Mar. 17, 2016
An international research team led by scientists from Vanderbilt University Medical Center has identified a genetic variant that protects people with HIV from developing active tuberculosis. The variant is near the gene encoding the infection-fighting cytokine IL-12.
The discovery, reported this month in the American Journal of Human Genetics,could lead to new treatments for TB, which is the No. 1 killer of patients with HIV in sub-Saharan Africa and which causes more than a million deaths worldwide each year.
“It was a very exciting finding for us, particularly in light of the potential translational implications,” said the paper’s first author, Rafal Sobota, an M.D./Ph.D. student in the Vanderbilt Medical Scientist Training Program. Sobota earned his Ph.D. in Human Genetics last year and will receive his M.D. in 2017.
People infected with HIV, which suppresses the body’s immune system, are at higher risk of developing active TB once they are infected by the TB bacterium. Some HIV-positive people, however, do not develop active TB, even in areas such as sub-Saharan Africa, where the potentially fatal lung infection is rampant.
To find out why, Sobota and colleagues from Dartmouth College in Hanover, New Hampshire, and Case Western Reserve University in Cleveland, conducted a genome-wide association study of 581 HIV-positive patients in Tanzania and Uganda.
Although all participants were exposed to the TB bacterium, only 267 developed active disease over the span of at least eight years. The 314 patients who did not develop clinical TB represented an extreme resistance phenotype, which the authors believe increased the power to detect the association.
The identified variant was in a regulatory element of the gene encoding IL-12, IL12B. Subjects with one form of the variant were protected from active TB, while those with the other form were more likely to develop active disease.
The researchers also found that the protective variant is strongly selected for, being found in up to 45 percent of various populations in sub-Saharan Africa, while being absent in other parts of the world.
Previous studies have shown that patients with very rare inherited IL-12 deficiency are prone to developing severe cases of active TB. And in several studies of mice infected with the TB bacterium, induction of IL12B expression or direct inoculation with the cytokine protected the animals from developing active disease.
Sobota began the study as his dissertation topic over five years ago under the direction of his thesis advisor, Scott Williams, Ph.D., the paper’s senior author. Williams is now on the faculty at Case Western Reserve University.
“I was fortunate enough to travel to Tanzania for six months and recruit the patients for the study,” Sobota said.
A collaborator on the faculty at Case Western Reserve University, Catherine Stein, Ph.D., recruited the study participants in Uganda. Other co-authors included Nuri Kodaman, who also earned his Ph.D. in Human Genetics at Vanderbilt last year.
See the full article here .
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