Dataset Information

No significant impact of IFN-? pathway gene variants on tuberculosis susceptibility in a West African population.

ABSTRACT: The concept of interferon-? (IFN-?) having a central role in cell-mediated immune defence to Mycobacterium tuberculosis has long been proposed. Observations made through early candidate gene studies of constituents of the IFN-? pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (TB). By analysing 20 major genes whose proteins contribute to IFN-? signalling we have assessed a large fraction of the variability in genes that might contribute to susceptibility to TB. Genetic variants were identified by sequencing the promoter regions and all exons of IFNG, IFNGR1, IFNGR2, IRF1, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, IL27, EBI3, IL27RA, IL6ST, SOCS1, STAT1, STAT4, JAK2, TYK2 and TBX21 in 69 DNA samples from Ghana. In addition, we screened all exons of IFNGR1 in a Ghanaian study group comprising 1999 TB cases and 2589 controls by high-resolution melting point analysis. The fine-mapping approach allows for a detailed screening of all variants, common and rare. Statistical comparisons of cases and controls, however, did not yield significant results after correction for multiple testing with any of the 246 variants selected for genotyping in this investigation. Gene-wise haplotype tests and analysis of rare variants did not reveal any significant association with susceptibility to TB in our investigation as well. Although this analysis was applied on a plausible set of IFN-? pathway genes in the largest African TB cohort available so far, the lack of significant results challenges the view that genetic marker of the IFN-? pathway have an important impact on susceptibility to TB.

SUBMITTER: Meyer CG

PROVIDER: S-EPMC4930082 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

No significant impact of IFN-γ pathway gene variants on tuberculosis susceptibility in a West African population.

Meyer Christian G CG Intemann Christopher D CD Förster Birgit B Owusu-Dabo Ellis E Franke Andre A Horstmann Rolf D RD Thye Thorsten T

European journal of human genetics : EJHG 20150805 5

The concept of interferon-γ (IFN-γ) having a central role in cell-mediated immune defence to Mycobacterium tuberculosis has long been proposed. Observations made through early candidate gene studies of constituents of the IFN-γ pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (TB). By analysing 20 major genes whose proteins contribute to IFN-γ signalling we have assessed a large fraction of the variability in genes that might con ...[more]

PMID: 26242990

Similar Datasets

Project description:BACKGROUND:HIV-1 derives from multiple independent transfers of simian immunodeficiency virus (SIV) strains from chimpanzees to human populations. We hypothesized that human populations in west central Africa may have been exposed to SIV prior to the pandemic, and that previous outbreaks may have selected for genetic resistance to immunodeficiency viruses. To test this hypothesis, we examined the genomes of Biaka Western Pygmies, who historically resided in communities within the geographic range of the central African chimpanzee subspecies (Pan troglodytes troglodytes) that carries strains of SIV ancestral to HIV-1. RESULTS:SNP genotypes of the Biaka were compared to those of African human populations who historically resided outside the range of P. t. troglodytes, including the Mbuti Eastern Pygmies. Genomic regions showing signatures of selection were compared to the genomic locations of genes reported to be associated with HIV infection or pathogenesis. In the Biaka, a strong signal of selection was detected at CUL5, which codes for a component of the vif-mediated APOBEC3 degradation pathway. A CUL5 allele protective against AIDS progression was fixed in the Biaka. A signal of selection was detected at TRIM5, which codes for an HIV post-entry restriction factor. A protective mis-sense mutation in TRIM5 had the highest frequency in Biaka compared to other African populations, as did a protective allele for APOBEC3G, which codes for an anti-HIV-1 restriction factor. Alleles protective against HIV-1 for APOBEC3H, CXCR6 and HLA-C were at higher frequencies in the Biaka than in the Mbuti. Biaka genomes showed a strong signal of selection at TSG101, an inhibitor of HIV-1 viral budding. CONCLUSIONS:We found protective alleles or evidence for selection in the Biaka at a number of genes associated with HIV-1 infection or progression. Pygmies have also been reported to carry genotypes protective against HIV-1 for the genes CCR5 and CCL3L1. Our hypothesis that HIV-1 may have shaped the genomes of some human populations in West Central Africa appears to merit further investigation.

Project description:BackgroundAfrica contains the most genetically divergent group of continental populations and several studies have reported that African populations show a high degree of population stratification. In this regard, it is important to investigate the potential for population genetic structure or stratification in genetic epidemiology studies involving multiple African populations. The presences of genetic sub-structure, if not properly accounted for, have been reported to lead to spurious association between a putative risk allele and a disease. Within the context of the Africa America Diabetes Mellitus (AADM) Study (a genetic epidemiologic study of type 2 diabetes mellitus in West Africa), we have investigated population structure or stratification in four ethnic groups in two countries (Akan and Gaa-Adangbe from Ghana, Yoruba and Igbo from Nigeria) using data from 372 autosomal microsatellite loci typed in 493 unrelated persons (986 chromosomes).ResultsThere was no significant population genetic structure in the overall sample. The smallest probability is associated with an inferred cluster of 1 and little of the posterior probability is associated with a higher number of inferred clusters. The distribution of members of the sample to inferred clusters is consistent with this finding; roughly the same proportion of individuals from each group is assigned to each cluster with little variation between the ethnic groups. Analysis of molecular variance (AMOVA) showed that the between-population component of genetic variance is less than 0.1% in contrast to 99.91% for the within population component. Pair-wise genetic distances between the four ethnic groups were also very similar. Nonetheless, the small between-population genetic variance was sufficient to distinguish the two Ghanaian groups from the two Nigerian groups.ConclusionThere was little evidence for significant population substructure in the four major West African ethnic groups represented in the AADM study sample. Ethnicity apparently did not introduce differential allele frequencies that may affect analysis and interpretation of linkage and association studies. These findings, although not entirely surprising given the geographical proximity of these groups, provide important insights into the genetic relationships between the ethnic groups studied and confirm previous results that showed close genetic relationship between most studied West African groups.

Project description:BACKGROUND:The two major class A scavenger receptors are scavenger receptor A (SRA), which is constitutively expressed on most macrophage populations, and macrophage receptor with collagenous structure (MARCO), which is constitutively expressed on a more restricted subset of macrophages, (e.g. alveolar macrophages) but whose expression increases on most macrophages during the course of infection. Although the primary role of SRA appears to be clearance of modified host proteins and lipids, mice defective in expression of either MARCO or SRA are immunocompromised in multiple models of infection and in vitro assays, the scavenger receptors have been demonstrated to bind bacteria and to enhance pro-inflammatory signalling to many bacterial lung pathogens; however their importance in Mycobacterium tuberculosis infection, is less clear. METHODS:To determine whether polymorphisms in either SRA or MARCO were associated with tuberculosis, a case-control study of was performed. DNA samples from newly-detected, smear-positive, pulmonary tuberculosis cases were collected from The Gambia. Controls for this study consisted of DNA from cord bloods obtained from routine births at local Gambian health clinics. Informed written consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint The Gambian Government/MRC Joint Ethics Committee. RESULTS:We studied the frequencies of 25 polymorphisms of MSR1 (SRA) and 22 in MARCO in individuals with tuberculosis (n=1284) and matched controls (n=1349). No SNPs within the gene encoding or within 1 kb of the promoter sequence of MSR1 were associated with either susceptibility or resistance to tuberculosis. Three SNPs in MARCO (rs4491733, Mantel-Haenszel 2x2 ?2 = 6.5, p = 0.001, rs12998782, Mantel-Haenszel 2x2 ?2 = 6.59, p = 0.001, rs13389814 Mantel-Haenszel 2x2 ?2 = 6.9, p = 0.0009) were associated with susceptibility to tuberculosis and one (rs7559955, Mantel-Haenszel 2x2 ?2 = 6.9, p = 0.0009) was associated with resistance to tuberculosis. CONCLUSIONS:These findings identify MARCO as a potentially important receptor in the host response to tuberculosis.

Dataset Information

No significant impact of IFN-? pathway gene variants on tuberculosis susceptibility in a West African population.

Publications

No significant impact of IFN-γ pathway gene variants on tuberculosis susceptibility in a West African population.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets