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Background. Interferon γ (IFN-γ) release assays (IGRAs) provide an in vitro measurement of antimycobacterial immunity that is widely used as a test for Mycobacterium tuberculosis infection. IGRA outcomes are highly heritable in various populations, but the nature of the involved genetic factors remains unknown. Methods. We conducted a genome-wide linkage analysis of IGRA phenotypes in families from a tuberculosis household contact study in France and a replication study in families from South Africa to confirm the loci identified. Results. We identified a major locus on chromosome 8q controlling IFN-γ production in response to stimulation with live bacillus Calmette-Guerin (BCG; LOD score, 3.81; P = 1.40 × 10−5). We also detected a second locus, on chromosome 3q, that controlled IFN-γ levels in response to stimulation with 6-kDa early secretory antigen target, when accounting for the IFN-γ production shared with that induced by BCG (LOD score, 3.72; P = 1.8 × 10−5). Both loci were replicated in South African families, where tuberculosis is hyperendemic. These loci differ from those previously identified as controlling the response to the tuberculin skin test (TST1 and TST2) and the production of TNF-α (TNF1). Conclusions. The identification of 2 new linkage signals in populations of various ethnic origins living in different M. tuberculosis exposure settings provides new clues about the genetic control of human antimycobacterial immunity.

In the mouse, innate resistance or susceptibility to infection with numerous mycobacteria is controlled by the Bcg host resistance locus located on the centromeric region of chromosome 1. The resistance/susceptibility phenotype is expressed by the mature tissue macrophage and Bcg has been identified as a locus that is involved in the regulation of macrophage activation and in the modulation of acquired immune responses to mycobacteria. Experiments aimed at the cloning of the Bcg gene via a "reverse genetics" approach have generated a detailed genetic map in the immediate vicinity of the locus, placing Bcg within the reach of long-range eukaryotic cloning techniques. The chromosomal segment around Bcg in the mouse is exactly conserved onto the long arm (q) of human chromosome 2. Linkage of genetic markers from human chromosome 2q with susceptibility to leprosy or tuberculosis would support both the existence of a susceptibility gene in humans and the contention that this susceptibility gene is a homologue of the mouse Bcg locus.