The Genetics of Sepsis: The Promise, the Progress and the Pitfalls

Physicians are used to taking a family history of cardiovascular disease because of the known significant hereditary risk; yet the familial risk of dying from infection is even greater than that for atherosclerotic disease (Sorensen et al. 1988). There is certainly no doubt that genetic differences impact on the risk of developing or dying from infection. Obvious but rare examples include selective immunoglobulin deficiencies, complement deficiencies, and neutrophil function abnormalities. Genetic factors may also be protective, such as with sickle cell trait and malaria or mutations conferring resistance to human immunodeficiency virus infection. Much more subtle differences in immune responses are now being described, usually as the result of one or more single nucleotide polymorphisms (SNP) in a gene. Rather than causing the failure of production of a protein or the production of a nonfunctional protein, SNPs are usually associated with changes in the rate of transcription, producing a much less severe phenotype than the classical examples of genetic defects mentioned above. It is now being appreciated that for many complex diseases, such as sepsis, the ultimate phenotype is the result of the interaction of genetic differences across many loci, not the dominant effect of a few key mutations. As seen in Fig. 3.1, since the mid 1990s, an increasing body of literature has focused on the role that gene polymorphisms in key inflammatory genes play in sepsis. Indeed, with advances in knowledge of the human genome, greater understanding of the inflammatory response, and the development of high throughput genotyping technologies, so many genetic associations have been described that discussion of each one is well beyond the scope of this chapter. I will however summarize those findings that have been reported by multiple groups, as well as give an overview of the major groups of genes that have been implicated in genetic predisposition to sepsis and its adverse outcomes.