Investigators Identify Variants Linked to Risk of Developing Infectious Diseases

Variants of the CISH gene increase susceptibility to several infectious diseases including tuberculosis and malaria, according to researchers from the Wellcome Trust Centre for Human Genetics, the Agency for Science, Technology and Research (A*STAR), and the National University Health System. CISH encodes a protein that is involved in the immune response to infectious diseases. It plays a role in dampening down messaging signals between cells of the immune system.

The study is published in The New England Journal of Medicine in a paper titled “CISH and Susceptibility to Infectious Diseases.”

The interleukin-2 mediated immune response is critical for host defense against infectious pathogens. CISH, a suppressor of cytokine signaling, controls interleukin-2 signaling. The team thus started testing for an association between CISH polymorphisms and susceptibility to major infectious diseases in blood samples from 8,402 people at clinical sites in Malawi, Kenya, Vietnam, Hong Kong, and Gambia over five years. They had previously tested 20 other immune-related genes in one or more of these sample collections.

A panel of five different genetic variants was identified within the CISH gene. Having one of these variants increased susceptibility to disease by 18% compared to somebody who does not have any risk variant. “That is a substantial effect size for a single gene,” comments Fredrik Vannberg, Ph.D., of the Wellcome Trust Centre for Human Genetics.

One variant in particular, -292, accounted for most of the genetic association with disease. Functional studies carried out in Singapore showed that blood cells from healthy Chinese volunteers carrying the -292 variant had lower levels of the CISH protein overall than individuals with the normal variant. This suggests that CISH exerts a significant genetic influence on our immune response.

“It's not clear from our study why having a reduced level of CISH associates with increased susceptibility to multiple infectious diseases, but it does suggest that CISH is a key regulator of the immune system,” remarks Chiea C. Khor from A*STAR's Singapore Institute for Clinical Sciences, who co-led the studies in Singapore.