Genetic variation in complement component 2 of the classical complement pathway is associated with increased mortality and infection: a study of 627 patients with trauma.
BACKGROUND
Trauma is a disease of inflammation. Complement Component 2 (C2) is a protease involved in activation of complement through the classical pathway and has been implicated in a variety of chronic inflammatory diseases. We hypothesized that genetic variation in C2 (E318D) identifies a high-risk subgroup of patients with trauma reflecting increased mortality and infection (ventilator-associated pneumonia [VAP]). Consequently, genetic variation in C2 may stratify patient risk and illuminate underlying mechanisms for therapeutic intervention.


METHODS
DNA samples from 702 patients with trauma were genotyped for C2 E318D and linked with covariates (age: mean 42.8 years, gender: 74% male, ethnicity: 80% white, mechanism: 84% blunt, injury severity score: mean 25.0, admission lactate: mean 3.13 mEq/L) and outcomes: mortality 9.9% and VAP: 18.5%. VAP was defined by quantitative bronchoalveolar lavage (> 10). Multivariate regression analysis determined the relationship of genotype and covariates to risk of death and VAP. However, patients with injury severity score > or = 45 were excluded from the multivariate analysis, as magnitude of injury overwhelms genetics and covariates in determining outcome.


RESULTS
Fifty-two patients (8.3%) had the high-risk heterozygous genotype, associated with a significant increase in mortality and VAP.


CONCLUSIONS
In 702 patients with trauma, 8.3% had a high-risk genetic variation in C2 associated with increased mortality (odds ratio = 2.65) and infection (odds ratio = 2.00). This variation: (1) identifies a previously unknown high-risk group for infection and mortality; (2) can be determined at admission; (3) may provide opportunity for early therapeutic intervention; and (4) requires validation in a distinct cohort of patients.
Morris
John A
JA
Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA. john.morris@vanderbilt.edu
Francois
Cedric
C
Olson
Paul K
PK
Cotton
Bryan A
BA
Summar
Marshall
M
Jenkins
Judith M
JM
Norris
Patrick R
PR
Moore
Jason H
JH
Williams
Anna E
AE
McNew
Brent S
BS
Canter
Jeffrey A
JA
D000328:Adult; D017677:Age Distribution; D000704:Analysis of Variance; D002423:Cause of Death; D015331:Cohort Studies; D003175:Complement C2 / Q000032:analysis / Q000235:genetics*; D003171:Complement Pathway, Classical / Q000235:genetics*; D003428:Cross Infection / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D017052:Hospital Mortality / Q000639:trends*; D006785:Hospitals, University; D006801:Humans; D015994:Incidence; D015601:Injury Severity Score; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D053717:Pneumonia, Ventilator-Associated / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D017678:Sex Distribution; D014193:Trauma Centers; D014947:Wounds and Injuries / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D055815:Young Adult
D003175:Complement C2