We combined two tuberculosis (TB) genome-wide association studies (GWAS) from Ghana and The Gambia with subsequent replication totalling 11,425 participants. A significant association with disease was observed at SNP rs4331426 located in a gene-poor region on chromosome 18q11.2 (P=6.8×10−9, OR=1.19, 95%CI=1.13-1.27). Our finding shows that GWAS can identify novel loci for infectious causes of mortality even in Africa where levels of linkage disequilibrium are particularly low.

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Background Host-related and environment-related factors have been shown to play a role in the development of tuberculosis (TB), but few studies were carried out to identify their respective roles in resource-poor countries.

Few studies have investigated the risk factors for tuberculosis (TB) infection in highly endemic countries. We conducted a household study in The Gambia, in which a tuberculin skin test (TST) was performed in members of the households of 315 smear-positive pulmonary TB cases and 305 community control subjects. The risk of being TST positive (10 mm or more) was higher in contacts of cases than in contacts of control subjects. It increased with age, male sex, and duration of stay in the household but was not associated with the presence of a bacille de Calmette-Guérin scar. Within the households of the TB cases, the risk of TST positivity was higher in males and was increased with age, social proximity to the case, and the radiologic extent of the disease in the case's chest X-ray. Adjusting on these, the risk of TST positivity was higher in first-degree relatives compared with more distant relatives and nongenetically related household members, but the effect was not statistically significant. In highly endemic areas, the risk of TB infection in contacts of TB infectious cases is associated with age, sex, intensity of exposure to the case, and severity of disease in the case, but it is possible that genetic factors contribute to the susceptibility to Mycobacterium tuberculosis infection.

Interferon (IFN)-gamma responsiveness to 12 purified protein derivative (PPD) and new tuberculin antigens from 9 species of mycobacteria was assessed, using a whole blood assay, in 616 young adults living in northern Malawi, where Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination provides no protection against pulmonary tuberculosis. The prevalence of IFN-gamma responsiveness was highest for PPDs of M. avium, M. intracellulare, and M. scrofulaceum (the MAIS complex). Correlations between responsiveness paralleled genetic relatedness of the mycobacterial species. A randomized, controlled trial was carried out, to assess the increase in IFN-gamma responsiveness to M. tuberculosis PPD that can be attributed to M. bovis BCG vaccination. The BCG-attributable increase in IFN-gamma response to M. tuberculosis PPD was greater for individuals with low initial responsiveness to MAIS antigens than for those with high initial responsiveness. Although not statistically significant, the trend is consistent with the hypothesis that prior exposure to environmental mycobacteria interferes with immune responses to BCG vaccination.

We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T-->C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.6-11.4, P = 0.004), while homozygotes for the McCoy b blood group defining variant K1590E in exon 29 of the complement receptor 1 (formerly CD35) gene appeared to be protected (OR = 0.3, 95% CI = 0.1-0.8, P = 0.02). Borderline evidence for association with leprosy susceptibility was found for seven polymorphic sites in an additional six genes. Some of these apparent associations may be false-positive results from multiple comparisons, and several associations suggested by studies in other populations were not replicated here. These data provide evidence of inter-population heterogeneity in leprosy susceptibility.

ABSTRACT. Objective. Tuberculosis (TB) infection is highly prevalent in developing countries. As infected children represent a large proportion of the pool from which TB cases will arise, knowledge of the factors that influence TB infection in children are of importance to evaluate transmission of infection in the community and adapt TB control activities. There are limited data on the risk of infection in child populations in developing countries.Methods. We performed a household contact study in The Gambia (West Africa), in which children who were living in contact with individuals who had proven smearpositive pulmonary TB cases were investigated. A questionnaire was addressed to the mother or caregiver of the child to investigate the presence of various risk factors and assess the degree of exposure of the child to the individual with TB within the household. A tuberculin skin test (TST) was performed on each child. TST sizes >5 and 10 mm, respectively, were considered positive.Results. Households of 206 TB cases were visited, and 384 children aged <5 years were examined. The median age was 2, and 48% were girls. The distribution of TST responses followed a bimodal pattern, with 135 (35%) children presenting a palpable induration. Random effects logistic regression analysis demonstrated that the risk of positive TST response in the child increased with the geographic proximity of the child to the individual with TB within the household and with the degree of activities shared with the individual with TB. It was also associated with the clinical severity of the disease in the index case. Nutritional status and presence of a bacille Calmette-Guérin (BCG) scar were not independent risk factors for TST positivity in this population. On multivariate analysis, the effect of geographic proximity to the individual with TB, household size, and duration of cough in the index case persisted for TST responses >5 mm.Conclusions. In a highly endemic country with high BCG vaccination coverage in Africa, TB infection in children who were in contact with individual with infectious TB was directly related to the intensity of exposure of the child to the individual with TB. Our data suggest that a positive TST in a child reflects most probably TB infection rather than previous BCG vaccination. Contact I n 1995, the World Health Organization estimated that at least 180 million children under the age of 15 years were infected with Mycobacterium tuberculosis worldwide and that nearly 170 000 children died of tuberculosis (TB). 1,2 TB infection and disease among children are much more prevalent in developing countries, where resources for TB control are scarce, than in industrialized countries. 3 However, despite the public health importance of the disease, TB is rarely investigated in children, as the diagnosis is difficult in the young age groups and children are usually not infectious. 4 In addition, contact tracing is rarely done in nonindustrialized countries because of lack of resources, and Isoniazid prophylaxis is not sys...

Twenty-seven polymorphisms from 12 genes have been investigated for association with tuberculosis (TB) in up to 514 cases and 913 controls from Karonga district, northern Malawi. Homozygosity for the complement receptor 1 (CR1) Q1022H polymorphism was associated with susceptibility to TB in this population (odds ratio [OR] = 3.12, 95% Confidence interval [CI] = 1.13-8.60, P = 0.028). This association was not observed among human immunodeficiency virus (HIV)-positive TB cases, suggesting either chance association or that HIV status may influence genetic associations with TB susceptibility. Heterozygosity for a newly studied CAAA insertion/deletion polymorphism in the 3'-untranslated region of solute carrier family 11, member 1 (SLC11A1, formerly NRAMP1) was associated with protection against TB in both HIV-positive (OR = 0.70, 95% CI = 0.49-0.99, P = 0.046) and HIV-negative (OR = 0.65, 95% CI = 0.46-0.92, P = 0.014) TB cases, suggesting that the SLC11A1 protein may have a role in innate TB immune responses that influence susceptibility even in immunocompromised individuals. However, associations of other variants of SCLA11A with TB reported from other populations were not replicated in Malawi. Furthermore, associations with vitamin D receptor, interferon-gamma, and mannose-binding lectin observed elsewhere were not observed in this Karonga study. Genetic susceptibility to TB in Africans appears polygenic. The relevant genes and variants may vary significantly between populations, and may be affected by HIV infection status.