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

To the Editor: In a recent article, Chapman et al.1 described a statistical association of the APOE genotype with long-term progression of disability in MS. They showed that the APOE-ε4 allele was not associated with higher risk of developing MS, but was associated with accumulation of disability (p 0.002); other studies have shown an association between MS disease activity and APOE-ε4 as well. It has been shown recently that genetic loci for autoimmune/inflammatory disorders tend to cluster or colocalize throughout the genome,2-5 suggesting, in some cases, common or shared loci involving underlying immune regulatory pathways. The overlap of inflammatory loci is particularly true on chromosome 19q13 at the point containing the APOE gene. The table shows polymorphic markers linked to autoimmune/inflammatory diseases that are identical, overlap, or are within 10 centimorgans of the APOE locus that has been associated with MS progression of disability. A number of candidate loci for susceptibility to infectious organisms have been mapped to this point as well (data not shown). These human diseases shown here include MS, celiac disease, asthma, type I diabetes, and systemic lupus erythematosus—all of which involve progressive disability brought on by chronic, immune-mediated tissue damage. Similarly, AD has been linked and associated with APOE-ε4 and is thought to have an inflammatory component. Overlap of multiple loci from multiple diseases to the point containing the APOE gene could occur for a number of reasons. These reasons could include coincidental associations, statistical artifacts, or biological artifacts due to gene and chromosome structural organization. One possible biological interpretation of multiple clinically related diseases mapping to identical or overlapping genetic intervals is that the contribution of the APOE genotype may not be disease specific, but may predispose to a basic component of the inflammatory response, which manifests itself in different immune-mediated diseases with an inflammatory component.