[Human genetics of tuberculosis]

Only about 10% of individuals infected with Mycobacterium tuberculosis develop tuberculosis, yet there are over eight million new cases and two million deaths each year. Complex interactions between environmental factors (microbial and non microbial) and human factors (genetic and non genetic) determine the clinical outcome of M. tuberculosis infection, accounting for the lack of symptoms in most individuals and the development of disseminated disease in childhood or pulmonary disease in adulthood in a minority of cases, Epidemiological evidence points to a major role of human genetic factors in the development of tuberculosis. Numerous association studies of various candidate genes have been conducted, with variable results. The most consistent findings concern certain HLA class II alleles and variants of the natural resistance-associated macrophage protein 1 (NRAMP1) gene. The first major locus identified by genome-wide linkage screening was recently mapped to chromosome region 8q12-q13 in a Moroccan population, and precise identification of this major gene is ongoing. One fascinating finding in recent years is a Mendelian predisposition to tuberculosis. Tuberculosis was found to be the only phenotypic manifestation in several children with genetic defects of the IL-12/23-IFNgamma circuit, and particularly those with complete IL-12Rbeta1 deficiency The human genetics of tuberculosis shows a continuum from Mendelian to complex predisposition with intermediate effects of major genes. A more thorough understanding of the molecular genetic basis of tuberculosis will have fundamental immunological and medical implications, particularly for the development of new vaccines and treatments.