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GWAS Leads to Potential TB Resistance Locus

NEW YORK (GenomeWeb) – In a study published online today in the American Journal of Human Genetics, an international team led by investigators at Case Western Reserve University described a chromosome 5 variant that appears to protect against tuberculosis in individuals who might otherwise be at risk of the disease.

The team focused on hundreds of HIV-infected individuals from Uganda and Tanzania for a genome-wide association study aimed at uncovering variants tied to TB susceptibility or resistance. The search led to a common variant on chromosome 5 near the IL12B gene, within a part of the genome that appeared to be under strong selection in equatorial African populations, based on allele frequency patterns.

"[O]ur results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals," senior author Scott Williams, an epidemiology and biostatistics researcher affiliated with Case Western and Dartmouth College's Geisel School of Medicine, and his colleagues wrote.

"Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease," they added.

Despite the toll that TB takes amongst HIV-infected individuals, who account for a substantial proportion of those who succumb to active TB each year, the team noted that many prior TB studies have excluded individuals with HIV.

On the contrary, though, authors of the new study reasoned that they might find genetic factors influencing TB resistance by following a group of immune-compromised individuals at higher-than-usual risk of active disease who might be exposed to Mycobacterium tuberculosis.

"We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyper-endemic, provide a model of natural resistance," they wrote.

The team tracked TB infections in three prospective cohorts from Tanzania and Uganda, together making up 581 adult individuals who had been diagnosed with HIV.

The group included individuals who had household contact with TB-infected family members. During the duration of the study, 267 individuals developed active TB and 314 did not.

When the researchers compared genetic profiles in the active TB-susceptible and resistant individuals using SNPs that were directly genotyped and imputed, they detected an apparent association involving a common variant called rs4921437 and a SNP in linkage disequilibrium with it.

The suspicious chromosome 5 site falls in an intron of the gene UBLCP1, the researchers noted, within a regulatory region associated with a histone acetylation mark and near the IL12B gene.

They noted that the latter gene codes for an IL-12 cytokine protein that's proven useful in past studies for decreasing M. tuberculosis bacteria burden, lowering inflammation, and stretching out survival in CD4 immune cell-deficient mice infected with TB, prompting interest in the IL-12 pathway as a potential source of new treatment strategies.

"IL12 and members of its pathway are … promising candidates for development of new TB treatments," the study's authors concluded, "which could be efficacious in both HIV-positive individuals and the general population."