Association of Mitochondrial Allele 4216C With Increased Risk for Complicated Sepsis and Death After Traumatic Injury

Objectives: Numerous studies have linked impaired mitochondrial activity with increased risk for clinical complications after injury. Furthermore, a number of nonsynonymous polymorphisms have been identified within the mitochondrial genome that are believed to impair cellular respiration. These DNA variants include a nonsynonymous polymorphism (T4216C) in the NADH dehydrogenase 1 gene (ND1), which encodes a key member of Complex I of the electron transport chain. We hypothesized that trauma patients who carry the ND1 4216C allele may be less able to generate the cellular energy necessary to mount an effective immune response and are at increased risk for death as well as sepsis complicated by organ dysfunction or shock. Methods: We enrolled a cohort of 136 patients admitted to the Parkland Hospital Surgical intensive care unit (ICU) with significant trauma (Injury Severity Score ? 16), >= 16 years of age, and with a minimum intensive care unit stay of ?24 hours under a protocol approved by the UTSW and Parkland IRBs. Patients with brain death, spinal cord injury, active malignancy, HIV/AIDS or who survived <48 hours after admission were excluded. Clinical data were collected prospectively and T4216C was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: After multivariate adjustment for mechanism, severity of injury, units of packed red blood cells given in the first 24 hours, age, gender,, and race/ethnicity, carriage of the 4216 C-allele was significantly associated with increased risk for sepsis complicated by organ dysfunction or septic shock (adjusted odds ratio [aOR] = 3.68; 95% CI: 1.17-11.52; p = 0.02) as well as death (aOR = 4.56; 95% CI: 1.05-19.79; p = 0.04), relative to carriers of the T-allele. Conclusion: Carriage of the mitochondrial 4216C-allele increases the risk for infectious complications and death after severe trauma.