Genome Scan of M. tuberculosis Infection and Disease in Ugandans

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFα) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10−3) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal α = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFα p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFα p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system.

Tuberculosis Vaccines and Prevention of Infection

“…Are any humans resistant to TB infection? Although many individuals become infected with M. tuberculosis after sustained exposure, only a small fraction resist infection as demonstrated by persistently negative TSTs or IFN-␥ release assays (IGRAs) (96,97). These individuals may have an innate macrophage response to M. tuberculosis that resists initial infection or rapidly clears the bacillus before a T-cell response develops.…”

Diagnosis of Mycobacterium tuberculosis

“…It has been shown that this reaction can be attributed to genetic factors. These genetic factors not only influence the interaction between humans and Mtb but they can affect the outcome of the exposure: exposure but no infection, infection without progression, or progression to disease (Stein et al, 2008). Subjectivity and inter-individual variability, in the administration and reading of the TST can be added to the disadvantages and resultant errors, because it is difficult to administer small amounts of the protein uniformly; that is, the amount of purified protein derivatives delivered in the TST may vary, and this affects the size of the reaction (Chaparas et al, 1985).…”

Evaluation of interferon-induced transmembrane protein-3 (IFITM3) rs7478728 and rs3888188 polymorphisms and the risk of pulmonary tuberculosis

“…The IFITM3 gene is mapped to an IFITM gene cluster on chromosome 11p15.5 (14). In a genome wide scan, Stein et al (15) identified that one of the TB-linked loci was located in this chromosome region. To the best of our knowledge, there is only one report regarding the impact of IFITM gene polymorphisms on the risk of TB (16).…”