Tuberculosis patients homozygous for the MCP-1 –2518G allele (GG) have the highest plasma levels of MCP-1.

High levels of the chemokine monocyte chemoattractant protein-1 (MCP-1) give tuberculosis (TB) the upper hand, according to a population study on page 1649. Flores-Villanueva and colleagues show that individuals whose cells are genetically programmed to produce copious amounts of MCP-1 are more likely to develop active disease when infected with Mycobacterium tuberculosis.

Infections with M. tuberculosis, the causative agent of TB, are on the rise; an estimated eight million new infections and two million TB-induced deaths occur annually. But not all people who are exposed to M. tuberculosis become ill—a phenomenon largely attributed to genetic differences that make some individuals more susceptible to disease than others. Indeed, a recent study identified a region on chromosome 17 that was linked to increased susceptibility to active tuberculosis, although the exact gene(s) responsible for this effect was not identified.

Flores-Villanueva and colleagues now show that a polymorphism in the promoter of the MCP-1 gene, which resides on chromosome 17, is the likely culprit of this increased susceptibility. In a group of infected individuals from Mexico, this polymorphism (-2518G) was five times more prevalent in patients with active TB than in those who remained healthy. This polymorphism was previously shown to cause increased expression of the MCP-1 protein.

MCP-1 is an attractant for monocytes and T cells, two cell types that help to form the granulomas that contain the bacteria, and is thus thought to help orchestrate the initial response to M. tuberculosis infection. But extremely high levels of MCP-1 can inhibit the expression of interleukin (IL)-12, a cytokine primarily produced by dendritic cells and monocytes that is required to activate antibacterial effector cells. Indeed, monocytes isolated from patients homozygous for the -2518G allele produced high levels of MCP-1 and low levels of IL-12 when stimulated with M. tuberculosis extracts.

In an accompanying commentary (page 1617), Alcais and colleagues note that the presence of the -2518G susceptibility allele in approximately half of the Mexican population means that, in the absence of other genetic factors, the attributable risk of this mutation for developing disease could exceed 60%—the largest genetic impact on adult TB ever described.