UK Critical Care Genomics (UKCCG) group

FUNCTIONAL GENOMIC INFLUENCES ON DISEASE PROGRESSION AND OUTCOMES IN SEPSIS DUE TO PNEUMONIA OR PERITONITIS

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It is now widely accepted that these inconsistent results can be explained in part by the limited power of the studies performed so far, over-interpretation of marginal results in small samples (sometimes compounded by multiple testing), the heterogeneity of the patient populations, the complexity of some haplotypic structures, unrecognised confounding effects, inadequate definition of phenotypes, ethnic differences and variable quality control of genotyping techniques and statistical analysis. Of particular relevance to this application the central major histocompatibility complex (MHC) has a very high density of genes, many of which are involved in immunity and inflammation, and a complex haplotypic structure which considerably complicates interpretation of SNP associations in this region.

AIMS OF STUDY
There is an overwhelming need for large collections to permit adequately powered genomics research in septic patients. The aims of this proposal are:

1.To deliver
- A high quality phenotypic resource of large, well-characterised, homogeneous groups of patients with, or at risk of, sepsis.
- A repository of DNA from these patients, (which will include whole genome amplification) for national and international collaboration.
- A resource of blood and urine samples and cryopreserved cell lines for functional genomic, proteomic and metabonomic analysis.
2.To perform high quality, functional association studies to determine the influence of a discrete number of candidate genes, alone and in combination on the development, progression and outcome of sepsis/severe sepsis/septic shock.
3.To undertake genome wide association studies using this resource when practicable and affordable. The long term objective is to substantially reduce the morbidity, mortality and costs associated with overwhelming infection and systemic inflammation by yielding new insights into the pathogenesis of sepsis and organ failure, discovering new targets for therapy or prevention, and identifying individuals who might benefit from specific treatments or preventative measures. chieve increased power and to allow replication.

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