Early ReportAssociation of apolipoprotein E polymorphism with outcome after head injury
Introduction
The considerable variability in outcome after an acute head injury is only partly explained by known prognostic features such as the age of the patient and clinical or investigative indices of severity of damage.1, 2 Relatively little attention has been given to the possibility that there may be genetically determined variation between individuals in the acute response to brain injury or in the capacity for repair and regeneration.
Evidence from animal models indicates that apolipoprotein E (apoE) has an important role in the response to nervous system injury.3 In human beings there are three common alleles of the APOE gene—ε2, ε3, ε4— which encode three isoforms of the protein (E2, E3, E4). In-vitro data indicate substantial differences in the behaviour of these isoforms.4, 5, 6 APOE genotype is the most important genetic determinant of susceptibility to Alzheimer's disease and acts synergistically with a history of a previous head injury.7
We have reported previously that there are APOE-genotype-dependent variations in the neuropathology of fatal head injury.8 We now report the results of a prospective clinical study designed to test the hypothesis that patients with APOE ε4 have a less favourable clinical outcome 6 months after head injury than those without the allele.
Patients with head injury who were admitted to the regional neurosurgical unit, Institute of Neurological Sciences, Glasgow, UK, were identified prospectively and no selection criteria were applied. Written or oral consent was obtained from the patient or a relative depending on circumstances. The study was approved by the ethics committee of the Southern General Hospital NHS Trust. The following data were collected: age and sex, pattern of injury (computed tomography scan), and initial clinical severity (Glasgow Coma Score [GCS]).9 6 months after injury, survivors and their relatives or carers were contacted. Patients were allocated to one of the categories of the Glasgow Outcome Scale10 by means of a structured interview.
APOE genotype was determined by PCR11 on blood samples taken for routine clinical purposes. Outcome was assessed without knowledge of the patient's APOE genotype and the results of the two tests were submitted independently for statistical analysis. We planned to recruit 100 patients, to test the hypothesis of an association between presence of the APOE ε4 allele and an unfavourable outcome after head injury, defined in advance by means of the Glasgow Outcome Scale as death, vegetative state, or severe disability at 6 months after injury.
The proportions of patients with an unfavourable outcome in the groups with and without an APOE ε4 allele were compared by use of a χ2 test. A logistic regression analysis was done to control for age, GCS, and computed tomography findings. These three key prognostic factors were agreed in advance. Age was included in the regression model as a continuous variable. GCS was grouped into three categories (3–8, 9–12, and 13–15) and included as a categorical variable. Computed tomography findings were allocated to one of three categories (diffuse injury with no swelling, diffuse injury with swelling or midline shift, and focal mass lesion) and included as a categorical variable.
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Results
Data about initial clinical state, APOE genotype, and 6-month outcome were available for 93 patients. The diagnosis was found not to be an acute head injury in three patients and samples were not available for APOE genotyping in four patients. The patients were typical of those admitted with head injuries to a neurosurgical unit: 76 (82%) were male; the median age was 38 years (<1–82 years); 22 had a severe injury (GCS 3–8), 19 a moderate injury (GCS 9–12), and 48 a mild/minor injury (GCS
Discussion
Our findings provide evidence for a genetic association with 6-month outcome after head injury, based on polymorphism of the APOE gene. Although the initial features of groups with and without APOE ε4 differed, the younger age of the patients with APOE ε4 and the lower frequency of a focal mass lesion should have indicated a better prognosis. However, the proportion of patients with lower GCS (<13), indicating a poorer prognosis, was higher in the APOE ε4 group. These factors are among the
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