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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By studying adoptees these investigators showed that the death of a biological parent from an infectious cause before the age of 50 years was associated with a relative risk of 5.81 for premature death of the natural child from infection, and that even for parental deaths at over 70 years the relative risk was 5.0. Conversely the death of an adoptive parent from infection resulted in relative risks in the adoptees that were close to unity. Since then a number of relatively small studies have indicated that individual variations in susceptibility to, and outcome from severe sepsis/septic shock may be explained in part by polymorphisms of the genes encoding proteins involved in mediating and controlling the innate immune response and inflammatory cascade. There is also evidence that such polymorphisms play a role in the development of certain organ failures. For example members of our group have reported that a polymorphism of the angiotensin converting enzyme gene is associated with susceptibility and outcome in acute respiratory distress syndrome (ARDS). It is, therefore highly likely that susceptibility to infection and the development, progression and outcome of sepsis/septic shock is influenced by genetic variants that might, in turn also influence the response to pharmacological interventions in sepsis.

Such simple candidate gene association studies must, however, be interpreted cautiously, not least because sepsis is a complex polygenic disorder and the functional importance of these polymorphisms is frequently uncertain; indeed many may simply represent a genomic marker for other more functionally relevant genetic variations with which they are in linkage disequilibrium (LD). Moreover results to date have often been inconsistent and failure to replicate positive findings has been frequent. For example some studies have failed to confirm the association between the TNF-308 single nucleotide polymorphism (SNP) and outcome from severe sepsis/septic shock and, in a study more than three times larger than any reported to date, the applicants and their collaborators were unable to demonstrate any associations between several individual TNF/LTA polymorphisms, or their haplotypes, and susceptibility or outcome in such patients.

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