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Evaluation of the Apo-1/Fas promoter Mva I polymorphism in multiple sclerosis

Department of Rheumatology, Neuroimmunology Unit, Westmead Hospital, Westmead, NSW, 2145, Australia, The first two authors contributed equally to this work

S M Teutsch

Department of Rheumatology, Neuroimmunology Unit, Westmead Hospital, Westmead, NSW, 2145, Australia, The first two authors contributed equally to this work

M McW Buhler

Department of Immunology, Neuroimmunology Unit, Westmead Hospital, Westmead, NSW, 2145, Australia

B H Bennetts

Department of Molecular Genetics, The New Children's Hospital, Westmead, NSW, 2145, Australia

R NS Heard

Department of Immunology, Neuroimmunology Unit, Westmead Hospital, Westmead, NSW, 2145, Australia

N Manolios

Department of Rheumatology, Neuroimmunology Unit, Westmead Hospital, Westmead, NSW, 2145, Australia

G J Stewart

Department of Immunology, Neuroimmunology Unit, Westmead Hospital, Westmead, NSW, 2145, Australia

The pathogenesis of multiple sclerosis is under strong genetic control involving several or more genes each of modest effect. Whilst the mechanisms underlying the pathogenesis of MS remain unknown, it has been hypothesised that either decreased apoptosis of autoreactive T cells in the CNS, or increased apoptosis of oligodendrocytes may play an important role. The Apo-1/Fas antigen (CD95), the gene for which is located in a chromosomal region showing linkage in MS genome screens, is a critical inducer of apoptosis and studies have shown aberrant expression of this molecule in MS, correlating with a decrease in T cell apoptosis or increase in CNS tissue damage. This study investigated an Mva I polymorphism in the Apo-1/Fas promoter region in a group of 124 Australian patients with relapsing-remitting MS and in 183 normal controls. Whilst there were increases in the Mva I*2 allele in MS individuals overall (59% vs 52%, P not corrected=0.08), and in HLA-DRB1*1501 negative MS patients (62% vs 55%), these were not significantly different from controls. Interactions were investigated between the Mva I alleles and T cell receptor beta chain variable region (TCRBV) germline polymorphisms, with a trend in MS individuals towards a decrease of the Mva I*1 allele when combined with the TCRBV3S1*2 allele (Relative Risk=0.25, P=0.067), and with the TCRBV8S1*1 allele (Relative Risk=0.44, P=0.12). Overall, the findings of this study indicate a possible effect of the Apo-1/Fas promoter Mva I polymorphism in MS susceptibility, which needs to be confirmed in further studies.

Key Words: Apo-1/Fas • apoptosis • autoimmunity • genetic susceptibility • multiple sclerosis • polymorphism

Multiple Sclerosis, Vol. 6, No. 1, 14-18 (2000)
DOI: 10.1177/135245850000600104


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