[Show abstract][Hide abstract] ABSTRACT: Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.
Acta Naturae 10/2015; 7(3):89-99. · 1.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allele frequencies and genetic diversity in the population of Teleuts were assessed by the Alu repeat polymorphism at eight autosomal loci (ACE, APOA1, PLAT, F13, PV92, A25, CD4, D1). For comparison, the study included previously obtained data on the Alu polymorphism in 19 indigenous populations of Siberia. On the dendrogram of genetic distances, the Teleut population is located in the cluster of Siberian ethnic groups, which are similar in origin, geography, and cultural traditions.
[Show abstract][Hide abstract] ABSTRACT: The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs0415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H
e = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F
ST = 0.79%), which was related to the high subdivision of the northern Eurasian population (F
ST = 11.83%), was observed.
[Show abstract][Hide abstract] ABSTRACT: X-chromosome microsatellite markers are a convenient tool for studying genetic variability in human populations and DNA identification, especially during the decreased informativeness of autosomal markers. The results of genetic analysis of Siberian populations by ten X-linked microsatellite markers (DXS8378, GATA172D05, DXS7132, DXS9898, DXS7423, DXS8377, DXS101, DXS6809, DXS6789, and HPRTB) are presented. The allele frequencies, criminalistics parameters, and genetic relations between populations were calculated. The average level of expected heterozygosity (He) was 0.73 in populations. The total level of genetic differentiation in ten populations was relatively low (Fst = 0.031) compared to the level determined by autosomal and Y chromosome markers. The high probability of the establishment of differences (PD) between two unrelated individuals using a ten X-STR marker system was demonstrated. The average PD value in the panel of ten X chromosome microsatellite markers was 0.9999999997 in women and 0.999998 in men. The total level of genetic differentiation in a pool of ten populations is 0.03186.
[Show abstract][Hide abstract] ABSTRACT: X-chromosome markers are informative tool for studying of the genetic diversity in human populations and become useful for DNA identification when certain complex kinship cases need to be unraveled. In this work, we present population genetic data of 10 X-chromosome STRs (DXS8378, DXS9898, DXS8377, HPRTB, GATA172D05, DXS7423, DXS6809, DXS7132, DXS101 and DXS6789). Average level of expected heterozygosity (He) in populations under study was 0.73. Total level of genetic differentiation for 10 studied populations was relatively low (Fst = 0.031 comparing to autosomal and Y-chromosomal markers. Allele frequencies and parameters of forensic interest for panel of X-STRs were calculated. The overall values of PDf and PDm are 0.9999999997, 0.999998 respectively. The overall level of genetic differentiation for 10 population (Fst) is 0.03186.
[Show abstract][Hide abstract] ABSTRACT: The variability of eight polymorphic variants of the IL4, IL4R, IL10, IL13, IL12A, and IL12RB2 genes encoding key cytokinesand their receptors in 57 world populations has been assessed. A correlation between the allele frequency distribution of the examined genes and climatic and geographic factors was observed.
[Show abstract][Hide abstract] ABSTRACT: This paper reports the results of replicative analysis of associations of 15 SNPs in a region of 14 genes previously identified in genome-wide association studies (GWAS) with early-onset schizophrenia in Kazakhs. An association of early-onset schizophrenia with genetic markers in three genes (VRK2, KCNB2, and CPVL) was found. An association of rs2312147 in the VRK2 gene with schizophrenia was also previously reported in the Chinese population, so this marker may be considered as possibly race-specific. Two groups consisting of four and six genes demonstrating intergenic epistatic interactions were revealed by multifactor dimensionality reduction methods. The gene ontologies of 14 studied genes were reduced to variants of one molecular function (peptidase activity) and one biological process (positive regulation of biosynthesis processes). Bioinformatic analysis of the protein-protein interactions of products of the genes under study demonstrates that the products of six out of 14 genes may be involved in a single interrelated network, the major connecting link of which is represented by their ubiquitination by the UBC protein.
[Show abstract][Hide abstract] ABSTRACT: Single nucleotide polymorphism (SNP) are the most common type of genetic polymorphisms. Despite the progress in sequencing and postgenomic technologies, point genotyping of SNPs remains the most demanded approach in human and medical genetics. In this paper, the experience in the application of multiple SNP genotyping using MALDI-TOF mass-spectrometry for the analysis of genetic diversity of immune response genes in human populations has been described. It is demonstrated that MALDI-TOF mass-spectrometry is rapid, accurate and efficient method for medium-scale SNP genotyping. In four populations (Russian, Komi, Khant, and Buryat) the similar spectrum of allelic frequencies for 56 SNPs in 41 genes implicated in the regulation of immune response was found. Populations under study have the similar level of genetic diversity and are clustered according their geographic location. Economic effectiveness of MALDI-TOF mass-spectrometry in comparison with a real time PCR technology is estimated.
[Show abstract][Hide abstract] ABSTRACT: A replicative association analysis of Alzheimer’s disease (AD) was carried out for 15 genetic markers that have been associated with cognitive disorders in genome-wide association studies. In the Russian population, AD was associated with CSMD1 rs2616984 (OR = 1.50, 95% CI 1.07–2.09, p-value = 0.018) and, potentially, with NOTCH4 rs313296 (OR = 1.53, 95% CI 0.98–2.39, p-value = 0.06) and NRIP1 rs2229741 (OR = 1.35, 95% CI 0.99–1.85, p-value = 0.061). Combinations of epistatically interacting genes (CSMD1 and NRIP1; NOTCH4, CSMD1, and NRIP1; and TLR4, CSMD1, and NRIP1) were identified, along with their genotype combinations that showed a significant association with AD and the highest predictive values. Possible molecular mechanisms of the gene involvement in AD pathogenesis are discussed. A bioinformatics analysis of the biological processes, molecular functions, and protein-protein interactions for the AD genes indicated that the genes may play a modulating or modifying role, acting together in various regulatory and signaling pathways involved in AD.
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is one of the most severe gestational complications which is one of the leading causes of maternal and perinatal morbidity and mortality. A growth in the incidence of severe and combined forms of the pathology has been observed in recent years. According to modern concepts, inadequate cytotrophoblast invasion into the spiral arteries of the uterus and development of the ischemia-reperfusion syndrome in the placental tissue play the leading role in the development of preeclampsia, which is characterized by multipleorgan failure. In this regard, our work was aimed at studying the patterns of placental tissue transcriptome that are specific to females with PE and with physiological pregnancy, as well as identifying the potential promising biomarkers and molecular mechanisms of this pathology. We have identified 63 genes whose expression proved to differ significantly in the placental tissue of females with PE and with physiological pregnancy. A cluster of differentially expressed genes (DEG) whose expression level is increased in patients with preeclampsia includes not only the known candidate genes that have been identified in many other genome-wide studies (e.g., LEP, BHLHB2, SIGLEC6, RDH13, BCL6), but also new genes (ANKRD37, SYDE1, CYBA, ITGB2, etc.), which can be considered as new biological markers of preeclampsia and are of further interest. The results of a functional annotation of DEG show that the development of preeclampsia may be related to a stress response, immune processes, the regulation of cell-cell interactions, intracellular signaling cascades, etc. In addition, the features of the differential gene expression depending on preeclampsia severity were revealed. We have found evidence of the important role of the molecular mechanisms responsible for the failure of immunological tolerance and initiation of the pro-inflammatory cascade in the development of severe preeclampsia. The results obtained elaborate the concept of the pathophysiology of preeclampsia and contain the information necessary to work out measures for targeted therapy of this disease. ;
Acta Naturae 04/2014; 6(2):71-83. · 1.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The structure of the Buryat gene pool has been studied based on the composition and frequency of Y-chromosome haplogroups in eight geographically distant populations. Eleven haplogroups have been found in the Buryat gene pool, two of which are the most frequent (N1c1 and C3d). The greatest difference in haplogroup frequencies was fixed between western and eastern Buryat samples. The evaluation of genetic diversity based on haplogroup frequencies revealed that it has low values in most of the samples. The evaluation of the genetic differentiation of the examined samples using an analysis of molecular variance (AMOVA) shows that the Buryat gene pool is highly differentiated by haplotype frequencies. Phylogenetic analysis within haplogroups N1c1 and C3d revealed a strong founder effect, i.e., reduced diversity and starlike phylogeny of the median network of haplotypes that form specific subclusters. The results of a phylogenetic analysis of the haplogroups identified common genetic components for Buryats and Mongols.
[Show abstract][Hide abstract] ABSTRACT: Autosomal gene pools of 27 populations representing 12 ethnic groups of Siberia, Central Asia, and the Far East have been characterized for the first time using a set of eight polymorphic Alu insertions. The results of our analysis indicate a significant level of genetic diversity in populations of northern Eurasian and the considerable differentiation of their gene pool. It was shown that the frequency of the Alu (−) allele at the CD4 locus was inversely related to the magnitude of the Mongoloid component of the gene pool: the lowest and highest frequencies of the CD4 Alu deletion were recorded in Eskimos (0.012) and in Russians and Ukrainians (0.35), respectively. A gene flow analysis showed that Caucasoid populations (Russians, Tajiks, and Uzbeks), as well as Turkic ethnic groups of southern Siberia (Altaians and Tuvans), Khanty, and Mansi populations, in contrast to ethnic groups of eastern Siberia and the Far East, have been recipients of a considerable gene flow. A correlation analysis showed that genetic distances determined using polymorphic Alu insertions were correlated with the anthropological characteristics of the populations studied.
[Show abstract][Hide abstract] ABSTRACT: The gene-pool structure of Tuvinians was examined in terms of the composition and frequency of Y-chromosome haplogroups in five geographically distanct populations. In the Tuvinian gene pool, a total of 22 haplogroups were identified with six of these, which were the most frequent (C3c, C3*, N1b, N1c1, Q1a3, and R1a1a). It was demonstrated that eastern regions of Tuva were most different from the other regions in haplotype frequencies. The evaluation of genetic diversity based on the frequencies of biallelic haplogroups and YSTR haplotypes revealed very high diversity values for all samples. In general, the genetic diversity values identified in Tuvinians were the highest for the indigenous ethnic groups of Siberia. The evaluation of the genetic differentiation of the samples examined using the analysis of molecular variance (AMOVA) showed that the gene pool of Tuvinians was relatively poorly differentiated with respect to haplogroup frequencies. Phylogenetic analysis within haplogroup N1b revealed strong founder effect, i.e., reduced diversity and star-like phylogeny of the median network of haplotypes, which formed a separate subcluster exclusive to Tuvinians. It was demonstrated that, in Tuvinians, haplogroup N1c1 was the most heterogeneous in haplotype profile and consisted of three different haplotype clusters, demonstrating considerable differences of western population from the rest of the Tuva populations. Phylogenetic analysis of haplogroups revealed common components for Tuvinians, Khakasses, Altaians, and Mongols.
[Show abstract][Hide abstract] ABSTRACT: A biological microchip (biochip) has been developed to study the genetic predisposition to sporadic form of Alzheimer’s disease (AD). The biochip allows of genotyping of ten genetic polymorphisms within APOE, TOMM40, APOJ, EXOC3L2, GAB2, A2M, CR1, BIN1, and PICALM genes. The assay includes the amplification of the loci of interest and subsequent allele-specific hybridization of the fluorescently labeled amplicons with oligonucleotides immobilized on the biochip. The genotyping of 166 patients and 128 controls revealed a significant association of APOE allele ɛ4 with susceptibility to AD (OR = 2.275, 95% CI 1.045–4.954, p = 0.034). Protective effects were observed for APOE allele ɛ2 and CLU (rs11136000) allele T (OR = 0.215, 59% CI 0.090–0.516, p = 0.001 and OR = 0.679, 95% CI 0.47–0.99, p = 0.042, respectively). A gene-gene interaction analysis revealed two AD-associated genotype combinations, APOE ɛ3/ɛ4 GAB2 G/G (OR = 2.49, 95% CI 1.43–4.32, p = 0.001) and APOE ɛ4/ɛ4 GAB2 G/G (OR = 3.55, 95% CI 1.23–10.24, p = 0.015). Based on the results of the combined multivariate analysis, an algorithm was developed to identify the individuals having a higher risk of AD.
[Show abstract][Hide abstract] ABSTRACT: Single-nucleotide polymorphisms (SNPs) are the most common type of genetic polymorphisms. Despite the progress in sequencing and postgenomic technologies, targeted SNP genotyping continues to be in highest demand in the approach to human and medical genetics. In this work, we describe the application of multiple SNP genotyping by MALDI-TOF mass spectrometry for analysis of genetic diversity of immune response genes in human populations. It was shown that MALDI-TOF mass spectrometry is a rapid, accurate, and efficient method of medium-scale SNP genotyping. Allele frequencies of 56 SNPs in 41 genes implicated in the regulation of immune response were similar in four populations studied (Russians, Komi, Khanty, and Buryats). These populations had similar levels of genetic diversity and were clustered according to their geographic location. The cost efficiency of MALDI-TOF mass spectrometry was evaluated compared to real-time PCR technology.
[Show abstract][Hide abstract] ABSTRACT: Type-I recessive congenital methemoglobinemia (RCM) is a rare autosomal disease characterized by a deficiency of the soluble form of nicotineamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) and clinically manifests as cyanosis of skin and mucous membranes. In the Russian Federation, type-I RCM is widely disturbed in Yakutia due to the local founder effect. The molecular genetics cause of type-I RCM in Yakutia is mutation c.806C>T in the CYB5R3 gene. In this work we used 13 polymorphic markers, which flanking the CYB5R3 gene to establish the founder haplotype. The age of the mutation was estimated as about 285 ± 135 years. In this work, we have evaluated the frequency of the c.806C>T mutation in Yakutia, which averaged 55 : 1000 Yakuts. The calculated frequency of disease was 1: 1250 Yakuts.
[Show abstract][Hide abstract] ABSTRACT: Moldova has a rich historical and cultural heritage, which may be reflected in the current genetic makeup of its population. To date, no comprehensive studies exist about the population genetic structure of modern Moldavians. To bridge this gap with respect to paternal lineages, we analyzed 37 binary and 17 multiallelic (STRs) polymorphisms on the non-recombining portion of the Y chromosome in 125 Moldavian males. In addition, 53 Ukrainians from eastern Moldova and 54 Romanians from the neighboring eastern Romania were typed using the same set of markers. In Moldavians, 19 Y chromosome haplogroups were identified, the most common being I-M423 (20.8%), R-M17* (17.6%), R-M458 (12.8%), E-v13 (8.8%), R-M269* and R-M412* (both 7.2%). In Romanians, 14 haplogroups were found including I-M423 (40.7%), R-M17* (16.7%), R-M405 (7.4%), E-v13 and R-M412* (both 5.6%). In Ukrainians, 13 haplogroups were identified including R-M17 (34.0%), I-M423 (20.8%), R-M269* (9.4%), N-M178, R-M458 and R-M73 (each 5.7%). Our results show that a significant majority of the Moldavian paternal gene pool belongs to eastern/central European and Balkan/eastern Mediterranean Y lineages. Phylogenetic and AMOVA analyses based on Y-STR loci also revealed that Moldavians are close to both eastern/central European and Balkan-Carpathian populations. The data correlate well with historical accounts and geographical location of the region and thus allow to hypothesize that extant Moldavian paternal genetic lineages arose from extensive recent admixture between genetically autochthonous populations of the Balkan-Carpathian zone and neighboring Slavic groups.
PLoS ONE 01/2013; 8(1):e53731. DOI:10.1371/journal.pone.0053731 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Analysis of the genome-specific linkage disequilibrium patterns in certain populations is a highly promising approach to the identification of functional variants that underlie susceptibility to complex diseases. In the present study, the linkage disequilibrium patterns of the methylenetetrahydrofolate reductase gene (MTHFR) were examined in a group of patients with coronary atherosclerosis (coronary artery disease, CAD) and in a control sample from the Russian population. It was demonstrated that in the samples from one population, which were differentiated by the presence or absence of CAD, the MTHFR linkage disequilibrium patterns had similar features. Association of the MTHFR rs7533315 and rs2066462 polymorphisms with CAD was demonstrated. In addition, the evolution of the haplotypes and their role in the formation of CAD in the Russian population was reconstructed. The data on the association between genetic variability in the MTHFR locus and pathogenetically important indices of lipid metabolism were obtained. The high informativeness of the haplotype approach in case-control tests for associations with CAD was demonstrated.