Genetic predisposition to respiratory infection and sepsis.

Chung, Li Ping; Waterer, Grant W

Genetic variations, in part, determine individual susceptibility to sepsis and pneumonia. Advances in genetic sequence analysis as well as high throughput platform analysis of gene expression has allowed for a better understanding of immunopathogenesis during sepsis. Differences in genes can also modulate immune and inflammatory response during sepsis thereby translating to differences in clinical outcomes. An increasing number of candidate genes have been implicated to play a role in sepsis susceptibility, most of which are controversial with few exceptions. This does not refute the significance of genetic polymorphisms in sepsis, but rather highlights the difficulties and pitfalls related to genetic association studies. These difficulties include differences in study design such as heterogeneous patient cohorts and differences in pathogenic organisms, linkage disequilibrium, and lack of power for detailed haplotype analysis or examination of gene-gene interactions. There is extensive diversity in the pathways of inflammation and immune response during sepsis making it even harder to prove the functional and clinical significance of one single genetic polymorphism which could be easily masqueraded or compensated by other upstream or downstream events of the pathway involved. The majority of studies have analysed candidate genes in isolation from other possible polymorphisms. It is likely that susceptibility to sepsis is the result of polymorphisms from multiple genes rather than one single mutation. Future studies should aim for multi-centered collaborative approach looking at genome wide association or gene profiling to provide a more complete appraisal of the key genetic players in determining genetic susceptibility to sepsis. This review paper will summarise the prominent candidate gene polymorphisms with known functional changes or those with haplotype data. In addition, a summary of the expanding research in the field of epigenetics and post-sepsis immunosuppression will be discussed.