Genetic variation in proinflammatory and anti-inflammatory cytokine production in multiple organ dysfunction syndrome

Objectives: The objectives of this study were to examine the prevalence of genetic variation for in vitro cytokine production (tumor necrosis factor [TNF]-α, interleukin-10, transforming growth factor-β1) in patients with multiple organ dysfunction syndrome, to measure circulating cytokine levels and relate these to genotype, and to identify the relationship between genetic variation and outcome. Design: Prospective analysis. Setting: Intensive care unit of a university teaching hospital. Patients: Eighty-eight critically ill patients with multiple organ dysfunction syndrome. Measurements and Main Results: The frequency of the different interleukin-10 genotypes (corresponding to high, intermediate, and low interleukin-10 production in vitro) were significantly different between controls and multiple organ dysfunction syndrome patients. High interleukin-10 producers were under-represented in the multiple organ dysfunction syndrome group: This genotype occurred in 30% of controls but in only 6% of patients (p <.001). There was no relationship between interleukin-10 genotype and mortality. The frequency of TNF-α genotypes was also significantly different between patients and controls. Intermediate TNF-α producers were under-represented (5.7% vs. 23%) and high TNF-α producers over-represented (35.2% vs. 16%) in the patient group (p <.001). TNF-α genotype was not related to mortality. The distribution of TNF-β genotypes (homozygous B1, homozygous B2, and heterozygotes) was also different between controls and patients (p = .008). The B2/B2 genotype (associated with high TNF-α production) tended to occur less frequently in the intensive care unit population (31% vs. 50%) and was associated with a higher mortality rate than either the B1/B1 or B1/B2 genotypes (48% vs. 11% and 33% respectively, p = .115). The combination of proinflammatory (TNF-α/TNF-β) and anti-inflammatory (interleukin-10/transforming growth factor-β1) cytokine genotypes was associated with prolonged patient survival time. Patients predisposed to produce a balanced cytokine response (e.g., intermediate interleukin-10/TNF-α producers) demonstrated the longest survival times, although overall mortality was no different. Conclusion: A genetic predisposition to high interleukin-10 production or intermediate TNF-α production in vitro may be protective of admission to the intensive care unit, although once admitted, any protection provided by these genotypes seems to be lost. TNF-β genotype conferred no advantage to patients with multiple organ dysfunction syndrome, the TNFB2 allele being associated with increased mortality. The combination of proinflammatory and anti-inflammatory cytokine genotypes supports the idea that a balanced cytokine response is favorable and was associated with prolonged patient survival time.