2,28-5,33%) или 1:28 чеовек. Разработанная панель может быть использована для скрининга гетерозиготных носителей МВ. The aim of the study was to create a panel for screening the carriers of mutations associated with the development of cystic fibrosis (CF), and testing the panel on 642 participants of the population-based cohort study (ESSE-Vologda). Variants were detected using the QuantStudio 12K Flex Real-Time PCR system. A custom panel that includes 60 CFTR variants was created. Among 642 participants in the study, 23 heterozygous carriers of 6 CFTR mutations were identified. The carrier frequency was 3.58% (CI95%: 2.28-5.33%) or 1:28. The custom panel can be used for screening heterozygous CF carriers.

The article presents the results of clinical, instrumental and molecular genetic tests of three generations of a family with inherited cardiomyopathy caused by a new variant in the MYBPC3 gene. A specific feature of this case is the phenotypic heterogeneity of the mutation — a combination of hypertrophic cardiomyopathy and left ventricular non-compaction in family members. Attention is drawn to the various severity of clinical manifestations in relatives of carriers of mutation: from asymptomatic to severe heart failure and acute cerebrovascular accident.

Целью работы было создание и апробация панели из 23 мутаций гена PAH, ответственных за развитие фенилкетонурии, и оценка частоты гетерозиготного носительства данных мутаций в популяционной выборке ЭССЕ-Вологда. Исследование включало 642 участника из популяционной выборки региона Вологды. Наличие мутаций в гене PAH определяли с помощью системы QuantStudio 12K Flex Real-Time PCR. Среди 642 участников исследования было выявлено 17 носителей мутаций в гене PAH. Частота гетерозиготных мутаций составила 2,65% (ДИ 95%: 1,55--4,21%) или 1:38 человек. Полученные данные свидетельствуют о высокой частоте носительства мутаций гена PAH в российской популяции. Предложенная панель может быть использована для скрининга носительства мутаций, вызывающих фенилкетонурию. The aim of the work was to create and test a custom panel of 23 PAH gene variants responsible for the development of phenylketonuria, and to evaluate the frequency of heterozygous carriers of these mutations among 642 participants of the population-based cohort study ESSE-Vologda. The presence of mutations was determined using QuantStudio 12K Flex Real-Time PCR system. 17 carriers of PAH variants among 642 participants were identified. The frequency of heterozygous carriers was 2.65% (CI95%: 1.55-4.21%), or 1:38. The data obtained indicate a high frequency of PAH variants in the Russian population. The proposed panel can be used for screening on heterozygous carriers of variants that cause phenylketonuria.

Нейросенсорная тугоухость является одним из наиболее распространенных наследственных сенсорных расстройств, наиболее частой причиной которой являются мутации гене GJB2. Целью работы было определение частоты носительства мутаций в гене GJB2 в популяционной выборке ЭССЕ-Вологда. Исследование включало 642 участника из популяционной выборки региона Вологды. Наличие мутаций в гене GJB2 определяли с использованием системы QuantStudio 12K Flex Real-Time PCR. Определены генотипы 642 образцов и выявлено 39 носителей мутаций в гене GJB2, частота гетерозиготных мутаций в выборке составила 6,07% (ДИ 95%: 4,36-8,21%) или 1:16. Высокая частота носительства мутаций гена GJB2, связанных с нарушением слуха свидетельствует о перспективности профилактического скрининга у молодых семей, планирующих детей. Non-syndromic hearing loss (NSHL) is one of the most prevalent inherited sensory disorder, mutations in GJB2 gene represent a major cause of NSHL worldwide. The aim of the work was to determine frequency mutations in GJB2 gene among 642 participants from a population-based cohort study ESSE-Vologda. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The genotypes of 642 samples were determined and 39 carriers of mutations in the GJB2 gene were detected, the frequency of heterozygous mutations in the sample was 6.07% (CI95%: 4.36-8.21%) or 1:16. The high frequency mutations in the GJB2 gene associated with NSHL indicates the potential for preventive screening in young families planning children.

Aim . To study the effect of the shelf life of frozen whole blood samples in a biobank on the amount of released deoxyribonucleic acid (DNA). Material and methods . The study included whole blood samples placed in tubes with the anticoagulant EDTA (ethylenediaminetetraacetic acid at a concentration of 1,8 mg/ml) from participants in the epidemiological study ESSE-RF-1 and ESSE-RF-2 and cohort studies conducted at the National Medical Research Center for Therapy and Preventive Medicine. The samples were stored in the biobank of the National Medical Research Center for Therapy and Preventive Medicine at temperature from -22О C to -32О C. The shelf life from blood collection to DNA extraction ranged from several weeks to 11 years. DNA was extracted using QIAamp DNA Blood Mini Kit (250) and 96 Blood Kit (Qiagen, Germany). Statistical analysis was performed using the R 3.6.1 software. To analyze the association of blood storage time with the logarithm of DNA concentration, a linear regression was used. Results. The analysis included data on the DNA concentration of 5405 samples. Multivariate regression showed that the blood shelf life was significantly associated with a decrease in concentration by 3,92% (3,16-4,68) for each year of storage (p <0,0001). For 509 samples, the DNA concentration was measured twice, immediately after isolation and after 4,5 years of DNA storage at -32О C. During storage, the concentration of DNA increased by an average of 2% (p=0,046). Conclusion. Long-term storage of whole blood samples at temperature from -22О C to -32О C is associated with a decrease in the DNA yield. Long-term storage of the isolated DNA at a temperature of -32О C is not associated with a decrease in its concentration.