Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture

The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h2 = 26.3%, 95% CI 23.7–29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5 × 10-8) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value=5.2 × 10-9) but failed to replicate variants previously associated with TB susceptibility. These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large-scale GWAS analysis across multiple ancestries experiencing different levels of infection pressure

Molecular answers to tuberculous questions

[No abstract available]Short Surve

SP110 polymorphisms are not associated with pulmonary tuberculosis in a South African population

Susceptibility to tuberculosis (TB) in mice has recently been attributed to the Ipr1 gene. Polymorphisms in the human homologue, SP110, have been investigated in various populations with only one study finding an association with TB susceptibility. We investigated eight SP110 polymorphisms in a South African population, including two novel polymorphisms. No significant association was found with any of the polymorphisms investigated, including two polymorphisms that were previously found to be associated with TB susceptibility in West African populations. © Springer-Verlag 2007.Articl

SP110 polymorphisms are not associated with pulmonary tuberculosis in a South African population

Susceptibility to tuberculosis (TB) in mice has recently been attributed to the Ipr1 gene. Polymorphisms in the human homologue, SP110, have been investigated in various populations with only one study finding an association with TB susceptibility. We investigated eight SP110 polymorphisms in a South African population, including two novel polymorphisms. No significant association was found with any of the polymorphisms investigated, including two polymorphisms that were previously found to be associated with TB susceptibility in West African populations. © Springer-Verlag 2007.Articl

Gene Polymorphisms in African Buffalo Associated with Susceptibility to Bovine Tuberculosis Infection

<div><p>Bovine tuberculosis (BTB) is a chronic, highly infectious disease that affects humans, cattle and numerous species of wildlife. In developing countries such as South Africa, the existence of extensive wildlife-human-livestock interfaces poses a significant risk of <i>Mycobacterium bovis</i> transmission between these groups, and has far-reaching ecological, economic and public health impacts. The African buffalo (<i>Syncerus caffer</i>), acts as a maintenance host for <i>Mycobacterium bovis</i>, and maintains and transmits the disease within the buffalo and to other species. In this study we aimed to investigate genetic susceptibility of buffalo for <i>Mycobacterium bovis</i> infection. Samples from 868 African buffalo of the Cape buffalo subspecies were used in this study. SNPs (n = 69), with predicted functional consequences in genes related to the immune system, were genotyped in this buffalo population by competitive allele-specific SNP genotyping. Case-control association testing and statistical analyses identified three SNPs associated with BTB status in buffalo. These SNPs, SNP41, SNP137 and SNP144, are located in the SLC7A13, DMBT1 and IL1α genes, respectively. SNP137 remained significantly associated after permutation testing. The three genetic polymorphisms identified are located in promising candidate genes for further exploration into genetic susceptibility to BTB in buffalo and other bovids, such as the domestic cow. These polymorphisms/genes may also hold potential for marker-assisted breeding programmes, with the aim of breeding more BTB-resistant animals and herds within both the national parks and the private sector.</p></div

Association between tuberculosis and a polymorphic NFκB binding site in the interferon γ gene

Interferon γ is believed to be crucial for host defence against many infections. To test the hypothesis that a polymorphism in the gene for interferon γ (IFNG) is associated with susceptibility to tuberculosis, we did two independent investigations. In a case-control study of 313 tuberculosis cases, we noted a significant association between a polymorphism (+874A→T) in IFNG and tuberculosis in a South African population (p=0.0055). This finding was replicated in a family-based study, in which the transmission disequilibrium test was used in 131 families (p=0.005). The transcription factor NFκB binds preferentially to the +874T allele, which is over-represented in controls. This preferential binding suggests that genetically determined variability in interferon γ and expression might be important for the development of tuberculosis.Articl

Comparative analysis of a putative tuberculosis-susceptibility gene, MC3R, and pseudogene sequences in cattle, African huffalo, hyena, rhinoceros and other African bovids and ruminants

Studies in humans have suggested the possible involvement of melanocortin-3-receptor (MC3R) and other components of the central melanocortin system in host defense against mycobacteria. We report a genomic DNA nucleotide sequence highly homologous to human MC3R in several bovids and non-bovid African wildlife species. Nucleotide sequence analysis indicates that the orthologous genes of cattle and buffalo are highly homologous (89.4 and 90%, respectively) to the human MC3R gene. Sequence results also identified a typical non-functional, duplicated pseudogene, MC3RP, in 7 species from the family Bovidae. No pseudogene was found in animals outside Bovidae. The presence of the pseudogene in tuberculosis-susceptible species could have possible immunomodulatory effects on susceptibility to bovine tuberculosis infection, as well as a considerable influence on energy metabolism and food conversion efficiency. Copyright © 2012 S. Karger AG

Genome-wide analysis of the structure of the South African Coloured Population in the Western Cape

Admixed populations present unique opportunities to discover the genetic factors underlying many multifactorial diseases. The geographical position and complex history of South Africa has led to the establishment of the unique admixed population known as the South African Coloured. Not much is known about the genetic make-up of this population, and the historical record is patchy. We genotyped 959 individuals from the Western Cape area, self-identified as belonging to this population, using the Affymetrix 500k genotyping platform. This resulted in nearly 75,000 autosomal SNPs that could be compared with populations represented in the International HapMap Project and the Human Genome Diversity Project. Analysis by means of both the admixture and linkage models in STRUCTURE revealed that the major ancestral components of this population are predominantly Khoesan (32-43%), Bantu-speaking Africans (20-36%), European (21-28%) and a smaller Asian contribution (9-11%), depending on the model used. This is consistent with historical data. While of great historical and genealogical interest, this information is also essential for future admixture mapping of disease genes in this population. © 2010 Springer-Verlag.Articl

Addition of trehalose to dipalmitoyl phosphatidylcholine, hexadecanaol and tyloxapol improves oxygenation in surfactant-deficient rabbits

We seek to develop a safe and cheap synthetic lung surfactant as a substitute for expensive, mammalian-derived products. The postinstillation physiological effects of three synthetic surfactant preparations in three treatment groups of adult New Zealand white rabbits, on gas exchange, percentage calculated shunt and histopathological changes, were compared with those of a saline-treated control group. Improvement in oxygenation and a reduction in percentage shunt occurred to a similar extent after instillation of a mixture of dipalmitoylphosphatidylcholine, tyloxapol, cetyl alcohol and a nonreducing disaccharide (trehalose), and the commercial product Exosurf Neonatal®, surpassing that of 'Exosurf, a synthetic formulation of the same composition as the other prepared on-site, or saline treatment. Intratracheal instillation of surfactants did not restore the lung to its pre-lavage condition. Lung light microscopy findings differed in regard to the presence of hyaline membranes. The mixture of dipalmitoylphosphatidylcholine with trehalose performed similarly to Exosurf Neonatal®, with neither the superior.Articl