Ethnic and Geographical Aspects of the Prevalence of the Polymorphic Variants of Genes Associated with Tuberculosis

Specificity of the structure of gene pools of different ethno-territorial groups of the human population can underlie the epidemiological features of the spread of tuberculosis (TB) and the structure of the genetic component of the susceptibility to the disease. The variability of 62 genetic variants potentially associated with the risk of the development of TB in the Russian population of the city of Tomsk has been studied and the differentiation of various ethno-territorial groups of the world by these markers has been assessed. The studied sample comprised 445 Russian residents of the city of Tomsk without bronchopulmonary pathology. For comparison, the data on the variability of the genetic markers of interest in 26 populations from the 1000 Genomes Project was involved. In the Tomsk population, only the ancestral allele was found for seven of the 58 SNPs studied; the allele frequencies for 36 markers were within the limits of the values seen in other European populations; for 12 SNPs, the observed frequencies were closer to populations with a significant Mongoloid component. By the total of the SNPs, the Tomsk population, despite the geographical distance from the rest of the European populations, did not differ from them (in genetic distances and G_st statistics), although it had some features of the gene pool. Intergroup differentiation of the world populations by these SNPs reflects mainly interracial differences. The greatest differences in the genetic structure between the studied populations were seen for the markers localized in intergenic regions. Statistically significant differences were found when comparing the levels of the average expected heterozygosity between groups of “L4 carrier populations” of mycobacteria and “non-L4” populations, which indicates the impact of the prevalence of different pathogenic lineages of M. tuberculosis on the formation of population specificity of the allelic frequencies.     

Polymorphisms of Tuberculosis Susceptibility Candidate Genes in the Slavonic Population of Siberia: A Pilot Study

The 469+14 G/C (INT4), 1465-85 G/A, and C274T polymorphisms of NRAMP1 and the A/C polymorphism of IL12 3"UTR were analyzed in ethnic Russians with (N = 58) or without (N = 127) tuberculosis (TB) from Tomsk. On evidence of allele and genotype frequencies, none of the polymorphisms was associated with TB. In the healthy controls, the three NRAMP1 polymorphisms were in linkage disequilibrium with each other (p < 0.001) but not with the IL12 polymorphism. Still the four polymorphisms are potentially informative as concerns their association with TB.     

Validation of the Results of Genome-Wide Association Studies of Tuberculosis in Russians of West Siberia

The genetically mediated ability of the host to provide an adequate immune response to the pathogen plays an important role in the development of tuberculosis infection. Genome-wide association studies performed in different populations revealed the association of a number of chromosomal regions with the development of tuberculosis (TB). At the same time, full characteristics of the factors of genetic susceptibility to the disease remains an unresolved problem, and the associations identified are not always reproduced in studies in other populations. A total of 45 single nucleotide polymorphisms (SNPs) were analyzed in 768 individuals, including 323 tuberculosis patients and 445 healthy individuals. Analysis of associations of tuberculosis with genetic markers was carried out using logistic regression. Permutations were used to account for multiple comparisons. Nominal statistically significant association with tuberculosis was detected for two SNPs, rs10515787 (intronic variant of the EBF1 gene) and rs10956514 (intronic variant of the ASAP1 gene) (p = 0.005 and 0.049, respectively). After the permutation test, only one of the associations was preserved, for rs10515787 (p = 0.003). Thus, in Russians from the city of Tomsk, the association of rs10515787 at the EBF1 gene with the development of tuberculosis was confirmed. However, the results of this study identify rare A allele as a risk factor for the development of TB, while in an earlier study, it was identified as being protective relative to the risk for developing of tuberculosis. The revealed “reverse association” is an interesting fact that requires further investigation.     

Polymorphisms of the candidate genes for genetic susceptibility to tuberculosis in the Slavic population of Siberia: a pilot study

The 469 + 14 G/C (INT4), 1465 - 85 G/A, and C274T polymorphisms of NRAMP1 and the A/C polymorphism of IL12 3'-UTR were analyzed in ethnic Russians with (N = 58) or without (N = 127) tuberculosis (TB) from Tomsk. On evidence of allele and genotype frequencies, none of the polymorphisms was associated with TB. In the healthy controls, the three NRAMP1 polymorphisms were in linkage disequilibrium with each other (P < 0.001) but not with the IL12 polymorphism. Still the four polymorphisms are potentially informative as concerns their association with TB.     

A comparative analysis of tuberculosis susceptibility genetic make-up in Tuvinians and Russians

The results of the first Russian study of polymorphisms of tuberculosis (TB) susceptibility genes SLC11A1, VDR, IL12B, IL1B, IL1RN in Tuvinians from Tuva Republic and Russians from Tomsk city are presented. In Tuvinians, as compared with Russians, the significantly higher prevalence of potentially disease-associated alleles of the genes studied was shown: SLC11A1*543N (0.139 and 0.043, respectively, p = 4.6E-5), IL12B*1188C (0.378 and 0.174, respectively, p = 1.1E-8), VDR*b (0.825 and 0.532, respectively, p = 3.2E-16), IL1B*(+3953A1) (0.865 and 0.806, respectively, p = 0.035). However, no one of these alleles was associated with TB in Tuvinians, whereas, in Russians TB patients, in comparison with the controls, there was a higher prevalence of the following markers: IL1RN*A2 (0.258 and 0.186, respectively, p = 0.024), SLC11A1*274T (0.251 and 0.164, respectively, p = 0.009), IL12B*1188C (0.240 and 0.174, respectively, p = 0.044), ILIB*(+3953A2) (0.259 and 0.194, respectively, p = 0.044). Distinct patterns of linkage disequilibrium between pairs of the polymorphisms studied in Tuvinians and Russians were shown. At whole, the data obtained demonstrate the ethnic specificity of the distribution and pathogenetic significance of the alleles of the TB susceptibility genes.     

Influence of polymorphism of immune defense modifier genes on celiac disease development and various clinical features of disease in Tomsk population

The results of investigation of influence of immune defense modifier genes polymorphism: IL1B (+3953A1/A2), IL1RN (VNTR), IL4A (3'-UTR G/C), IL4RA (I50V), IL12B (1188A/C) and VDR (F/f and B/b) on celiac disease development and various clinical features of disease are presented. The study was performed in 49 families with proband affected by celiac disease (139 people) and 129 unaffected controls of Russian ethnicity from Tomsk. No associations were shown between these alleles and celiac disease by case-control study. However, in family-based investigation, the association was detected for 3'-UTR G/C polymorphism of IL4 gene (p = 0.024). Furthermore, for this polymorphic variant the associations with atypical form of the disease was shown (p = 0.001), as well as with osteopenic (p = 0.039) and thyriopatic (p = 0.042) complications of celiac disease. Association with clinical course of the disease (typical form) was obtained for 150V polymorphism of IL4RA gene and for F/f polymorphism of VDR gene (p = 0.001 and p = 0.009, respectively). Thus, in this investigation it was detected that the associations with the studied phenotypes were found mainly for polymorphic variants of Th2-immunity genes.     

Association of polymorphisms of immune response modifier genes with celiac disease and its clinical forms in the Tomsk population

Association of different alleles of immune response modifier genes IL1B (+3953A1/A2), IL1RN (VNTR), IL4 (3′-UTR G/C), IL4RA (I50V), IL12B (1188A/C), and VDR (F/f and B/b) with celiac disease (CD) and its clinical forms was investigated in a family cohort of CD patients from the Tomsk region (N = 139, including 49 probands, i.e., affected children). The control group comprised 129 healthy Russians from Tomsk. A case-control study did not associate any of the polymorphic markers with CD. In a family-based study, the 3′-UTR G/C polymorphism of IL4 was associated with CD (P = 0.024), its atypical form (P = 0.001), and its complications such as osteopenia (P = 0.039) and autoimmune thyroiditis (P = 0.042). IL4RA and VDR polymorphisms I50V and F/f were associated with the typical form of CD (P = 0.001 and P = 0.009, respectively). In general, associations with CD phenotypes were shown primarily for polymorphisms of the genes involved in Th2 immunity.