APOE genotypes and disease severity in multiple sclerosis

Abstract

Apolipoprotein E (opoE) is involved in the transport of lipids necessary for membrane repair and is encoded by a gene on chromosome 19q13, a region positive for linkage in two multiple sclerosis (MS) genome-wide screens. The APOE epsilon4 allele confers susceptibility to both familial and sporadic Alzheimer's disease (AD). Carriage of epsilon4 is associated with defective dendritic remodeling in AD, and with unfavorable clinical outcome in head trauma and cerebrovascular disease. According to the results of previous studies, APOE epsilon4 does not increase the risk of developing MS, but it may influence disease progression and ultimate disability. From a total cohort of over 900 MS patients, we compared APOE epsilon2-4 genotypes in, roughly, the cohort's least disabled and most disabled septiles. 'Benign MS' (n=124) was defined as an Expanded Disability Status Scale (EDSS) score of 3.0 or less, despite at least 10 years of disease duration, and 'severe MS' (n=140) as the attainment of an EDSS score of 6.0 within 8 years of disease onset. We found no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles; however, the risk conferred by epsilon4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles.

Apolipoprotein E and the Risk of Breast Cancer in African-American and Non-Hispanic White Women

“…The ε3 allele has been shown to support the effective repair and remodelling after injury by noxious agents in a dose-dependent fashion. In contrast, the ε4 allele may be less effective in these processes of repair after DNA damage, as it does not generally appear to support maintenance of healthy neurites and neuronal cells [1, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40]. This is perhaps due to the variable levels and types of oestrogen receptors within different brain regions and the effect of oestrogen on APO E since the mechanism of this effect may also vary within different regions of the brain [34, 35].…”

“…The APO E genetic polymorphism has been shown to modify the risk for a variety of diseases, including breast cancer [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]. We refer the reader to important reviews by Mahley and Rall [1]and Smith [23], who provide detailed discussions of APO E on the risk of common human diseases and on ageing.…”

Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis

“…However, a similar number of studies failed to replicate this association. [16][17][18][19][20][21][22][23] There is moderate evidence supporting a susceptibility locus on chromosome 19; however, this locus is likely to be more distal to APOE than the region considered here. 24,25 The APOE gene is a plausible candidate modifier gene, owing to its involvement in other neurodegenerative disorders, including Alzheimer's disease, 26 Parkinson disease 27 and amyotrophic lateral sclerosis.…”

Investigations in the Hungarian Multiple Sclerosis Patient Population: New Data on the Genetic Background and Validation of the Fatigue Impact Scale

“…The present study did not consider the genotype-phenotype relationship, but in the series in the study by Masterman et al, the APOE ε3/ε4 genotype was more common in severe MS than in benign MS [53]. Fazekas et al found that patients carrying the ε3/ε4 genotype exhibited a significantly higher black hole ratio, demonstrating the disabling effect of the є4 allele [48].…”

“…In contrast, 2.1-7.7% of the patients were genotyped as є4/є4 in studies from Denmark [51,56], Sweden [53] and Kuwait [41]. In general, the low frequency of ɛ4 homozygotes limits the analyses as concerns an independent effect of this genotype.…”