Gene ID may help map TB susceptibility
Gene ID may help map TB susceptibility
Research vital to eventual vaccine development
What makes one patient develop active tuberculosis disease while another patient in the same population never progresses beyond infection? Genetic makeup holds part of the answer, and researchers in Boston may have identified the first gene associated with susceptibility to TB disease.
Scientists have identified several genetic factors that may explain the reasons for relative susceptibility and resistance to TB disease, such as mutations of interferon receptor genes and impaired tumor necrosis factor secretions. More recently, they have tried to identify whether specific HLA class I or class II alleles are associated with clinical TB.
Toward that end, researchers from Harvard Medical School and the Dana-Faber Cancer Institute conducted a study of TB-infected people in Cambodia, where the prevalence of TB infection has been found in random samples as high as 75%. Two groups of patients with clinical TB and those without were studied in 1995 and 1996 for a case-controlled trial involving more than 100 subjects. A molecular typing analysis of HLA class I and class II alleles, as well as 2TNF alpha alleles, was performed on blood samples.
Previous research had shown that progression of TB may be associated with the HLA-DR2 serotype. But further study had identified no specific allele that was associated with increased susceptibility. The Boston researchers found no specific HLA-DR2 alleles that were increased significantly in the study group. However, they did find an association between clinical TB and HLA-DQB1*0505 allele, which was confirmed with a second study sample, making it the first known gene linked to TB progression.
"The finding allows one to begin to understand how mycobacterial antigen presentation is going on and that certain HLA alleles that present certain mycobacterium peptides to T cells would be better at doing that than other ones," says Anne Goldfeld, MD, associate professor of medicine at Harvard University and lead author of the study, published in the Journal of the American Medical Association.1
Although the researchers didn’t find an allele associated with resistance to TB disease, they found its opposite a linkage with susceptibility. "There is something about the way these people are presenting antigen that is not eliciting an effective immune response," Goldfeld tells TB Monitor. "This helps give us a handle on how to understand susceptibility and resistance."
Researchers have known that transplantation antigens, as they are called, are found in all of our cells. A person inherits a particular HLA molecule connected to their cells, but they are extremely polymorphic that is, they pass through various stages of development. Depending on the population and its exposure to TB, the same gene may not be selected for resistances in different parts of the world, Goldfeld explains.
Consequently, the findings in Cambodia may not hold true in western Europe, where TB probably has been around much longer. A similar study in the United States or Europe would be interesting, but the relatively low prevalence of TB disease makes it difficult to conduct without enrolling large numbers of participants.
One practical application of knowing what gene is associated with TB susceptibility could be its use in screening TB patients who are PPD positive. Those who have a high presence of the gene might be candidates for preventive therapy, she adds.
The finding also is important for adding to the groundwork for developing a TB vaccine, she notes. "What you are looking for in a vaccine is understanding which peptide or TB proteins are the strongest in eliciting an immune response, so this kind of work is lending insight into that process," she adds.
Reference
1. Goldfeld A, Delgado J, Thim S, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998; 279:226-228.
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