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

Abstract

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 trauma patients 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 trauma patients were genotyped for C2 E318D and linked with covariates (age: mean 42.8 years, gender: 74% male, ethnicity: 80% Caucasian, mechanism: 84% blunt, ISS: 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 (>104). Multivariate regression determined the relationship of genotype and covariates to risk of death and VAP. However, patients with ISS ≥ 45 were excluded from the multivariate analysis, as magnitude of injury overwhelms genetics and covariates in determining outcome. Results 52 patients (8.3%) had the high-risk heterozygous genotype, associated with a significant increase in mortality and VAP. Conclusion In 702 trauma patients, 8.3% had a high-risk genetic variation in C2 associated with increased mortality (OR=2.65) and infection (OR=2.00). This variation: 1) Identifies a previously unknown high risk group for infection and mortality; 2) Can be determined on admission; 3) May provide opportunity for early therapeutic intervention; and 4) Requires validation in a distinct cohort of patients.

Rare inborn errors associated with chronic hepatitis B virus infection

“…C2 is part of the membrane attack unit of complement C4b2a3b that causes cell lysis. Its antiinfective role is supported by a previous observation that carriers of the same mutation have higher mortality rates and more complications of infection 20. Our study is the first to show an association of this variant with CHB, suggesting that an unimpaired complement system may play an important, although as yet unexplained, role in anti‐CHB infection.…”

“…The TMEM2 variant p.Ser1254Asn was entered in the dbSNP133 during our investigation with no indication of its immunological function. C2 p.Glu318Asp is reported in the literature, 20 but not with regard to HBV infection.…”

Genetic influences on survival time after severe hemorrhage in inbred rat strains

“…An in vitro model of myocardial ischemia (4) indicated that the infarct size was least in hearts from BN, whereas hearts from SS rats demonstrated the most adverse consequences of ischemia. Finally, data from trauma patients have demonstrated that differences in single nucleotide polymorphisms in mitochondrial DNA (9), complement (31), and ␤ 2 -adrenergic receptors (32) are associated with differences in mortality.…”

Life or Death? A Physiogenomic Approach to Understand Individual Variation in Responses to Hemorrhagic Shock

“…Such investigations indicate that specific polymorphisms associated with mitochondrial Complex 1 [65] and complement component 2 [66] may be associated with increased mortality of trauma victims. Alternatively, a polymorphism in a β-2 adrenergic receptor (ADBR2: Q27E) was associated with enhanced survival after various blunt and penetrating injuries [67].…”