Thursday, June 03, 2010

Genetics of Infectious Disease

The role our genes play in increasing or decreasing our susceptibility to various diseases has become an area of intense study in the biomedical sciences. News stories often report about studies that find that a particular gene increases the risk of various chronic diseases, like cancer and Alzheimer's disease.

But our genes also influence our risk of infectious disease. In this earlier post I noted this study which identified a group of genes that helped make the 1918 flu so deadly. And in this previous post I linked to a recent study that found a family of genes that influence the ability of HIV to cause infection.

The latest issue of the New England Journal of Medicine has this study which examines the risk CISH alleles have for the development of infectious disease. Here is the abstract:

Background The interleukin-2–mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling.

Methods Using a case–control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections.

Results We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions –639, –292, –163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10–11 for all comparisons), with –292 accounting for most of the association signal (P=4.58x10–7). Peripheral-blood mononuclear cells obtained from adult subjects carrying the –292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production — that is, 25 to 40% less CISH expression.

Conclusions Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.