Genetic basis for clinical expression in multiple sclerosis.

Journal Article (Journal Article)

Multiple sclerosis is a clinically heterogeneous demyelinating disease and an important cause of acquired neurological disability. An underlying complex genetic susceptibility plays an important role in multiple sclerosis aetiology; however, the role of genetic factors in determining clinical features of multiple sclerosis is unknown. We studied 184 stringently ascertained Caucasian multiple sclerosis families with multiple affected cases. A detailed evaluation of patient histories identified clinical variables including age of onset, initial clinical manifestations and disease severity. The concordance within families for continuous and categorical clinical variables was investigated using an intraclass correlation or Cohen's kappa coefficient, respectively. Genetic analyses included model-dependent, model-independent and association methodology. Linear and logistic regression models were used to evaluate the effect of human leucocyte antigen (HLA)-DR2 (DRB1*1501, DQB1*0602) on clinical outcome, taking account of correlation within families. Significant concordance for early clinical manifestations within families was observed for individuals with exclusive optic neuritis and/or spinal cord involvement as first and second multiple sclerosis attacks (P < 10(-6)). Linkage (LOD = 3.80, theta = 0.20) and association (P = 0.0002) to HLA-DR were present in the dataset; however, linkage was restricted to families in which the DR2 haplotype was present in at least one nuclear member. No evidence for linkage to HLA-DR in DR2-negative families was observed. When families were stratified by concordance of early clinical manifestations, a significant DR2 association was present in all subgroups. Concordance for early manifestations of multiple sclerosis was present in this familial dataset, but was not associated with HLA-DR2. The association of DR2 in families with different clinical presentations suggests that a common basis exists for susceptibility in multiple sclerosis. However, non-HLA genes or other epigenetic factors must modulate disease expression. Locus heterogeneity at the HLA region suggests a distinct immunopathogenesis in DR2 negative patients.

Full Text

Duke Authors

Cited Authors

  • Barcellos, LF; Oksenberg, JR; Green, AJ; Bucher, P; Rimmler, JB; Schmidt, S; Garcia, ME; Lincoln, RR; Pericak-Vance, MA; Haines, JL; Hauser, SL; Multiple Sclerosis Genetics Group,

Published Date

  • January 2002

Published In

Volume / Issue

  • 125 / Pt 1

Start / End Page

  • 150 - 158

PubMed ID

  • 11834600

International Standard Serial Number (ISSN)

  • 0006-8950

Digital Object Identifier (DOI)

  • 10.1093/brain/awf009


  • eng

Conference Location

  • England