An eQTL variant of ZXDC is associated with IFN-γ production following Mycobacterium tuberculosis antigen-specific stimulation

There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-gamma production after stimulation with live BCG (Bacillus Calmette-Guerin), and a second locus on chromosome region 3q affecting IFN-gamma production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-gamma production induced by BCG (IFN gamma-ESAT6(BCG)). High-density genotyping and imputation identified similar to 100,000 variants within each linkage region, which we tested for association with the corresponding IFN-gamma phenotype in families from a tuberculosis household contact study in France. Significant associations were replicated in a South African familial sample. The most convincing association observed was that between the IFN gamma-ESAT6(BCG) phenotype and rs9828868 on chromosome 3q (p = 9.8 x 10(-6) in the French sample). This variant made a significant contribution to the linkage signal (p < 0.001), and a trend towards the same association was observed in the South African sample. This variant was reported to be an eQTL of the ZXDC gene, biologically linked to monocyte IL-12 production through CCL2/MCP1. The identification of rs9828868 as a genetic driver of IFN gamma production in response to mycobacterial antigens provides new insights into human anti-tuberculosis immunity.