Question 23

College Answer

1) Sepsis – It is now believed that genetic predisposition influences the risk of serious infection and outcome from severe injury. These genetic variations are thought to be the result of single nucleotide polymorphisms (SNP). These are thought to influence the severity of injury by controlling the induction of TNF, NF kappa B and toll receptors. Some examples include polymorphisms in TLR 2, 4 and 5 genes, CD14 and mannose binding lectin genes.

2) Acute lung injury The genetic susceptibility to the development of and variable outcomes in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has become a topic of great interest in the pulmonary and critical care community. Published studies of variable genetic susceptibility to ALI/ARDS already have identified some important candidate genes and potential gene-environment interactions. Some examples include variant alleles in Mannose binding lectin genes and surfactant protein B gene polumorphism.

3) Head injury – There is now data to suggest that the presence of certain Apo
Lipoprotein genes may have an adverse outcome in head injury.

4) Pharmacogenomics: Response to and adverse effects of a drug are thought to have a genetic basis

5) IHD, CVA also have some genetic basis.

Discussion

In brief, the following specific associations between genotype and response to critical illness have been found:

• Risk of developing MODS from acute pancreatitis is influenced by TNF-α gene variants (Bishehsari et al, 2012)
• Risks of developing ARDS in community acquired pneumonia is related to genes encoding proteins A and D of pulmonary surfactant (García-Laorden et al, 2011)
• Susceptibility to sepsis (and to death from sepsis) seems to be related to a whole host of genetic variations, specifically in the genes encoding interleukin (IL)-1 receptor antagonist gene, the heat shock protein gene, the IL-6 gene, the IL-10 gene, the CD-14 gene, the Toll-like receptor (TLR)-4 gene, and the TLR-2 gene (Holmes et al, 2003)
• Delirium in critical illness is associated with a apolipoprotein E4 polymorphism (Ely et al, 2007)
• Outcome in brain injury seems to be worse for people featuring the apolipoprotein E-ε4 genotype (Friedman et al, 1999)

In addition, the following comorbidities feature significantly in ICU outcomes, and have a known genetic basis:

• NIDDM
• IHD
• Emphysema (α-1 antitrypsin deficiency)
• Cerebrovascular disease
• Various genetic disorders and sporadic mutations / chromosomal abnormalities; of which some notable examples are Down syndrome, which results in congenital cardiac defects, and Prader-Willi, which is associated with OSA and obesity hypoventilation syndrome.

Chung, T. Philip, et al. "Functional genomics of critical illness and injury." Critical care medicine 30.1 (2002): S51-S57.

Villar, Jesús, et al. "Bench-to-bedside review: understanding genetic predisposition to sepsis." Critical Care 8.3 (2004): 180.

Ely, E. Wesley, et al. "Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients*." Critical care medicine 35.1 (2007): 112-117.

Bion, J. F. "Susceptibility to critical illness: reserve, response and therapy."Intensive care medicine 26.1 (2000): S057-S063.

Bishehsari, Faraz, et al. "TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis." Pancreatology 12.2 (2012): 113-118.

García-Laorden, M. Isabel, et al. "Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia: a prospective, observational, genetic study." Crit Care 15.1 (2011): R57.

Holmes, Cheryl L., James A. Russell, and Keith R. Walley. "Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy." CHEST Journal 124.3 (2003): 1103-1115.

Ely, E. Wesley, et al. "Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients*." Critical care medicine 35.1 (2007): 112-117.

Friedman, G., et al. "Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury." Neurology 52.2 (1999): 244-244.