Gene implicated in infectious disease susceptibility

25 May 2010

Infectious diseases such as tuberculosis (TB), malaria, and invasive bacterial disease together account for more than 5 million deaths each year in the developing world, with one third of the world’s population currently infected with TB bacillus according to the World Health Organization (WHO). Although differences in disease susceptibility can be attributed in part to environmental factors such as malnutrition and poor hygiene as well as infection with human immunodeficiency virus (HIV), a large proportion of variation is still unexplained with studies suggesting that genetics also plays a role.
A new study published in The New England Journal of Medicine identifies genetic variants within a single gene as associated with increasing susceptibility to major infectious diseases [Khor et al. (2010) New Eng J Med 19 May; doi:10.1056/NEJMoa0905606]. The CISH gene encodes the cytokine-inducible SRC homology 2 domain protein, a regulator of cytokine signalling and a candidate gene for involvement in susceptibility to infectious diseases.
Khor et al. analysed susceptibility to TB, severe malaria or bacteraemia using case-control data from seven studies involving nearly 8,500 individuals from clinical sites in Kenya, the Gambia, Malawi, Hong Kong and Vietnam. Forty-eight individuals (24 cases and 24 controls) from the Kenyan Bacteraemia (KB) study had their CISH gene sequenced, identifying eight common SNPs. These SNPs were then genotyped in the remaining individuals from the KB study with four SNPs showing association (-639, -292, -163, 3415). Further genotyping in the other six case-control studies identified an additional SNP ( 1320). These five SNPs when pooled across all studies did not show any significant interaction but did show increased disease susceptibility relative to the number of risk alleles carried by an individual (0, 1, 2, 3, or ≥4) although one SNP (-292) accounted for most of the disease association observed.
A small gene expression study looking at three of these SNPs in a different population (healthy adult Han Chinese) indicated that one (-292) may affect expression of the CISH protein following stimulation with interleukin-2.
Comment: The authors identified five SNPs located within the CISH gene that show increased association with three major forms of infectious disease. Disease susceptibility also increased in relation to the number of risk alleles carried. The association with the -292 SNP, located in the promoter region, was also statistically significant in six of the seven individual contributing studies. This SNP was shown in a small number of individuals to reduce gene expression levels for a protein that is a member of the suppressor of cytokine signalling family. The inflammatory cytokine response is a key element of the host immune response to infection, and these results suggest that regulators of cytokine signalling, such as the CISH gene, may as postulated play an important role in resistance or susceptibility to several infectious diseases.

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