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Identification of genetic determinants of sepsis which modulate gene expression

Final Activity Report Summary - MODULATORS OF SEPSIS (Identification of genetic determinants of sepsis which modulate gene expression)

Susceptibility to infectious diseases such as sepsis is in part determined by our individual genetic makeup. Advances in genetics research over recent years have enabled specific gene regions to be identified as likely to be important in determining disease susceptibility, such as the major histocompatibility complex (MHC) on chromosome 6. However, it remains a significant challenge to identify the specific causative genetic variant(s) as there are many different polymorphisms which are often co-inherited (the combination of variants are described as 'haplotypes').

This project sought to complement population genetic studies of infectious disease by identifying functionally important genetic variants which modulate levels of gene expression in the MHC. To do this, large numbers of B cells (lymphoblastoid cell lines) from different people carrying different MHC haplotypes were analysed using a microarray following cell stimulation with endotoxin. The microarray was used to determine regions of the MHC which were important for the control of gene expression by means of a DNase I hypersensitivity site assay.

This assay looks at how sensitive regions of DNA are to digestion with the enzyme DNase I. This in turn depends on the state of the chromatin coat found around DNA - in an open chromatin conformation, a state associated with regulatory regions, the DNA is more sensitive to DNase I digestion. This work has generated a novel haplotype-specific DNase I hypersensitivity map of the MHC and identified a number of important novel DNase I hypersensitive sites, including some which are stimulus specific, and some which are haplotype specific.