Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P=.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P=.03), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P=.02).

Figure 1

Physical map of SNPs on cosmid F19374 containing APOE. snp888 and snp988 are within the TOM40 gene (LocusLink 10452). snp952 is in the 5′ UTR of APOE. A functional relationship with any particular APOE allele or other effect on APOE expression is not known.

Figure 2

Comparison of APOE genotypes for severe and nonsevere MS. P values from PROC GENMOD, using logistic regression with correction for familial correlations and adjustment for age at onset, sex, and DR2 status. Odds ratio of severe MS for APOE-4 carriers = 2.67, 95% CI 1.12–6.36, P=.03; reference group APOE-3/3 genotype.

Figure 3

Comparison of APOE genotypes for mild and nonmild MS. P values from PROC GENMOD, using logistic regression with correction for familial correlations and adjustment for age at onset, sex, and DR2 status. Odds ratio of mild MS for APOE-2 carriers = 2.10, 95% CI 1.11–3.95, P=.02; reference group APOE-3/3 genotype.