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Recent reports, primarily in patients with secondary progressive and relapsing-remitting multiple sclerosis have suggested that the apolipoprotein (APOE) ε4 allele may be associated with a worse prognosis.1-3 The ε class of APOE is involved in lipid transport and plays a part in brain development, synapse repair, and response to neuronal injury. It has been postulated that patients possessing the ε4 allele might have a reduced capacity for neuronal remodelling after multiple sclerosis relapses.3
There is general agreement that patients with primary progressive multiple sclerosis have a worse outcome both in relation to development of disability over time and in mortality. Such patients do not have a relapsing course. Moreover, there are pathological and imaging differences between primary progressive and secondary progressive multiple sclerosis suggesting that primary progressive disease may be a less inflammatory form of the disease.4 The relation between APOE and outcome has not been specifically considered in patients with primary progressive multiple sclerosis, although 11 patients with primary progressive disease were included in one previous study.3
A possible role for the ε4 allele in primary progressive multiple sclerosis was therefore studied in a well characterised cohort of 50 patients with primary progressive disease (32 men, 18 women), all of whom were under the care of the National Hospital for Neurology and Neurosurgery and had been seen from their initial presentation. The mean age of onset was 40.3 (range 18–63) years, mean disease duration 8.7 (range 2–26) years, and the mean Kurtzke expanded disability status scale (EDSS) was 5.5 (range 2–8.5). All were white northern Europeans, recruited after local ethics committee approval. No patient had received disease modifying therapy at the time of recruitment. Disability was measured using the EDSS. In addition, age of onset, sex, and disease duration were noted. One hundred and fifty nine randomly selected healthy white subjects served as controls (60% women, 40% men, mean age 45.6 (SD 12.8 years).
DNA was isolated from leucocytes using a standard phenol/chloroform extraction method. APOE genotypes were determined after polymerase chain reaction (PCR) amplification and Hha Irestriction digestion. Fragments from PCR were separated on an 8% polyacrylamide gel.
Associations between the ε4 allele and disease outcome were investigated using two previously described stratifications of disability: firstly EDSS 0–5.5 v 6–10. An EDSS score of 6 (need for unilateral support) is clinically important and a clearly defined division. It may therefore be subject to less interrater variability than other points on the EDSS. As long term prognosis may be more clearly established in patients with a greater disease duration,5 patients with a disease duration of either ⩾5 years or ⩾9 years disease duration were included. For the purposes of comparison with previous data we also used a second method of stratification (EDSS score divided by disease duration to give a “severity score”). Patients were divided into those with “mild” and those with “aggressive” disease using the median “severity score” as the threshold.3
The Pearson χ2 test was used to compare the ε4 allele frequency between cases and controls and between outcome groups. The influence of the ε4 allele on outcome was also studied by logistic regression analysis (Stata statistical package version 5.0, Stata Corp, Texas, USA). This allowed correction for sex, disease duration, and age of onset, as each has previously been shown to influence outcome.5
Genotype distribution did not significantly differ between the sexes (p=0.21). There was no significant difference in ε4 allele frequency between cases and controls (p=0.95). Furthermore, usingt test analysis, possession of the ε4 allele did not significantly influence the age of onset (p=0.78).
Outcome was not significantly influenced by ε4 allele possession (for EDSS ⩾6, p=0.71, n=34 at ⩾5 year disease duration, and p=0.59, n=23 at ⩾9 year disease duration, and for the “severity score” p=0.76, n=50). The table illustrates the frequency of allele ε4 possession in patients stratified according to outcome. Using logistic regression to correct for potential confounding factors (sex, age of onset, and disease duration), no significant effect of the ε4 allele was found on the likelihood of having an EDSS of ⩾6 at ⩾5 or ⩾9 years (OR=1.09, p=0.92, n=34; OR= 0.67, p=0.69, n=23 respectively) or having a “severity score” greater than the median value (OR=1.24, p=0.74, n=50).
The results of this investigation in patients with primary progressive disease suggest that the ε4 allele does not influence prognosis in this group. When considered together with our findings in a large cohort of 370 patients with relapsing-remitting and secondary progressive disease which also showed no evidence of an association between allelic variation of APOE and disability,6 we suggest it is unlikely that the ε4 allele when considered alone significantly influences prognosis in multiple sclerosis.
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