title: CD14-159 C allele is associated with increased risk of mortality after burn injury.
abstract: Although comprehension of postburn pathophysiology has grown in recent years, we are still unable to accurately identify burn patients who are at an increased risk of infectious complications and death. This unexplained variation is likely influenced by heritable factors; the genetic predisposition for death from infection has been estimated as greater than that for cardiovascular disease or cancer. Identify genetic variants associated with increased mortality after burn injury. A total of 233 patients with burns of 15% of total body surface area or greater or smoke inhalation injury who survived more than 48 h after admission and were without significant nonburn-related trauma (injury severity score > or = 16), traumatic or anoxic brain injury, or spinal cord injury. We examined the influence of genotype at five candidate loci (interleukin [IL]-1beta, IL-6, tumor necrosis factor-alpha, toll-like receptor 4, CD14) on mortality risk after burn injury. DNA was isolated from residual blood from laboratory draws and candidate genotypes were determined by real-time polymerase chain reaction using TaqMan probes. Clinical data were prospectively collected into a local, curated database. Allelic associations were analyzed by multivariate logistic regression. After adjustment for age, full-thickness burn size, inhalation injury, ethnicity, and sex, carriage of the CD14-159 C allele imparted at least a 1.3-fold increased risk for death after burn injury, relative to TT homozygotes (adjusted odds ratio, 2.9; 95% confidence interval, 1.3-6.8; P = 0.01). This association was stronger (adjusted odds ratio, 3.3; 95% confidence interval, 1.3-8.4; P = 0.01) when the analysis was conducted only on deaths accompanied by severe sepsis. In addition, a gene dosage effect for increased mortality was apparent for carriage of the CD14-159 C allele (P = 0.006). The gene dosage effect remained when white, Hispanic, or African American patients were analyzed independently, although statistical significance was not achieved in the subgroup analysis. None of the other single nucleotide polymorphisms examined were significantly associated with mortality. These data provide strong evidence that a CD14 promoter allele that is known to impart lower baseline and induced CD14 transcription also affects mortality risk after burn injury. A potential (although untested) mechanism for our observation is that reduced signaling through CD14/toll-like receptor 4 in response to challenge by gram-negative bacteria after burns results in a blunted innate immune response and subsequent increased likelihood for systemic infection and death.
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9160, USA. robert.barber@utsouthwestern.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Barber
authors.forename: Corinne C
authors.initials: CC
authors.lastname: Aragaki
authors.forename: Ling-Yu E
authors.initials: LY
authors.lastname: Chang
authors.forename: Gary F
authors.initials: GF
authors.lastname: Purdue
authors.forename: John L
authors.initials: JL
authors.lastname: Hunt
authors.forename: Brett D
authors.initials: BD
authors.lastname: Arnoldo
authors.forename: Jureta W
authors.initials: JW
authors.lastname: Horton
mesh_terms: D000328:Adult; D000483:Alleles; D002056:Burns / Q000235:genetics* / Q000401:mortality*; D003422:Critical Care; D005260:Female; D005838:Genotype; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012307:Risk Factors; D013997:Time Factors
chemical_list: D018950:Lipopolysaccharide Receptors