APOE genotype is a major predictor of long-term progression of disability in MS

ArticleinNeurology 56(3):312-6 · March 2001with11 Reads
DOI: 10.1212/WNL.56.3.312 · Source: PubMed
Abstract
The authors recently reported that the APOE epsilon4 allele is associated with significantly greater progression of disability in a 2-year follow-up of patients with MS. In this study, these findings are substantiated and extended in a much larger group of patients followed for up to 40 years. Two hundred five patients with clinically definite MS who were genotyped for the APOE epsilon4 carrier state were included. Groups of patients with (n = 41) and without (n = 164) APOE epsilon4 alleles were compared for latency to expanded disability status scale (EDSS) scores of 4.0 and 6.0 by Kaplan-Meier analysis with the log rank test. The results were adjusted for age at onset and sex by Cox regression analysis. The APOE epsilon4 allele frequency in patients with MS (0.10) was similar to that in the general Israeli population. There was a significant effect of APOE genotype on the latency to reach EDSS 4.0 and 6.0 (p = 0.0002 and p = 0.0006 by two-tailed log rank test). Median latencies were shorter by 12 and 11 years in the APOE epsilon4 group for these outcomes. These results were significant after adjustment for age at onset and sex. The APOE epsilon4 allele is associated with significantly faster progression of disability in MS. This is the first genetic factor to be identified with a major impact on the progression of disability in this disease.
    • "The encoding APOE alleles are designated ε2, ε3, and ε4. Epidemiologic studies have firmly established the 4 allele as a risk factor for vascular101112 and also neurologic disorders including Alzheimer's disease (AD)131415 and a poor prognosis in multiple sclerosis (MS)161718. Both AD and MS are chronic progressive disorders likely involving focal inflammatory processes: reactive microglia, complement fixation and expression of inflammatory cytokines192021. "
    Full-text · Dataset · Jul 2015 · PLoS ONE
    • "The human APOE gene has 3 alleles at its locus on chromosome 19: APOE2, APOE3, the most frequent allele, and APOE4. APOE4 is often associated with late onset Alzheimer's disease [10], poor recovery after neurological injury [11], and associated with increased oxidative stress [12]. ApoE-deficient mice have been shown to have impaired innate immune defenses in models of Listeria monocytogenes [13] and Klebsiella pneumonia [14] infections. "
    [Show abstract] [Hide abstract] ABSTRACT: Apolipoliprotein E (apoE), a critical targeting protein in lipid homeostasis, has been found to have immunoinflammatory effects on murine models of infection and malnutrition. The effects of apoE in undernourished and Cryptosporidium parvum-infected mice have not been investigated. In order to study the role of apoE in a model of C. parvum infection, we used the following C57BL6J mouse genetic strains: APOE-deficient, wild-type controls, and APOE targeted replacement (TR) mice expressing human APOE genes (E3/3; E4/4). Experimental mice were orally infected with 10(7)-unexcysted-C. parvum oocysts between post-natal days 34-35 followed by malnutrition induced with a low-protein diet. Mice were euthanized seven days after C. parvum-challenge to investigate ileal morphology, cytokines, and cationic arginine transporter (CAT-1), arginase 1, Toll-like receptor 9 (TLR9), and inducible nitric oxide synthase (iNOS) expression. In addition, we analyzed stool oocyst shedding by qRT-PCR and serum lipids. APOE4/4-TR mice had better weight gains after infection plus malnutrition compared with APOE3/3-TR and wild-type mice. APOE4/4-TR and APOE knockout mice had lower oocyst shedding, however the latter exhibited with villus blunting and higher ileal pro-inflammatory cytokines and iNOS transcripts. APOE4/4-TR mice had increased ileal CAT-1, arginase-1, and TLR9 transcripts relative to APOE knockout. Although with anti-parasitic effects, APOE deficiency exacerbates intestinal inflammatory responses and mucosal damage in undernourished and C. parvum-infected mice. In addition, the human APOE4 gene was found to be protective against the compounded insult of Cryptosporidium infection plus malnutrition, thus extending our previous findings of the protection against diarrhea in APOE4 children. Altogether our findings suggest that apoE plays a key role in the intestinal restitution and immunoinflammatory responses with Cryptosporidium infection and malnutrition.
    Full-text · Article · Feb 2014
    • "In vivo data indicates that apoE plays an isoform-specific role in mediating systemic and brain inflammatory responses [19]. Furthermore, apoE genotype is associated with progression and clinical deterioration of MS202122. Consistently, apoE-knockout mice are more susceptible to and have greater disability in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS [23,24]. Thus, we hypothesize that apoE may represent an ideal target for development of novel therapeutics for MS and other demyelination diseases based on its roles in reducing inflammation and promoting myelination and regeneration. "
    Full-text · Article · Jan 2014 · PLoS ONE
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