TCF7L2 gene polymorphism in populations of f ive Siberian ethnic groups

Investigation of the frequencies of functionally signif icant gene variants in the context of medical biology and gene geography is a relevant issue for studying the genetic structure of human populations. The transition from a traditional to an urbanized lifestyle leads to a higher incidence of civilizational diseases associated with metabolic disorders, including type 2 diabetes mellitus. The goal of the present paper is to analyze the frequencies of functionally signif icant gene alleles in the metabolic prof iles of indigenous Siberian peoples to identify the gene pool resilience, evaluate the susceptibility of various ethnic groups to metabolic disorders under changing environmental conditions, and predict the epidemiological situation that may occur in the near future. The study was performed in the monoethnic samples of eastern and western Buryats, Teleuts, Dolgans, and two territorial groups of Yakuts. A real-time PCR was used to determine the frequencies of single nucleotide polymorphisms (SNPs) G103894T, rs12255372, and C53341T, rs7903146 in the TCF7L2 gene. The results obtained were compared to the frequencies identif ied for Russians from Eastern Siberia and the values available in the literature. The frequencies of the polymorphic variants studied in the samples from the indigenous Siberian peoples place them in between Caucasian and East Asian populations, following the geographic gradient of polymorphism distribution. A signif icantly lower occurrence of type 2 diabetes risk alleles TCF7L2 (103894T) and TCF7L2 (53341T) in the samples of indigenous Siberian peoples compared to Russians was observed, which agrees with their lower susceptibility to metabolic disorders compared to the newcomer Caucasian population. Taking into account urbanization, a reduced growth in type 2 diabetes incidence may be predicted in indigenous Siberian peoples, i. e. Buryats, Yakuts, Dolgans, and Teleuts, compared to the newcomer Caucasian population. A further study of population structure with respect to different metabolic prof ile genes is required to better understand the molecular genetic foundations of the adaptive potential of indigenous Siberian peoples

Polymorphism of lipid exchange genes in some populations of South and East Siberia

Lipid metabolism disorders underlie the pathogenesis of a number of diseases. Indigenous peoples of Siberia have a specific genetically determined type of metabolism supporting such lipid blood parameters that favor increased consumption (in comparison with Caucasians) of animal products. At the same time, indigenous Siberian ethnic groups are less susceptible to metabolic diseases. The objective of the presented study was to investigate the allele frequencies of lipid metabolism genes in indigenous populations of Siberia to identify the ethnic features of allele frequency distribution for polymorphic variants in genes CETP (G1264A, rs5882), LPL (C1791G, rs328) and FTO (C83401A, rs8050136) in the samples taken from Buryats, Teleuts and Russians of Eastern Siberia, and to compare them with data on world populations. Samples of the Eastern (N = 132) and Western (N = 278) Buryats, Teleuts (N = 120), Russians (N = 122) and persons of mixed Buryat-Russian origin (N = 56) were genotyped by real-time PCR using competitive TaqMan-probes. The obtained results have for the first time demonstrated that the CETP and FTO allele frequencies in the Buryat samples are intermediate between European and East Asian populations. Significantly lower incidence of the obesity-assossiated 83401A allele of the FTO gene has been shown in Buryats, compared with Russians, which is consistent with lower susceptibility of the indigenous ethnic groups to metabolic disorders. There have been no population differences in the distribution of LPL gene polymorphic variants associated with dyslipidemia, which means they probably do not contribute to the ethnic characteristics of the lipid profile. The intermediate frequencies of the CETP 1264G and FTO 83401A alleles found in the metis group demonstrate that the metabolic disorders associated with these variants can be rather expected in the descendants of mixed marriages than among Buryats. It has also been demonstrated that Teleuts differ by FTO 83401A allele frequency from some of the European groups and have the lowest detected frequency of the allele CETP 1264G associated with the favorable lipid blood parameters

Genetic polymorphism of CYP1A1 and CYP2D6 in populations of Buryats, Teleuts and Russians of Eastern Siberia

The study of the gene polymorphism of the system of biotransformation of xenobiotics is an important area of modern medical and genetic research. The aim of this work is to study the frequency of the alleles of the CYP1A1 (A2455G (*2C), rs1048943), CYP2D6 (A2549del (*3), rs35742686); G1846A (*4), rs3892097) genes of Teleuts (n = 115), Eastern Buryats (n = 132), Western Buryats (n = 280), their Métis (n = 56), and Russians of East Siberia (n = 122). Genotyping was performed using real-time PCR with competitive TaqMan allele-specific probes. The frequency of the CYP1A1*2C (2455G) allele was 28.8 % in the Eastern Buryat, 34.6 % in the Western Buryat, 16.7 % in the Teleut, and 31.3 % in the Métis cohort. The frequency of CYP1A1*2C (2455G) in the Russians of Eastern Siberia (4.1 %) corresponds to the frequency range found in European populations. A high-frequency occurrence of CYP1A1*2C (2455G) among Buryats and Teleuts may be indicative of a higher population-wide risk of diseases influenced by technogenic pollutants – substrates of CYP1A1. The CYP2D6*3 (2549del) allele was not detected in cohorts of indigenous populations, among Russians it was 0.4 %, and it was 2.7 % among Métis. The frequency of CYP2D6*4 (1846A) in Eastern and Western Buryats was 5.3 % and 4.3 %, respectively, for Teleuts it was 7.4 %. It was significantly higher in the Russian population (12 %), and among Métis (9.8 %). The obtained data makes it possible to predict a reduced risk of side effects of drugs and cancer associated with CYP2D6*3 (2549del) and CYP2D6*4 (1846A) in the Buryat and Teleut populations. However, metisation introduces new polymorphic variants into indigenous populations, shifts gene frequencies and changes the degree of risks

Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage

Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.Natural Sciences and Engineering Research Council of Canada (NSERC); European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Beatrice Hunter Cancer Research Institute; Terry Fox Foundationinfo:eu-repo/semantics/publishedVersio

Association of Single Nucleotide Polymorphisms in the IL-18 Gene with Production of IL-18 Protein by Mononuclear Cells from Healthy Donors

IL-18 has proinflammatory effects and participates in both innate and adaptive cellular and humoral immunity. A number of SNPs that influence IL-18 production are found in the gene promoter region. We investigated the association of SNPs in the IL-18 promoter at −607 and −137 with the level of IL-18 protein production by PBMC from healthy donors from Southwestern Siberia. The genetic distribution of these SNPs in the promoter site was established by PCR. IL-18 protein production was determined by ELISA. Our results showed that PBMC from donors carrying allele 137C have lower levels of both spontaneous and LPS-stimulated IL-18 production. In contrast, PBMC from donors carrying allele 607A showed significant increases in spontaneous and stimulated IL-18 production compared to wild type. Our study suggests that the SNPs −607 and −137 in the promoter region of the IL-18 gene influence the level of IL-18 protein production by PBMC from healthy donors in Southwestern Siberia

The ILE462VAL polymorphism of the cytochrome P450 CYP1A1 gene among Tundra Nenets in Yamalo-Nenets Autonomous Okrug, Nganasans in the Taimyr Peninsula and Russians in Siberia

The work concerns a polymorphism of the cytochrome Р450 CYP1A1 gene, the CYP1A1*2C variant (Ile462Val, rs1048943). This substitution results in a two- fold increase in enzyme activity, which leads to accumulation of active intermediates and increases the risk of DNA mutations and chemically induced carcinogenesis. It has been demonstrated that the 462Val allele may be a risk factor in some oncological and other multifactorial diseases. This study was performed on Tundra Nenets in Yamalo-Nenets Autonomous Okrug (N = 271), Nganasans in the Taimyr Peninsula (N = 186) and Russians in North Siberia (N = 267). The cohorts did not include descendants of mixed marriages. Genotyping was performed using Real-Time PCR with competitive TaqMan allele-specific probes. The frequency of the 462Val allele in the Tundra Nenets cohort was 23.8 % (95 % CI 20.4–27.6 %), which corresponds to the frequency range found in East Asian populations and is higher than the values typical of European populations. The 462Val allele frequency in the Russian cohort was 5.8 % (95 % CI 4.1–8.1 %), which corresponds to the frequency range of European populations. The 462Val allele frequency in the Nganasans cohort was 39.0 % (95 % CI 34.2–44.0 %), which is higher than the frequencies found in European, Asian and African populations. Frequencies of the  462Val variant close to that in Nganasans have been observed in Greenland Inuits, native Americans as a whole and the Southern Chinese. A high-frequency occurrence of the 462Val allele among Tundra Nenets and Nganasans may be indicative of a populationwide risk of diseases influenced by this genetic polymorphism, especially when traditional mainstays are gone or previously unknown ecotoxicants appear in the areas

DETERMINING REFERENCE RANGES FOR TREC AND KREC ASSAYS IN IMMUNE DEFICIENCY SCREENING OF NEWBORNS IN RUSSIAN FEDERATION

In this work, we used a reference population of newborns and sampled dried blood spots on Guthrie cards of 2,739 individual samples to determine the reference intervals for TRECs and KRECs values, in order to diagnose primary immunodeficiency by means of neonatal screening. The median absolute values for TRECs and KRECs were 195 (CI95%: 185-206) and 185 (CI95%: 176-197) copies per μl, respectively; the normalized value for TRECs was 2780 (CI95%: 2690-2840), and for KRECs, 2790 (CI95%: 2700-2900) copies per 2 × 105 copies of the albumin gene or 105 cells. The reference interval was calculated for 99 and 99.9 percentiles of total TRECs and KRECs individual values. Due to asymmetric distribution of data, the outliers were filtered off, using the Tukey’s criterion applied after logarithmic transformation of the data. When analyzing absolute values for TREC/KREC (per μL of blood), no “drop-down” TRECs values were identified; for KRECs, 18 experimental values were excluded from further analysis (from 9.8 to 13.5). The outlying values were not identified among the normalized values of TRECs/KRECs. The obtained reference values for TRECs and KRECs (at the 0.1 percentile level) were, respectively, 458 and 32 per 105 cells, or 23 and 17 per μl of blood samples from neonates

Polymorphism rs3088232 in the BRDT gene is associated with idiopathic male infertility in the West Siberian Region of Russia

Allelic variants of genes involved in spermatogenesis can contribute to the genetic predisposition to idiopathic male infertility. In the present study we investigated the association of polymorphism rs3088232 in the BRDT gene with the risk of this pathology on the sample of 105 infertile patients and 230 healthy controls. We revealed the association of allele G (OR = 1.80; CI 1.16—2.80; p = 0.008) and genotype GG (OR = 6.47; CI 1.23—34.15; p = 0.01) with idiopathic male infertility

Study of relationships between HLA-G gene polymorphism, intrauterine infection and recurrent miscarriage in women

The relationship between the HLA-G gene polymorphism (rs41551813, rs12722477, rs41557518), intrauterine infection and recurrent miscarriage (RM) in women were studied. The case group consisted of 180 patients with RM, defined as two or more consecutive miscarriages (min = 2; max = 8) at up to 20 weeks of gestation, and with clinically confirmed pregnancies and non-viable fetuses. At the time of examination. the women were enrolled from the Genetic Counseling Center at the Kemerovo Regional Clinical Hospital, Kemerovo, Russia, and were not pregnant. Each patient underwent a gynecological examination. We excluded women with a history of medical abortion, birth, and ectopic pregnancies. In addition, we excluded women with endocrine (e.g. diabetes) disorders. To exclude other known causes of spontaneous abortion, the following tests were performed: ultrasound examination of pelvic organs, and karyotyping in women and men. The women’s mean age in the RM group, was 29.6±4.8 (SD) years. The control group comprised 408 fertile women. These women didn’t have a history of spontaneous abortion, or a family history of congenital malformations. They have born, at least, 1-2 healthy children. Women’s mean age at birth of last child was 26.8±5.2 (SD) years. Influence of the intrauterine infection was analyzed on the basis of laboratory tests. Diagnostics of bacterial vaginosis and vulvo-vaginal candidiasis by microscopic examination was conducted. Viral agent infections (herpes simplex virus type 2, cytomegalovirus, human papilloma virus type 16/18), Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Gardnerella vaginalis and Trichomonas vaginalis were detected by enzyme-linked immunoassay and polymerase chain reaction (PCR). The data were obtained from the medical cards of the surveyed women. All the women gave a written informed consent before participating in the study. Typing of polymorphisms of Thr31Ser (rs41551813, HLA-G*01:03) in exon 2, Leu110Ile (rs12722477, HLA-G*01:04) and 1597 delС (rs41557518, HLA-G*01:05N) in exon 3 HLA-G genes were performed by realtime PCR followed by melting analysis. The study showed that the intrauterine infection was not a risk factor for RM (p = 0.30) in the examined women. It was found that the 110 Ile allele (HLA-G *01:04) was a risk factor for RM both in women with intrauterine infection [ORa = 4.50 (2.41-8.38), p = 2.09e-06], and in women without infection [ORa = 2.46 (1.44-4.21), p = 0.0009]. The cooperative influence of genetic and infections factors with the risk of RM in women was revealed [ORa+f = 3.50 (2.01-6.09), p = 8.78e-06]. Our results will be useful in understanding the molecular mechanisms of immune disorders in fetomaternal interface, and for choosing the strategy of management and treatment in women with RM