More MS news articles for June 2002

Genetics of multiple sclerosis: linkage and association studies

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12083953&dopt=Abstract

Am J Pharmacogenomics 2002;2(1):37-58
Giordano M, D'Alfonso S, Momigliano-Richiardi P.
Dipartimento di Scienze Mediche, Universita del Piemonte Orientale 'Amedeo Avogadro', Novara, Italy.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system caused by an interplay of environmental and genetic factors.

The only genetic region that has been clearly demonstrated by linkage and association studies to contribute to MS genetic susceptibility is the human leukocyte antigen (HLA) system.

The majority of HLA population studies in MS have focused on Caucasians of Northern European descent, where the predisposition to disease has been consistently associated with the class II DRB1*1501-DQA1*0102-DQB1*0602 haplotype.

A positive association with DR4 was detected in Sardinians and in other Mediterranean populations.

Moreover DR1, DR7, DR11 have been found to be protective in several populations.

Systematic searches aimed at identifying non-HLA susceptibility genes were undertaken in several populations by means of linkage studies with microsatellite markers distributed across the whole genome.

The conclusion of these studies was that there is no major MS locus, and genetic susceptibility to the disease is most likely explained by the presence of different genes each conferring a small contribution to the overall familial aggregation.

The involvement of several candidate genes was tested by association studies, utilizing either a population-based (case control) or a family-based (transmission disequilibrium test) approach.

Candidate genes were selected mainly on the basis of their involvement in the autoimmune pathogenesis and include immunorelevant molecules such as cytokines, cytokine receptors, immunoglobulin, T cell receptor subunits and myelin antigens.

With the notable exception of HLA, association studies met only modest success.

This failure may result from the small size of the tested samples and the small number of markers considered for each gene.

New tools for large scale screening are needed to identify genetic determinants with a low phenotypic effect.

Large collaborative studies are planned to screen several thousands of patients with MS with several thousands of genetic markers.

The tests are increasingly based on the DNA pooling procedure.