Mitochondrial DNA Haplogroups and Delirium During Sepsis

Abstract

Objectives: Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.

Design: Retrospective cohort study.

Setting: Medical and surgical ICUs at a large tertiary care center.

Patients: Caucasian and African American adults with sepsis.

Measurements and main results: We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).

Conclusions: Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.

Figure 1.

Partial phylogenetic tree demonstrating approximate relationships between mitochondrial DNA haplogroups examined in the current investigation. Haplogroups, which are groups of similar haplotypes that share a common ancestor, are defined by specific single nucleotide polymorphisms that have emerged in the genome over millennia. Because mitochondrial haplogroups have a well-defined phylogeny (11), they can be used to understand variations in mitochondrial genetics within populations.

Figure 2.

Mental status according to day after ICU admission. Delirium was identified on days the CAM-ICU was positive; coma was identified when RASS was −4 or −5. Days when both coma and delirium were present (at different times) were considered delirium days. Missing CAM-ICU/RASS assessments on ICU days were imputed. The first assessment was considered ICU day 1, CAM-ICU use was limited to ICUs. The proportion of assessed patients declined as patients were discharged or died; the denominator remains fixed at 958, i.e., the size of the entire study cohort.

Figure 3.

Caucasian mitochondrial DNA haplogroups and delirium during sepsis. After adjusting for age, patients in haplogroup clade IWX were estimated to spend 36% (95% confidence interval, 13%−64%; p = 0.001) more days delirious on average than those in the reference group, haplogroup H.

Figure 4.

African mitochondrial DNA haplogroups and delirium during sepsis. After adjusting for age, patients in haplogroup L2 were estimated to spend 40% (95% confidence interval, 6%−72%; p = 0.03) fewer days delirious on average than those in the reference group, haplogroup L3.