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Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy

From The Royal Melbourne Hospital (A.v.d.W., H.B.), Parkville; Howard Florey Institute (J.P.R., H.B.) and Centre for Neuroscience (A.v.d.W., T.J.K., J.P.R.), University of Melbourne; Walter and Eliza Hall Institute of Medical Research (J.S., M.B., S.J.F.), Parkville; Box Hill Hospital (A.v.d.W., H.B.), Box Hill; and Menzies Research Institute (J.S., B.V.T., I.A.F.v.d.M.), University of Tasmania, Hobart, Australia.

Address correspondence and reprint requests to Dr. Anneke van der Walt, Royal Melbourne Hospital, Department of Neurology, Grattan St., Parkville, VIC 3050 Australia Anneke.vanderwalt{at}mh.org.au

Background: The influence of APOE allelic heterogeneity on multiple sclerosis (MS) disease severity has been reported in multiple datasets with conflicting results. Several studies have reported an unfavorable association of APOE 4 with more severe clinical disease course while, in contrast, APOE 2 has been associated with a more benign disease course. In this study, we examine the influence of heterogeneity of the APOE gene on disease severity in a large, Australian, population-based MS cohort.

Methods: Associations between APOE allele status, 2 promoter region single nucleotide polymorphisms (–219 G/T and +113 C/G), and 4 measures of disease severity were tested in 1,006 patients with relapsing-remitting MS and secondary progressive MS: 1) Multiple Sclerosis Severity Score; 2) Progression Index (Expanded Disability Status Scale/disease duration); 3) age at first symptom; and 4) interval between the first and second attack. The Symbol Digit Modalities Test was used as a single cognitive marker in 889 patients. Brain atrophy was measured in 792 patients using the intercaudate ratio. APOE 4 and 3 carriers were stratified by –219 G/T or +113 C/G to investigate haplotypic heterogeneity in the APOE gene region.

Results: In this MS study, neither APOE allele status nor promoter region heterogeneity at positions –219 G/T or +113 C/G influenced the clinical disease severity, cognition, or cerebral atrophy.

Conclusions: Allelic and haplotypic heterogeneity of the APOE gene region does not influence multiple sclerosis disease course in this well-defined Australian multiple sclerosis cohort.

Abbreviations: AD = Alzheimer disease; EDSS = Expanded Disability Status Scale; ICD = intercaudate distance; ICR = intercaudate ratio; LD = linkage disequilibrium; MS = multiple sclerosis; MSSS = MS Severity Score; PI = Progression Index; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SDMT = Symbol Digit Modalities Test; SNP = single nucleotide polymorphism; SPMS = secondary progressive multiple sclerosis; TSD = transverse skull diameter.

Supplemental data at www.neurology.org

*These authors contributed equally.

Disclosure: Author disclosures are provided at the end of the article.

Received November 16, 2008. Accepted in final form June 24, 2009.