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

Abstract

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-likelihoodbinomial 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

Tuberculin Skin Test Negativity Is Under Tight Genetic Control of Chromosomal Region 11p14-15 in Settings With Different Tuberculosis Endemicities

“…Hence, the overlap of TST1 with TNF1 provides additional support for the interpretation of the TST1 locus as conferring resistance to M. tuberculosis infection. In addition, the observation that the suggestive locus on chromosomal region 19q13 mapped in the vicinity of a locus also found to be linked to TNF production in the South African family sample ( P < .01 from 58.1 to 59.1 Mb [ 15 ]) reinforces the hypothesis of a genetic connection between TST negativity and TNF production.…”

“…Interestingly, the major locus at chromosomal region 11p14-15 overlaps the TNF1 locus identified for mycobacteria-driven tumor necrosis factor α (TNF-α) production by leukocytes in the South African family sample (Figure 1 C and 1 D ) [ 15 ]. TNF is a key effector molecule of tuberculosis resistance that is critical for the sequestration of M. tuberculosis in infectious granuloma during latent M. tuberculosis infection [ 1 ].…”

Genetic Resistance to Mycobacterium tuberculosis Infection and Disease

“…Hence, TST2 reflects intensity of T-cell mediated anti-mycobacterial immune responses. The mapping of TST1 has been confirmed in an independent sample of different ethnic origins in France, and it was also shown that TST1 cannot be distinguished by linkage from TNF1 , a locus controlling TNF production in response to BCG/IFN-gamma ( 88 , 89 ).…”

Major Loci on Chromosomes 8q and 3q Control Interferon γ Production Triggered by Bacillus Calmette-Guerin and 6-kDa Early Secretory Antigen Target, Respectively, in Various Populations

“…It is also likely that the functions of skin-homing cells are more diverse than the production of IFN-γ alone. For instance, the production of the proinflammatory cytokine tumor necrosis factor α (TNFα) is thought to play a major role in the initiation of the TST reaction, a hypothesis supported by the overlap of linkage regions between TST1 and the TNF1 locus controlling mycobacterium-driven tumor necrosis factor α production [ 18 , 42 ]. In this context, the identification of 2 new loci controlling BCG- and ESAT-6–triggered IFN-γ production adds 2 new pieces to the puzzle of how human antimycobacterial immunity is assembled.…”