Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage

Nahara A Martínez-González; Cathie LM Sudlow

doi:10.1136/jnnp.2006.097543

. Author manuscript; available in PMC: 2009 Mar 25.

Published in final edited form as: J Neurol Neurosurg Psychiatry. 2006 Aug 22;77(12):1329–1335. doi: 10.1136/jnnp.2006.097543

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage

Nahara A Martínez-González ¹, Cathie LM Sudlow ¹

PMCID: PMC2077401 EMSID: UKMS2651 PMID: 16926234

Abstract

Background:

Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E genotype (APOE) influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.

Methods:

We comprehensively sought, identified, assessed and performed meta-analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke (IS), intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).

Results:

Our main analyses included data from 9 studies in a total of 2262 patients (1453 IS, 199 ICH, 610 SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (RR 1.40, 95% CI 1.06 to 1.84), with a trend toward a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not IS (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.

Conclusions:

APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.

By contrast with the many studies assessing the role of various candidate genes in the causation of stroke and its subtypes ¹^,²^,³, the role of genetic factors influencing outcome after acute stroke has been relatively little studied in humans ⁴^,⁵. However, studies of animal models of stroke comparing outcomes among genetically manipulated compared with wild type animals suggest that this should be a promising area, which may ultimately improve our understanding of the pathways of neuronal protection and recovery, and even lead to new therapeutic insights ⁴^,⁶.

The apolipoprotein E gene (APOE) is one of the most widely studied genes in vascular and neurodegenerative diseases. Its protein product is a 34 kDa glycoprotein with three common isoforms, E2, E3 and E4, encoded by the alleles, ε2, ε3 and ε4, giving rise to six genotypes, the ε3/ε3 genotype occurring in about one half to two thirds of people in most populations ⁷. Apolipoprotein E has a major role in lipid redistribution, which is important in the brain for membrane maintenance and repair, and in the regulation of synaptic remodelling during or following brain injury ⁶^,⁸^,⁹^-¹¹. Rodent models of head injury and ischaemic stroke suggest that APOE influences neuronal repair, regeneration and survival after brain injury ⁶^,¹¹. In clinical studies, possession of an APOE ε4 allele is associated with poor outcome after head injury ⁵. These observations suggest that APOE might influence outcome after acute stroke in humans, but clinical studies have produced conflicting results ⁵.

Here, we use systematic review and meta-analysis methods to assess the effect of APOE on outcome after the three main pathological types of acute stroke: ischaemic stroke (IS), intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH).

Methods

Study identification and selection

We sought all available published studies of the influence of APOE on outcome (death or the combination of death or dependency) after acute stroke in adult humans. We identified studies by searching Medline and Embase from 1966 through May 2005 (see Appendix), the reference lists of relevant papers thus identified, and recent textbooks on stroke or stroke genetics. We only included studies that analysed the main pathological stroke types separately. For studies with more than one publication describing results among overlapping groups of patients, we included only the largest of the available published datasets, to avoid double counting. We requested summary data from the authors of two studies for which relevant data had been obtained but were not reported in the publications.

We independently selected relevant studies, resolving disagreements by discussion.

Data extraction

From each study selected, we extracted information on: year of publication; setting and country; subjects' ethnicity; number of subjects; definition of acute stroke; whether recruitment was consecutive or not; subjects' mean age and gender distribution; method, definition and timing of outcome assessment; blinding of genotyping to outcome assessment, and of outcome assessors to genotype; genotyping samples and methods. We extracted data on the numbers of subjects who had died or who were dead or dependent at the end of follow-up with genotypes containing the ε4 allele (ε4+ genotypes) or not, and with ε2+ genotypes or not. We independently extracted the information from each study, resolving disagreements by discussion.

Statistical analyses

We assessed the effects of ε4+ versus ε4− genotypes (primary analysis) and of ε2+ versus ε2− genotypes (secondary analysis) on death and death or dependency by calculating study specific and fixed effects pooled relative risks using Cochrane RevMan software (version 4.2) ¹². We used χ² tests to assess heterogeneity between studies and different pathological types of stroke.

Because data from two eligible studies were unavailable and so excluded from our main analyses (see below), we carried out sensitivity analyses for the ε4+ versus ε4− comparison to assess what effect a range of plausible results for these studies might have had on our conclusions (see Webtables 1 and 2 for details).

Results

Characteristics of studies included

From 949 articles identified by our search, we selected 11 eligible studies in 3120 subjects ¹³^-²³. We had to exclude two of these from our main analyses, since outcome data that had been collected were unavailable in the publications, and the authors could not provide us with unpublished summary data ¹⁵^,¹⁷. Thus, we included nine studies in 2262 subjects in our main analyses (Figure 1). Details of the characteristics of all eligible studies are shown in the table, and summarised below.

Table.

Characteristics of studies included

Study	Year	Setting	Country	Ethnicity	Consecutive recruitment	Stroke definition	Follow-up method	No. of subjects (no. with APOE and outcome data)	% male	Mean age (years)	Time of outcome assessment	Outcomes with data available
Ischaemic stroke studies
McCarron-1 ¹³	1998	University hospital stroke unit	Scotland	Caucasian	Patients ‘unselected’	Acute IS proven on CT or MR brain scan	Scottish death register and database of hospital discharge records	640 (616)	47	71	3 months	Poor outcome (dead or living in an institution)
McCarron-3 ¹⁴	2000	University hospital stroke unit	Scotland	Caucasian	Y	Acute IS proven on CT or MR brain scan	Patients observed prospectively (further details not given)	189 (157)	47	69	3 months	Poor outcome (mRS 4-6); death
Catto ¹⁵ ^‡	2000	University hospital	UK	Caucasian	Y	Acute IS proven on CT brain scan	UK national death register	532 (532)	50^¶	73^¶	Median 2.4 years	Death
Broderick ¹⁶	2001	Hospitals in the USA participating in trial of ivtPA versus placebo	USA	Caucasian	N	Acute IS proven on CT brain scan	Examination	624 (409)	61	67	3 months	Unfavourable outcome (mRS 2-6)
MacLeod ¹⁷ ^‡	2001	University hospital stroke unit	UK	Caucasian	Patients ‘unselected’	Acute IS proven on CT brain scan	Patients observed prospectively (further details not given)	266 (266)	56	65.7	?	Unfavourable outcome (mRS 3-6)

Intracerebral haemorrhage studies
McCarron-1 ¹³	1998	University hospital stroke unit	Scotland	Caucasian	Patients ‘unselected’	ICH proven on CT or MR brain scan	Scottish death register and database of hospital discharge records	74 (67)	45	74	3 months	Poor outcome (dead or living in an institution)
McCarron-2 ¹⁸	1999	University hospital	USA	Mixed: 73% Caucasian 27% African American	?	CT proven diagnosis of ICH considered secondary to hypertension, cerebral amyloid angiopathy or thrombolysis	?	125 (102)	52	64	Hospital discharge	Death
Catto ¹⁵ ^‡	2000	University hospital	UK	Caucasian	Y	ICH proven on CT brain scan	UK national death register	532 (532)	?	?	Median 2.4 years	Death

Subarachnoid haemorrhage studies
Leung ¹⁹	2002	University hospital	China	Chinese	Y	Spontaneous aneurysmal SAH confirmed by CT or lumbar puncture and CT angiography +/− digital subtraction angiography	Face-to-face or telephone interviews with patient or carers	72 (72)	35	58	6 months	Unfavourable outcome (GOS 1-3)
Niskakangas ²⁰	2001	University hospital neurosurgery department	Finland	Caucasian	Y	Spontaneous aneurysmal SAH confirmed by CT and catheter angiography	Examination, telephone interview or postal questionnaire	126 (108)	40	52	6 months	Unfavourable outcome (GOS 1-3); death
Dunn ²¹	2001	University hospital neurosurgery department	Scotland	Caucasian	Y	Spontaneous SAH confirmed by CT scan or lumbar puncture	Telephone interview	125 (96)	40	49	6 months	Unfavourable outcome (GOS 1-3)
Tang ²²	2003	Hospital neurosurgery department	China	Chinese	?	Aneurysmal SAH confirmed by CT brain scan and digital substraction angiography +/− surgery	Examination or telephone interview	120 (104)	48	45	3 months	Unfavourable outcome (GOS 1-3)
Ruigrok ²³	2005	University hospital	Netherlands	Caucasian	Y	Aneurysmal SAH confirmed by CT brain scan and CT or conventional angiography	?	167 (167)	48	53	3 months	Death or dependency (GOS 1-3)

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of publication

Y = yes; N = no; ? = not stated or unclear; CT = computed tomography; MR = magnetic resonance; ivtPA = intravenous tissue plasminogen activator

^‡

Not included in the main analyses

^¶

of total patients in study (n= 592, including 60 with ICH)

The studies were mainly conducted in European countries in whites, but one in the USA was done in whites and African Americans ¹⁸, and two were done in Chinese patients ¹⁹^,²². All were hospital-based. Six studies recruited consecutively admitted patients ¹⁴^,¹⁵^,¹⁹^-²¹^,²³, one recruited patients from a randomised trial of thrombolysis for acute ischaemic stroke (i.e. highly selected patients) ¹⁶, two stated that the patients were ‘unselected’ ¹³^,¹⁷, and two did not state whether recruitment was consecutive or in some way selective ¹⁸^,²².

Genotype and outcome data were available in 1898 (84%) of the 2262 subjects from the nine studies in our main analyses. All had data on ε4+ genotypes, while only five had data on ε2+ genotypes ¹⁴^,¹⁶^,¹⁸^,²²^,²³. One study included both IS and ICH patients ¹³. Mean age was 69 years in the IS patients, 68 years in the ICH patients, and 51 years in the SAH patients. Around half of the patients were male.

Eight of the nine studies in the main analyses presented data on the combined outcome of death or dependency, defined on the basis of the Glasgow Outcome Scale (GOS) in the five SAH studies ¹⁹^-²³, discharge to an institution in one study ¹³, the modified Rankin scale (mRS) and the Barthel index (BI) in one study ¹⁴, and the mRS, BI, GOS, and National Institutes of Health Stroke Scale in another ¹⁶. We used the mRS data for our analyses for these last two studies. Only four of the studies in the main analyses presented data on death separately ¹⁴^,¹⁵^,¹⁸^,²⁰. Outcomes were assessed at three months in five studies ¹³^,¹⁴^,¹⁶^,²²^,²³, six months in three studies ¹⁹^-²¹, and hospital discharge in one study ¹⁸. Follow-up was generally by examination and/or telephone interview. Outcomes were assessed blind to genotype and vice versa in all but one study which did not comment on blinding ¹⁸.

All studies used blood samples for DNA extraction, and one also used buccal smears ²⁰. Genotype analysis was by restriction enzyme digestion of PCR product in all but one study, which assessed APOE genotypes indirectly by measuring the apoE protein phenotypes ¹⁶.

Effects on death or dependency – main analyses

Overall there was no significant effect of ε4+ versus ε4− genotypes (summary relative risk [RR] 1.08, 95% confidence interval [CI] 0.96 to 1.21) (Figure 2). However, there was significant heterogeneity between the studies (χ²_8df = 25.4, p = 0.001) some of which appeared to be accounted for by pathological type of stroke. We found no significant effect on IS (RR 0.98, 95% CI 0.85 to 1.12), but a trend towards an association with poor outcome after ICH (RR 1.38, 95% CI 0.99 to 1.92) and a significant association with poor outcome after SAH (RR 1.40, 95% CI 1.06 to 1.84). There was significant heterogeneity between the pooled results for the three pathological types of stroke (χ²_2df = 10.4, p = 0.005), and residual heterogeneity between the results of the five SAH studies (Figure 2).

Meta-analysis of effect of ε4+ genotypes on death or dependency several months after acute stroke. n = number dead or dependent at time of outcome assessment. N = number with specified genotype. Squares represent point estimates of relative risks, with size proportional to the statistical weight of each study. Horizontal lines correspond to 95% confidence intervals. Pooled relative risks are shown as diamonds, whose width is their 95% confidence interval.

There was no significant effect of ε2+ versus ε2− genotypes, either overall or for the pathological types of stroke considered separately. However, the reliability of these analyses is limited, since they were based on less than half of the available data.

Effects on death – main analyses

The pattern of the results for ε4+ versus ε4− genotypes was similar to that for death or dependency, although less than half of the total subjects contributed to these analyses. Overall there was a just significant increase in the risk of death with an ε4+ genotype (RR 1.24, 95% CI 0.92 to 1.67). There was no significant effect for IS (RR 1.08, 95% CI 0.75 to 1.55), but ε4+ genotypes conferred a non-significant trend towards an increased risk of death for patients with ICH (RR 1.63, 95% CI 0.89 to 2.98), and SAH (RR 1.98, 95% CI 0.72 to 5.49). However, since there was no statistically significant heterogeneity between results of the individual studies or the three pathological types of stroke, these subgroup analyses should be interpreted with caution (Figure 3).

Meta-analysis of effect of ε4+ genotypes on death several months after acute stroke. n = number who had died by the time of outcome assessment. N = number with specified genotype. Notation otherwise as for Figure 2.

Data on the effects of ε2+ versus ε2− genotypes were only available for about one third of the available data, making the results of limited reliability. There was no significant effect on death overall or for the separate pathological types of stroke.

Most studies presented both unadjusted results and results adjusted for potential confounders of the association between APOE and outcome. Unadjusted and adjusted results were generally very similar, although in two of the SAH studies the association of ε4+ genotypes with poor outcome became more extreme after adjustment ¹⁹^,²⁰.

Sensitivity analyses

Results are shown in Webtables 1 and 2. Including plausible values for the eligible studies with unavailable data did not affect the results of our meta-analyses of the effect of ε4+ genotypes on outcome after ischaemic stroke ¹⁵^,¹⁷. However, including plausible data for ICH from Catto et al produced a range of meta-analysis results, which included the possibility of no effect of ε4+ genotypes on death after intracerebral haemorrhage ¹⁵.

Discussion

These results suggest that ε4 carriers may be at increased risk of poor outcome (death or dependency, or death alone) several months after ICH or SAH but not after IS.

However, it is important to consider whether the apparently deleterious effect of ε4+ genotypes on outcome after ICH or SAH could be a false positive finding. Residual confounding seems unlikely to explain our findings, since unadjusted and adjusted results were generally similar. However, various potential sources of bias make false positive results a possibility. First, publication bias (where the results of small positive studies are more likely to be published than those of small negative studies) could explain why the pooled results of the smaller ICH and SAH studies (mean number of subjects 116) were positive while those of the larger IS studies (mean number of subjects 484) were not. Publication bias has been identified frequently in systematic reviews of observational epidemiological studies ³¹, including candidate gene studies, for example our own of the role of APOE in incidence of different pathological types of stroke ³. Second, reporting bias could have affected our findings, since data on both outcomes of interest were not available from all studies. Furthermore, data from 60 ICH patients in one study could not be included in our main analyses ¹⁵, but including plausible values for the results of this study in a sensitivity analysis produced a range of meta-analysis results that included the possibility of no effect of ε4+ genotypes on death after ICH. Third, selection and loss-to-follow-up biases may have affected our results because, although several studies recruited consecutive patients, patients had to survive long enough to give consent and provide a sample for DNA, with the inevitable exclusion of the most severely affected stroke patients who died early. In addition, outcome data were not available for all recruited patients, and one ICH study reported outcome at hospital discharge, which may have introduced bias if time to discharge varied between APOE genotype groups ¹⁸.

Could the result of no apparent effect on outcome after IS be a false negative finding? This seems less likely, particularly since two additional eligible studies for which we were unable to obtain data found no association between APOE and outcome after IS, and including plausible values for these in sensitivity analyses did not alter our findings ¹⁵^,¹⁷. Our meta-analysis of effects on death or dependency after IS included studies with varying outcome definitions, but this seems unlikely to have affected the overall results since the RRs for the different studies were very similar. Another possibility is that we may have missed an effect on outcome after IS because of an interaction with age. The patients in the IS studies were slightly older than the patients with haemorrhagic stroke, particularly SAH. A recent study found that the effect of ε4+ genotypes on death or severe disability six months after acute head injury was age-dependent, with the most pronounced association occurring in children and young adults ³². This raises the possibility that an association between APOE genotype and outcome after IS might only be detectable in younger patients, and that the association between APOE genotype and outcome after ICH or SAH may be stronger in younger age groups. However, given the small difference in mean age between the patients in IS, ICH and SAH studies, this seems unlikely to be the only reason for the difference in results between haemorrhagic and ischaemic pathological types of stroke.

The explanation for the apparent differences between the effects on different pathological types of stroke, if real, is uncertain. Some studies have suggested that the effects on SAH might be due to an association of ε4+ genotypes with delayed ischaemic neurological deficit ²¹^,³³. A study exploring the reasons for the association between ε4+ genotypes and poor outcome after ICH found no detectable effect of APOE on haematoma or oedema volumes ¹⁸. Another study that examined whether the effects of APOE on coagulation profiles might explain the different effects on outcome after IS and ICH found inconclusive results ²⁶.

In summary, our results suggest that APOE may affect outcome after ICH and SAH, but not IS. Further, much larger studies are needed to confirm or refute these findings and to assess the possibility of an interaction between the effects of APOE genotype and age. If the apparent differences between pathological types of stroke are confirmed, research into the reasons for this should enhance our understanding of the role of apoE in recovery after stroke, and may ultimately lead to new therapeutic insights.

Acknowledgements

We are very grateful to Brenda Thomas for her help with designing the electronic search strategy, and to Peter Sandercock, Charles Warlow and Caroline Jackson for their helpful comments on an earlier draft.

Funding

NAM-G is supported by CONACyT México. CLMS is supported by a Wellcome Trust Clinician Scientist award. Neither funding source had any role in the design, analysis or interpretation of the results this study, or in the writing of the paper or the decision to submit for publication.

Appendix

Search Strategy in Medline*

apolipoproteins/ or apolipoproteins e/
((apolipoprotein$ adj e) or (apoprotein$ adj e) or apo-e or apo e or apoe).tw.
((apolipoprotein$ adj e2) or (apoprotein$ adj e2) or apo-e2 or apo e2 or apoe2).tw.
((apolipoprotein$ adj e3) or (apoprotein$ adj e3) or apo-e3 or apo e3 or apoe3).tw.
((apolipoprotein$ adj e4) or (apoprotein$ adj e4) or apo-e4 or apo e4 or apoe4).tw.
((apolipoprotein$ adj e5) or (apoprotein$ adj e5) or apo-e5 or apo e5 or apoe5).tw.
((apolipoprotein$ adj e7) or (apoprotein$ adj e7) or apo-e7 or apo e7 or apoe7).tw.
1 or 2 or 3 or 4 or 5 or 6 or 7
exp cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp cerebrovascular accident/ or exp hypoxia-ischemia, brain/ or exp intracranial arterial diseases/ or exp “intracranial embolism and thrombosis”/ or exp intracranial hemorrhages/ or vasospasm, intracranial/
(stroke$ or apoplexy or cerebral vasc$ or cerebrovasc$ or cva$).tw.
9 or 10
8 and 11
limit 12 to human

* A similar strategy was designed for Embase

Footnotes

Competing interests

None

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PERMALINK

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage

Nahara A Martínez-González

Cathie LM Sudlow