A matrix metalloproteinase 9 (MMP9) gene single nucleotide polymorphism is associated with predisposition to tick-borne encephalitis virus-induced severe central nervous system disease.

The progression of infectious diseases depends on causative agents, the environment and the host's genetic susceptibility. To date, human genetic susceptibility to tick-borne encephalitis (TBE) virus-induced disease has not been sufficiently studied. We have combined whole-exome sequencing with a candidate gene approach to identify genes that are involved in the development of predisposition to TBE in a Russian population. Initially, six exomes from TBE patients with severe central nervous system (CNS) disease and seven exomes from control individuals were sequenced. Despite the small sample size, two nonsynonymous single nucleotide polymorphisms (SNPs) were significantly associated with TBE virus-induced severe CNS disease. One of these SNPs is rs6558394 (G/A, Pro422Leu) in the scribbled planar cell polarity protein (SCRIB) gene and the other SNP is rs17576 (A/G, Gln279Arg) in the matrix metalloproteinase 9 (MMP9) gene. Subsequently, these SNPs were genotyped in DNA samples of 150 non-immunized TBE patients with different clinical forms of the disease from two cities and 228 control randomly selected samples from the same populations. There were no statistically significant differences in genotype and allele frequencies between the case and control groups for rs6558394. However, the frequency of the rs17576 G allele was significantly higher in TBE patients with severe CNS diseases such as meningo-encephalitis (43.5%) when compared with TBE patients with milder meningitis (26.3%; P = 0.01), as well as with the population control group (32.5%; P = 0.042). The results suggest that the MMP9 gene may affect genetic predisposition to TBE in a Russian population.

Single nucleotide polymorphism rs1800872 in the promoter region of the IL10 gene is associated with predisposition to chronic hepatitis C in Russian population.

Previously, we studied an association of two IL28B gene single nucleotide polymorphisms (SNPs) and three IL10 gene SNPs with predisposition to tick-borne encephalitis in a Russian population. In this study, a possible involvement of these SNPs in the development of predisposition to chronic hepatitis C (caused by structurally similar, related virus from the Flaviviridae family) was investigated in the same population. Only the IL10 promoter rs1800872 SNP was associated with predisposition to chronic hepatitis C. This SNP seems to be a common genetic marker of predisposition to two diseases caused by hepatitis C and tick-borne encephalitis viruses in Russian population.

Association of IL28B and IL10 gene polymorphism with predisposition to tick-borne encephalitis in a Russian population.

Genetic predisposition to tick-borne encephalitis (TBE) is rather poorly studied in human populations. Human genes encoding crucial components of antiviral immune response are most likely involved in protective mechanisms against TBE virus. Previously, several single nucleotide polymorphisms (SNPs) located in interleukin 28B (IL28B) and interleukin 10 (IL10) genes were associated with predisposition to chronic hepatitis C (caused by a structurally similar virus from the same Flaviviridae family) in a number of human populations. The aim of the present study was to estimate a possible association of the IL28B gene rs8103142 and rs12980275 SNPs and IL10 gene rs1800872, rs3021094, and rs3024498 SNPs with predisposition to TBE in a Russian population. Genotypic and allelic frequencies for these SNPs were analyzed in 132 non-immunized TBE patients (34 with fever, 60 with meningitis, and 38 with severe central nervous system disease) and compared with the population control (221 Novosibirsk citizens). The results obtained suggest that both studied IL28B gene SNPs, as well as the IL10 gene rs1800872 SNP are associated with predisposition to TBE in Russian population.

MtDNA Haplogroup A10 Lineages in Bronze Age Samples Suggest That Ancient Autochthonous Human Groups Contributed to the Specificity of the Indigenous West Siberian Population.

BACKGROUND: The craniometric specificity of the indigenous West Siberian human populations cannot be completely explained by the genetic interactions of the western and eastern Eurasian groups recorded in the archaeology of the area from the beginning of the 2nd millennium BC. Anthropologists have proposed another probable explanation: contribution to the genetic structure of West Siberian indigenous populations by ancient human groups, which separated from western and eastern Eurasian populations before the final formation of their phenotypic and genetic features and evolved independently in the region over a long period of time. This hypothesis remains untested. From the genetic point of view, it could be confirmed by the presence in the gene pool of indigenous populations of autochthonous components that evolved in the region over long time periods. The detection of such components, particularly in the mtDNA gene pool, is crucial for further clarification of early regional genetic history. RESULTS AND CONCLUSION: We present the results of analysis of mtDNA samples (n = 10) belonging to the A10 haplogroup, from Bronze Age populations of West Siberian forest-steppe (V-I millennium BC), that were identified in a screening study of a large diachronic sample (n = 96). A10 lineages, which are very rare in modern Eurasian populations, were found in all the Bronze Age groups under study. Data on the A10 lineages' phylogeny and phylogeography in ancient West Siberian and modern Eurasian populations suggest that A10 haplogroup underwent a long-term evolution in West Siberia or arose there autochthonously; thus, the presence of A10 lineages indicates the possible contribution of early autochthonous human groups to the genetic specificity of modern populations, in addition to contributions of later interactions of western and eastern Eurasian populations.

Association between polymorphisms in OAS2 and CD209 genes and predisposition to chronic hepatitis C in Russian population.

Chronic hepatitis C is a severe liver disease caused by positive-strand RNA virus. Previously, we reported an association between seven single nucleotide polymorphisms (SNPs) in four innate immunity genes (OAS2, OAS3, CD209, and TLR3) and human predisposition to tick-borne encephalitis, caused by a virus from the same Flaviviridae family, in a Russian population. Currently, genotype and allele frequencies for these SNPs were analyzed in 75 chronic hepatitis C patients and compared with the population control (269 Novosibirsk citizens). Data obtained suggest that the OAS2 rs1293762 and CD209 rs2287886 SNPs are associated with predisposition to chronic hepatitis C in Russian population.

Association of single nucleotide polymorphism rs3775291 in the coding region of the TLR3 gene with predisposition to tick-borne encephalitis in a Russian population.

Tick-borne encephalitis (TBE) is a central nervous system (CNS) disease caused by the neurotropic, positive-sense RNA virus, tick-borne encephalitis virus (TBEV). A possible association between predisposition to TBE in a Russian population and two polymorphisms, a 32bp deletion in the coding region of the chemokine receptor CCR5 gene and the rs3775291 single nucleotide polymorphism (SNP) (G/A, Leu412Phe) in exon 4 of the toll-like receptor TLR3 gene, was investigated. The genotypic and allelic frequencies of these polymorphisms were analyzed in 137 non-immunized TBE patients with different clinical manifestations, including fever (35), meningitis (62), and severe CNS disease (40), as well as in a control population (269 randomly selected Novosibirsk citizens). The frequencies of the TLR3 G allele and G/G homozygotes were significantly higher among the patients with TBE compared with the control group (P=0.029 and 0.037, respectively), especially among patients with severe disease (P=0.018 and 0.017, respectively). These results indicate that the G allele (within the G/G homozygous genotype) of the TLR3 rs3775291 SNP is associated with predisposition to TBE in the Russian population.

CCL5/RANTES gene polymorphisms in Slavonic patients with myocardial infarction.

Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1 T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously.

Variability in the 2'-5'-oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease.

The 2'-5'-oligoadenylate synthetase (2'-5'-OAS) family members are interferon-induced antiviral proteins. Twenty-three single nucleotide polymorphisms located within the OAS1, OAS2, OAS3, and OASL genes were analyzed in 142 patients with Russian tick-borne encephalitis. Statistically significant differences in genotype, allele, and haplotype frequencies for 3 OAS2 single nucleotide polymorphisms (rs1293762, rs15895, and rs1732778) and 2 OAS3 single nucleotide polymorphisms (rs2285932 and rs2072136) were detected between patients with central nervous system disease and both those with fever and/or meningitis and the control group. The data suggest a possible association between these 5 OAS single nucleotide polymorphisms and the outcome of tick-borne encephalitis virus infection in a Russian population.

The macrophage migration inhibitory factor (MIF) gene polymorphism in Czech and Russian patients with myocardial infarction.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine implicated in early and advanced atherosclerosis. The aim of this study was to investigate whether polymorphism of MIF gene is associated with myocardial infarction (MI). METHODS: Single nucleotide polymorphism (SNP) in MIF gene (-173G/C, rs755622) was investigated in Czech (n=219) and Russian (n=240) MI patients and population control from the same geographical areas (Czech, n=137; Russian, n=174). Further, another SNP (rs1007888) located within the 3' flanking region of the MIF gene was investigated in Czech MI patients and control subjects. RESULTS: There were no significant differences in the distribution of MIF -173G/C genotypes, alleles or carriage rates between case and control groups in either populations. However, the GG genotype of the MIF SNP rs1007888 was associated with MI in Czech female patients (p=0.027). CONCLUSIONS: Taken together with previous reports, our study suggests that particular MIF gene polymorphisms may contribute to MI susceptibility in females.

Concerted changes in the nucleotide sequences of the intragenic promoter regions of eukaryotic genes for tRNAs of all specificities.

RNA polymerase III promoter is located within the coding region in all eukaryotic tRNA genes, whereas in prokaryotic tRNA genes, the promoter is located upstream of the transcription initiation site. We analyzed the nucleotide sequence context of the A and B boxes of RNA polymerase III promoters from different unicellular eukaryotes, plants, and animals and the homologous sequences in the tRNA genes of prokaryotic species (Archaea, Eubacteria). The long and short sequence variants of the A box are nonrandomly distributed across different types of the eukaryotic tRNA genes. In contrast, the sequences from the prokaryotic counterparts of the long and short variants are randomly scattered among prokaryotic tRNA genes. The sequence diversity of the 3' portion of the A box in the eukaryotic tRNA genes was sharply reduced compared to that of the homologous segments of the prokaryotic tRNA genes. Analysis of the frequencies of oligonucleotide variants from different parts of the A box suggested that the prominent changes in the structure of the A box occurred at about the same time in all tRNA genes during the prokaryote eukaryote evolutionary transition.