Search

Objective. To assess the association of single nucleotide polymorphisms of genes potentially involved in the comorbidity of bronchial asthma (BA) and essential hypertension (HTN) in patients with different time onset of the diseases.Design and methods. Genotyping of 92 SNPs was performed using MALDI-TOF mass spectrometry in patients with BA and HTN (n = 97) and healthy individuals (n = 153). The group of patients with comorbid pathology was divided into two subgroups depending on the time of onset of symptoms of BA relative to HTN, and the prevalence of all studied SNPs was compared in each subgroup relative to the control.Results. The variant rs11590807 regulating expression for UTP25, TRAF3IP3, C1orf74, HSD11B1-AS 1, IRF6 genes in the heart, blood vessels, and lung is associated with BA and HTN, regardless of the time onset of each of these diseases. Associations of other variants are specific with respect for each subgroup of comorbid diseases. The rs1010461 variant, which regulates the expression of RNASE4 and ANG genes, is linked with HTN as the first phenotype of the comorbidity. The rs769214, rs11032700, rs11032699, rs484214, and rs480575 variants, which regulate the expression of CAT gene, are associated with BA as the first phenotype of disease comorbidity.Conclusions. We found specific associations of the studied polymorphic variants in the development of comorbid phenotypes of BA and HTN, which differ in the time of manifestation of each of the diseases relative to each other.

The simultaneous development of several diseases (comorbidity, syntropy) in particular patients is a common phenomenon in modern clinical practice. However, the results of recent epidemiological studies have pointed to the new phenomenon of inverse comorbidity (or dystropy)—that means that some diseases can occur together in one person more rarely than in other people according to frequencies of these disorders in the population as a whole. Such dystropic (inversely comorbid) diseases are Huntington’s disease and oncological ones. In this paper, we perform a review of existing information supporting the hypothesis of the oncoprotection in carriers of HTT mutation, also including features of interactions of genes and proteins in such processes as autophagy and apoptosis.

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

In this study we performed a comparative gene expression analysis of carotid arteries in the area of atherosclerotic plaques and healthy internal mammary arteries of patients with advanced atherosclerosis by using microarray HumanHT-12 BeadChip ("Illumina"). The most down-regulated genes were APOD, FABP4, CIDEC and FOSB, and up-regulated gene was SPP1 (|FC|64; pFDR0.05). The majority of differentially expressed genes were down-regulated in advanced atherosclerotic plaques. Unexpectedly, genes involved in immune and inflammatory responses were down-regulated in advanced atherosclerotic plaques to compare with the healthy arteries (arachidonic acid metabolism, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, Jak-STAT signaling pathway, TNF signaling pathway). "Cellular response to metal ion" (metallothioneins) and "Extracellular matrix organization" were the most significant Gene ontology terms among the down- and up-regulated genes, respectively.S ispol'zovaniem mikrochipov HumanHT-12 BeadChip (“Illumina”, SShA) proveden sravnitel'nyĭ polnogenomnyĭ analiz ékspressii genov v kletkakh sonnykh arteriĭ, porazhennykh aterosklerozom, i kletkakh intaktnykh vnutrennikh grudnykh arteriĭ u patsientov s klinicheski vyrazhennym aterosklerozom na pozdnikh stadiiakh patologicheskogo protsessa. Sushchestvennoe snizhenie urovnia ékspressii v kletkakh sonnykh arteriĭ, porazhennykh aterosklerozom, po sravneniiu s intaktnymi vnutrennimi grudnymi arteriiami, vyiavleno dlia genov APOD, FABP4, CIDEC i FOSB, a uvelichenie ékspressii – dlia gena SPP1 (|FC|64; pFDR0,05). V kletkakh ateroskleroticheski porazhennykh arteriĭ po sravneniiu s intaktnymi sosudami vyiavleno preobladanie doli genov so snizhennoĭ funktsional'noĭ aktivnost'iu. V chastnosti, vyiavleno snizhenie ékspressii genov immunovospalitel'nogo otveta (metabolizm arakhidonovoĭ kisloty, vzaimodeĭstvie “tsitokin-tsitokinovyĭ retseptor”, signal'nye puti NOD-podobnykh retseptorov, Jak-STAT i TNF). Naibolee znachimymi biologicheskimi protsessami, v kotorykh uchastvuiut belkovye produkty genov so snizheniem ékspressii v ateroskleroticheski porazhennykh sonnykh arteriiakh po sravneniiu s intaktnymi vnutrennimi grudnymi arteriiami, iavliaiutsia otvety kletki na deĭstvie ionov metallov (metallotioneiny), a dlia belkovykh produktov genov s uvelicheniem ékspressii v ateroskleroticheski izmenennykh arteriiakh - organizatsiia vnekletochnogo matriksa.

Background Recent studies have focused on the potential role of epicardial adipose tissue (EAT) in the development of coronary artery disease (CAD). ABCA1 and ABCG1 transporters regulate cell cholesterol content and reverse cholesterol transport. We aimed to determine whether DNA methylation and mRNA levels of the ABCA1 and ABCG1 genes in EAT and subcutaneous adipose tissue (SAT) were associated with CAD. Methods Paired EAT and SAT samples were collected from 82 patients undergoing elective cardiac surgery either for coronary artery bypass grafting (CAD group, N = 66) or valve surgery (NCAD group, N = 16). ABCA1 and ABCG1 mRNA levels in EAT and SAT samples were analyzed using real time polymerase chain reaction, ABCA1 protein levels in EAT samples were assessed by western blotting. ABCA1 and ABCG1 DNA methylation analysis was performed in 24 samples from the CAD group and 9 samples from the NCAD group via pyrosequencing. Results DNA methylation levels in the ABCA1 promoter and ABCG1 cg27243685 and cg06500161 CpG sites were higher in EAT samples from patients with CAD compared with NCAD (21.92% vs 10.81%, p = 0.003; 71.51% vs 68.42%, p = 0.024; 46.11% vs 37.79%, p = 0.016, respectively). In patients with CAD, ABCA1 and ABCG1 DNA methylation levels were higher in EAT than in SAT samples (p ABCA1 mRNA levels in EAT samples were reduced in the subgroup of patients with CAD and concomitant carotid artery disease or peripheral artery disease compared with the NCAD group (p = 0.024). ABCA1 protein levels in EAT samples tended to be lower in CAD patients than in the NCAD group (p = 0.053). DNA methylation levels at the ABCG1 cg27243685 site positively correlated with plasma triglyceride concentration (r = 0.510, p = 0.008), body mass index (r = 0.556, p = 0.013) and waist-to-hip ratio (r = 0.504, p = 0.012) in SAT samples. Conclusion CAD is associated with ABCA1 and ABCG1 DNA hypermethylation in EAT. CAD with concomitant carotid artery disease or peripheral artery disease is accompanied by decreased ABCA1 gene expression in EAT. DNA methylation levels at the ABCG1 cg27243685 locus in SAT are associated with hypertriglyceridemia and obesity.

Objectives To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course. Methods We included in this study 404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with "stats" and "genetics" packages. Results We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character of the course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; р=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; р=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; р=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; р=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; р=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; р=0.0274). Conclusion Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).

Background The history of human populations occupying the plains and mountain ridges separating Europe from Asia has been eventful, as these natural obstacles were crossed westward by multiple waves of Turkic and Uralic-speaking migrants as well as eastward by Europeans. Unfortunately, the material records of history of this region are not dense enough to reconstruct details of population history. These considerations stimulate growing interest to obtain a genetic picture of the demographic history of migrations and admixture in Northern Eurasia. Results We genotyped and analyzed 1076 individuals from 30 populations with geographical coverage spanning from Baltic Sea to Baikal Lake. Our dense sampling allowed us to describe in detail the population structure, provide insight into genomic history of numerous European and Asian populations, and significantly increase quantity of genetic data available for modern populations in region of North Eurasia. Our study doubles the amount of genome-wide profiles available for this region. We detected unusually high amount of shared identical-by-descent (IBD) genomic segments between several Siberian populations, such as Khanty and Ket, providing evidence of genetic relatedness across vast geographic distances and between speakers of different language families. Additionally, we observed excessive IBD sharing between Khanty and Bashkir, a group of Turkic speakers from Southern Urals region. While adding some weight to the “Finno-Ugric” origin of Bashkir, our studies highlighted that the Bashkir genepool lacks the main “core”, being a multi-layered amalgamation of Turkic, Ugric, Finnish and Indo-European contributions, which points at intricacy of genetic interface between Turkic and Uralic populations. Comparison of the genetic structure of Siberian ethnicities and the geography of the region they inhabit point at existence of the “Great Siberian Vortex” directing genetic exchanges in populations across the Siberian part of Asia. Slavic speakers of Eastern Europe are, in general, very similar in their genetic composition. Ukrainians, Belarusians and Russians have almost identical proportions of Caucasus and Northern European components and have virtually no Asian influence. We capitalized on wide geographic span of our sampling to address intriguing question about the place of origin of Russian Starovers, an enigmatic Eastern Orthodox Old Believers religious group relocated to Siberia in seventeenth century. A comparative reAdmix analysis, complemented by IBD sharing, placed their roots in the region of the Northern European Plain, occupied by North Russians and Finno-Ugric Komi and Karelian people. Russians from Novosibirsk and Russian Starover exhibit ancestral proportions close to that of European Eastern Slavs, however, they also include between five to 10 % of Central Siberian ancestry, not present at this level in their European counterparts. Conclusions Our project has patched the hole in the genetic map of Eurasia: we demonstrated complexity of genetic structure of Northern Eurasians, existence of East-West and North-South genetic gradients, and assessed different inputs of ancient populations into modern populations. Electronic supplementary material The online version of this article (10.1186/s12863-017-0578-3) contains supplementary material, which is available to authorized users.

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

Background Atherosclerotic plaque formation results from complex cellular interactions in the intima of arteries, which take place between resident cells of the vessel wall (smooth muscle cells (SMC) and endothelial cells) and cells of the immune system (macrophages (MF)). Less well known is the genomic alterations in cells involving in the atherosclerotic process as can be important in plaque progression and instability. Aim The main purpose of the study is to assess the spectrum of structural genomic alterations in the tissue of atherosclerotic artery wall and to evaluate of difference between structural variants (SV) in SMC and MF. Materials and methods Samples of atherosclerotic plaques of the internal carotid artery (ICA) was collected from patients during endarterectomy (n=100) and the atherosclerotic coronary arteries (ACA) was obtained by coronary artery bypass surgery (n=10, group: bpACA) and by autopsy (n=8, apACA). Specimens were stored in liquid nitrogen. White blood cells (WBC) derived from the same patients. Control group was the health persons with same age (WBC, n=100). The genomic imbalances in bpACA were assessed by array comparative genomic hybridization (array-CGH, CGH Microarray 2x400K). Identified SVs was verified by droplet-digital PCR using TaqMan-assays (reference assay is RNAse P) in bpACA and ICA groups.SMC and MF were immunostained (Anti-Human CD68 Antibody and Alpha-SMA Antibody) and collected by laser capture microdissection of fresh frozen apACA samples (30–40 cells of each per sample). Collected cells were lysed and DNA amplified by whole genome amplification technique along with WBC of the same person, then analyzed by array-CGH. Results We found 90 SV in atherosclerotic coronary arteries, 13% of them were no mentioned before in Database of Genomic Variants. We selected interested SVs that contains only one gene (ACACB, ABCC9, ERLIN1, SFMBT1, PRKRA, and SIRPB1). The loss in the 3p21.1 region (SFMBT1) was in 11.48% patients and 8.5% in control group. Among patients who had diabetes mellitus (DM2) had more frequently loss of SFMBT1 (16%) than patients without DM2 (8%). The frequency of gain 2q31.2 (PRKRA) was 6% in patients whereas in control group we identified it in only one person. The frequency of loss 20p13 (SIRPB1) was approx. 67% in both groups. Several aneuploidies were found in MF (9 trisomies and 3 monosomies) and SMCs (1 trisomy and 8 monosomies). In two patients, SMCs had a normal karyotype. The ratio of duplications and deletions in MF and SMCs was 1:0.8 and 1:7, respectively. In MF of 6 patients identified same duplication in chromosome region 9q34.13-q34.2, (arr[hg19] 9q34.13(9:134337452-135931774)x3) about 2Mb in size. Conclusion Our study indicates that genomic alterations are diverse in their structure and are widely represented in cells involved in the atherosclerotic process.

Tuberculosis is a global pressing healthcare issue in the modern world. Host genetics is an important modifier of the disease risk. Genetic and genomic studies aim to reveal key inherited variants of the human genome associated with the susceptibility to tuberculosis. Much attention is given to the study of differential genetic susceptibility to various stages of tuberculous infection, particularly latent tuberculosis, the detection of which is most challenging. Susceptibility genes have been identified and most of which exhibit a relatively small effect on the disease risk. On the other hand, a proportion of children suffer from Mendelian susceptibility to tuberculosis associated with rare mutations with deterministic effect in genes for the components of cellular immunity against intra-cellular infections. This review focuses on the current achievements in genomic studies devoted to the identification of genes important for the implementation of the immune response and protection against the development of the infection in different populations in the world.

For identification of somatic mitochondrial DNA (mtDNA) mutations, the mtDNA major noncoding region (D-loop) sequence in blood samples and carotid atherosclerosis plaques from patients with atherosclerosis was analyzed. Five point heteroplasmic positions were observed in 4 of 23 individuals (17%). Only in two cases could heteroplasmy have resulted from somatic mutation, whereas three heteroplasmic positions were found in both vascular tissue and blood. In addition, length heteroplasmy in a polycytosine stretches was registered at nucleotide positions 303-315 in 16 individuals, and also in the 16184-16193 region--in four patients. The results suggest that somatic mtDNA mutations can occur during atherosclerosis, but some heteroplasmic mutations may appear in all tissues, possibly being inherited.

Aim to study associations of polymorphic genetic variants of inflammatory response, endothelial function, lipid metabolism, and blood coagulation with impaired renal function in patients with ST elevation myocardial infarction (STEMI). Material and methods We enrolled in the study 171 patients admitted to the Kemerovo Cardiology Dispensary within 24 hours after onset of STEMI. All patients underwent genotype identification of 25 polymorphic variants of 18 major candidate genes for cardiovascular disease. Genotyping was performed with DNA chip SINKAR-1 (Institute of Medical Genetics and LLC "Genomic Diagnosis"). Glomerular filtration rate (GFR) was estimated using serum creatinine level measured at admission. Results Comparison of allelic and genotype frequencies of the studied polymorphisms revealed that angiotensin-converting enzyme (ACE) gene rs4291 was associated with decreased GFR: odds ratio (OR) for carriers of rare TT genotype was 2.31 [1.01-5.25], =0.043. Analysis of genotype combinations of ACE rs4343 polymorphism and hepatic lipase gene (LIPC) rs1800588 showed that AA genotype of rs4343 polymorphism in combination with CC genotype of rs1800588 polymorphism was associated with lowest risk of renal dysfunction, whereas GG and AG genotypes of ACE rs4343 in combination with TT and CT genotypes of LIPC rs1800588.

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19-2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05-2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06-4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07-2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03-2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02-2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

The Russian Federation is the largest and one of the most ethnically diverse countries in the world, however no centralized reference database of genetic variation exists to date. Such data are crucial for medical genetics and essential for studying population history. The Genome Russia Project aims at filling this gap by performing whole genome sequencing and analysis of peoples of the Russian Federation.Here we report the characterization of genome-wide variation of 264 healthy adults, including 60 newly sequenced samples. People of Russia carry known and novel genetic variants of adaptive, clinical and functional consequence that in many cases show allele frequency divergence from neighboring populations. Population genetics analyses revealed six phylogeographic partitions among indigenous ethnicities corresponding to their geographic locales. This study presents a characterization of population-specific genomic variation in Russia with results important for medical genetics and for understanding the dynamic population history of the world's largest country.

To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course.We included in this study 404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with "stats" and "genetics" packages.We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character of the course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; р=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; р=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; р=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; р=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; р=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; р=0.0274).Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).

The concept of syntropic diseases was proposed at the beginning of the last century to emphasize the phenomenon of nonrandom co-occurrence of human disorders. Common genes underlying specific syntropic diseases were called syntropic genes. The application of this concept to contemporary genomic studies will facilitate the understanding of the molecular basis of complex diseases, provide future direction for discovering new targets for therapy and prognosis, and may even lead to the reassessment of disease classification for the practice of more precise personalized medicine. With the acceptance of the syntropic genes theory, new genetic tests, focused on markers pointing to a set of pathogenetically linked diseases rather than to a single nosology, can be developed.

In contrast to the modest progress made in the interpretation and clinical application of genomic data, genotyping technologies have experienced great progress. Genotyping costs are progressively decreasing making individual genotyping more commonly available. Financial availability of individual genome analysis and the strong desire of many people to know about their individual genomic characteristics, promotes the marketing of genetic tests of variable predictive value directly to the public. A survey of 2000 Russian respondents revealed very positive attitudes and beliefs towards these genetic developments: 85% of surveyed individuals would like to have their genetic risk for avoidable diseases estimated, and 89% responded stating that they would try to change their lifestyle by giving up bad habits, following a recommended diet or taking medications if a high risk of disease was identified. It is believed that with time, validated genetic information will find its rightful place in medicine, by supplementing phenotypic clinical data with validated genetic interpretations.

We performed an association analysis for the mtDNA major common variants and haplogroups with incidence of myocardial infarction and essential prognostic characteristics in patients. A comparison of patients (N = 406) and control groups (N = 183) uncovered a higher frequency of HV0 haplogroup in patients (6.9% vs. 2.2%; p = 0.033). Patients with early infarction (before age of 55 in men) had a higher frequency of 16189C variant, compared to patients who endured first infarction at age older than 55 (24.1% vs. 12.5%; p = 0.008). In addition, haplogroup U2e was only detected in the subgroup with early infarction (4.4%; p = 0.004). Haplogroup U5 was less frequent in patients with early infarction (5.1% vs. 15.4%; p = 0.002). Observations during a 1-year follow-up uncovered that patients with recurring cardiovascular incidents had higher frequency of haplogroup H1 (20%, versus 4.5% in patients without complications, p = 0.002) and variant 16189C (30% versus 13.5%; p = 0.018). Haplogroup U5 was more frequent in the subgroup of patients with lower (

The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the alien Russian population. All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.

In this review, the development of ideas focused on the phenomenon of disease combination (comorbidity) in humans is discussed. The genetic bases of the three forms of the phenomenon, comorbidity (syntropias), inverse comorbidity (dystropias), and comorbidity of Mendelian and multifactorial diseases, are analyzed. The results of personal genome-wide association studies of the genetic risk profile that may predispose an individual to cardiovascular disease continuum (CDC), including coronary heart disease, type 2 diabetes, hypertension, and hypercholesterolemia (CDC syntropy), as well as the results of bioinformatic analysis of common genes and the networks of molecular interactions for two (bronchial asthma and pulmonary tuberculosis) diseases rarely found in one patient (dystropy), are presented. The importance of the diseasome and network medicine concepts in the study of comorbidity is emphasized. Promising areas in genomic studies of comorbidities for disease classification and the development of personalized medicine are designated.

We have performed association analysis for mtDNA most common variants and haplogroups with myocardial infarction and some prognostic characteristics in patients. Comparison of patients (N=406) and controls (N=183) has shown higher frequency of HV0 haplogroup in patients (6.9% vs. 2.2%; p=0.033). Patients with early infarction (before age 55), comparing to patiens older than 55 and the first infarction, had higher frequency of 16189C variant (24.1 vs. 12.5%; p=0.008); also, haplogroup U2e was registered only in the subgroup with early infarction (4.4%; p=0.004). On the other side, haplogroup U5 was less frequent in the patients with early infarction (5.1% vs. 15.4%; p=0.002). The patients with recurring cardiovascular incidents during one year follow-up had higher frequency of haplogroup H1 (20% versus 4.5% in the patients without complications, p=0.002) and variant 16189C (30% versus 13.5%; p=0.018). Haplogroup U5 was more frequent in the group of patients with left ventricular ejection fraction less than 40%: 17.1% comparing to 8.2% in the group with ejection fraction>40%; p=0.034. The results suggest that mtDNA polymorphism contributes to coronary atherosclerosis. The associations could be explained by the polymorphism effect on oxidative phosphorylation and reactive oxygen production in mitochondria.

BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma.METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects.RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at pCONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.

The objective of this study was to identify genes targeted by both copy number and copy-neutral changes in the right coronary arteries in the area of advanced atherosclerotic plaques and intact internal mammary arteries derived from the same individuals with comorbid coronary artery disease and metabolic syndrome. The artery samples from 10 patients were screened for genomic imbalances using array comparative genomic hybridization. Ninety high-confidence, identical copy number variations (CNVs) were detected. We also identified eight copy-neutral changes (cn-LOHs) > 1.5 Mb in paired arterial samples in 4 of 10 individuals. The frequencies of the two gains located in the 10q24.31 (ERLIN1) and 12q24.11 (UNG, ACACB) genomic regions were evaluated in 33 paired arteries and blood samples. Two patients contained the gain in 10q24.31 (ERLIN1) and one patient contained the gain in 12q24.11 (UNG, ACACB) that affected only the blood DNA. An additional two patients harboured these CNVs in both the arteries and blood. In conclusion, we discovered and confirmed a gain of the 10q24.31 (ERLIN1) and 12q24.11 (UNG, ACACB) genomic regions in patients with coronary artery disease and metabolic comorbidity. Analysis of DNA extracted from blood indicated a possible somatic origin for these CNVs.

According to epidemiological observations, Opisthorchis felineus liver fluke invasion is negatively associated with the development and severity of allergic diseases in endemic regions of Russia. We hypothesized that the invasion is an important factor in gene-environmental interactions (GEI) underlying allergy. To prove this, we tested 10 single nucleotide polymorphisms of immune response modifying genes in 428 individuals stratified by atopic bronchial asthma presence and O. felineus invasion. Using regression models, a statistically significant interaction between the rs6737848 polymorphism of SOCS5 gene and O. felineus invasion was observed (pint=0.001, OR=5.66, 95% CI 1.96-16.31 for dominant model; pint=0.003; OR=4.38, 95% CI 1.68-11.45 for additive model). The interaction is based on the statistically significant association between the SOCS5 gene and atopic bronchial asthma in patients without O. felineus infection, while no such association is seen in patients infected by the helminth. These data confirm for the first time the importance of the helminth invasion as an environmental factor influencing the association between genetic factors and atopic bronchial asthma. In particular, O. felineus diminishes the risk of atopic bronchial asthma associated with the SOCS5 gene polymorphism.

Helminths have accompanied mankind since the earliest periods of its formation, parasites and humans have been coevolving for a long time and it is considered that it was helminths that played an important selective role in evolution of genes of the human immune system. The article presents the data on the genetic contribution to the intensity and clinical course of helminth infections in different populations, including the results of genome-wide association studies, and discusses the concept of commonality of genes of susceptibility to helminthiases and allergic diseases.

The first data on the existence of multiple genomic rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity, in vascular tissues and peripheral blood leukocytes from patients with atherosclerosis, are presented. Compared to internal mammary arteries and peripheral blood leukocytes, right coronary arteries in the atherosclerotic plaque area presented with a higher CNV length and number of genes located in their vicinity. In each of the patients, 6-16% of CNVs were common to the three types of tissues examined. Therefore, most of the copy number variations in the tissues affected by atherosclerosis (from 68 to 91% in each of the patients) were of somatic origin. The gains in 3p21.31 (CACNA2D2), 7q32.1 (FLNC), 19p13.3 (C19orf29, PIP5K1C), and 21q22.3 (COL6A1) were detected in vascular tissues but not in peripheral blood leukocytes. Moreover, the gain in 7p15.2 (SKAP2), detected in the patients with atherosclerosis, did not overlap with any CNV regions currently reported in The Database of Genomic Variants. The loss of heterozygosity in 12 out of 13 chromosomal regions was copy neutral and covered tumor suppressor genes (SFRP1, CEBPD, RB1CC1, DIRAS3, TUSC3, and ZDHHC2).

The distribution of the allele and genotype frequency for the TOMM40 gene polymorphic variants rs741780, rs157580, rs1160985, rs2075650, and rs8106922 was analyzed in a sampling of ethnic Russians from the city of Kemerovo. The study of the structure of linkage disequilibrium in terms of five studied polymorphic variants showed the presence ofa haplotype block 2 Kb in length, which includes three polymorphic variants, i.e., rs741780, rs1160985, and rs8106922. The differences in the frequencies of alleles and genotypes in terms of the polymorphic rs2075650 and rs157580 variants between ethnic Russians from the city of Kemerovo and other European populations were detected. It was discovered that polymorphic variants of TOMM40 rs741780, rs1160985, and rs8106922 are associated with serum triglyceride concentrations. In men, the polymorphic variant rs2075650 is associated with low-density lipoprotein cholesterol levels. In women, the polymorphic variant rs741780 is associated with diastolic blood pressure levels.