Genetic variation and the assessment of risk in septic patients

Excerpt

The intensivist routinely attempts to assess risk in critically ill patients to determine the type of therapy indicated for life-threatening infections. Multiple clinical variables contribute to this risk: comorbid conditions, the presence of organ failure, as well as the types and sites of infection. The rapidly emerging improvements in technologies that enable analysis of common genetic variation has led to high expectations for determining the contribution of genetics to risk assessment. While the promise of associating gene variants with prevention, treatment, or prognosis of a disorder is very alluring, the road ahead is tortuous and will require delicate navigation. Already many investigators have used the most common form of genetic variation, the single nucleotide polymorphism (SNP), to assess risk in septic patients. SNPs are stable substitutions of a single base with a frequency of more than 1% in at least one population and are strewn throughout the genome including promoters and intergenic regions. The total number of common SNPs in the human genome is estimated to be more than 10 million [1]. SNPs are genetic markers, and at most only a small percentage (2–3%) is known to alter the function or the expression of a gene. Focusing on the latter SNPs that are associated with candidate genes that play a role in the pathogenesis of a disorder [i.e., tumor necrosis factor (TNF) and associated pathway members] has important advantages but is a limited strategy. Variation in these genes has biological plausibility, fits with known hypothesis, suggests risk factors for susceptibility or protection, and can provide insight regarding downstream pathways. However, this approach currently can only target a small percentage of genes. The concept of whole genome scans to detect all of these genetic variants is appealing but daunting because of the practical correlates related to sufficient accrual and data analysis. …