Identification of a Major Locus, TNF1, That Controls BCG-Triggered Tumor Necrosis Factor Production by Leukocytes in an Area Hyperendemic for Tuberculosis

• Published in: Clinical infectious diseases Vol. 57; no. 7; pp. 963 - 970
• Main Authors: Cobat, Aurelie, Hoal, Eileen G., Gallant, Caroline J., Simkin, Leah, Black, Gillian F., Stanley, Kim, Jaïs, Jean-Philippe, Yu, Ting-Heng, Boland-Auge, Anne, Grange, Ghislain, Delacourt, Christophe, van Helden, Paul, Casanova, Jean-Laurent, Abel, Laurent, Alcaïs, Alexandre, Schurr, Erwin
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2013; Oxford University Press (OUP)
• Subjects: Adult; Analysis of Variance; and Commentaries; ARTICLES AND COMMENTARIES; Bacillus calmette guerin vaccine; Bacterial diseases; BCG Vaccine - administration & dosage; Biological and medical sciences; Chi-Square Distribution; Child; Chromosomes; Chromosomes, Human, Pair 11; Drug resistance; Drug therapy; Endemic Diseases; Family; Genetic loci; Genetic Pleiotropy; Genetics; Genomics; Human bacterial diseases; Human health and pathology; Humans; Infections; Infectious diseases; Interferon; Interferon-gamma - administration & dosage; Interferon-gamma Release Tests; Latent tuberculosis; Leukocytes; Leukocytes - drug effects; Leukocytes - immunology; Life Sciences; Linkage Disequilibrium; Medical sciences; Mycobacterium bovis - immunology; Mycobacterium tuberculosis; Phenotype; Phenotypic traits; Quantitative Trait Loci; South Africa - epidemiology; TNF inhibitors; Tuberculosis; Tuberculosis - blood; Tuberculosis - epidemiology; Tuberculosis - immunology; Tuberculosis and atypical mycobacterial infections; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factors; South Africa; Infection; Prevention; Tuberculosis; Tumor necrosis factor; Leukocyte; BCG; Bacteriosis; Check; Identification; Mycobacterial infection; pleiotropic locus; multivariate linkage analysis; TNF; tuberculosis
• ISSN: 1058-4838; 1537-6591; 1537-6591
• DOI: 10.1093/cid/cit438

Background. Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy. Methods. We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis. Results. Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P < 10 −5 ) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ. Conclusions. The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell—independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.