Golli-MBP gene in multiple sclerosis susceptibility

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Abstract

Multiple sclerosis (MS) is an oligo- or polygenic disease but no specific susceptibility genes have been identified so far. In the Finnish population we have previously found evidence for linkage between MS and the myelin basic protein gene (here called Golli-MBP gene) suggesting that either Golli-MBP or another gene in its vicinity contributes to MS suceptibility. Here we have screened the Golli-MBP gene for nucleotide variations and carried out multipoint association analyses in a Finnish case-control data-set as well as in an independent data-set composed of 151 MS families from Finland and Sweden. In both data-sets we found association between MS and alleles in the 1.27 kilobase (kb) range at a tetranucleotide repeat element (TGGA)n which is located 1 kb upstream of the MBP exon 1. Haplotype analyses suggested that the MS-associated 1.27 kb alleles can be split into predisposing and non-predisposing variants and provided evidence that the candidate DNA region contributing to MS susceptibility should be located at the Golli-MBP gene within a 20–25 kb segment that was conserved in the predisposing haplotypes. These findings suggest a role for the Golli-MBP locus in MS susceptibility, at least in a subset of patients, and serve as a basis for highly focused attempts to identify predisposing mutation(s).

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by multifocal damage in the central nervous system myelin. It is most common in populations of northern European origin with a prevalence of approximately 0.1% (Ebers and Sadovnick, 1994). The etiology of MS is unknown but is considered to involve one or several environmental (presumably infectious) agents which would trigger the disease in genetically susceptible individuals. Autoimmunity against myelin basic protein (MBP) or other components of the myelin sheath has been proposed as a pathogenetic mechanism leading to demyelination (Wucherpfennig et al., 1991; Voskuhl et al., 1993; Kerlero de Rosbo et al., 1993; Raine, 1997). Ethnic and sex differences in risk as well as twin (Ebers and Sadovnick, 1994), adoption (Ebers et al., 1995), and HLA-association (Olerup and Hillert, 1991) studies have established the concept that genetic factors contribute to the expression of the disease. The observed concordance rates in monozygotic (approximately 30%) vs. dizygotic twins (2–5%) as well as segregation analyses tend to suggest an oligo- or polygenic model with reduced penetrance. Recent studies including genome-wide screenings indicate that the HLA complex on chromosome 6p21.3 as well as chromosome 5p14–p12 most probably contain loci that contribute to MS susceptibility in diverse Caucasian populations (Ebers et al., 1996; Kuokkanen et al., 1996; The Multiple Sclerosis Genetics Group, 1996; Sawcer et al., 1996), whereas the effect of other loci may be population-specific, specific to particular subtypes of the disease, or so small that they escape detection with the approaches used to date.

In the genetically homogeneous Finnish population we have so far found evidence for the contribution of three loci in determining MS-susceptibility (Tienari et al., 1992a, Tienari et al., 1993; Kuokkanen et al., 1996), namely a locus linked to the MBP gene on chromosome 18, a locus close to or within the HLA-DR/DQ subregion on chromosome 6, and a locus on chromosome 5p14–p12. In the case of MBP an association with MS was originally reported in a Canadian data-set (Boylan et al., 1990a) utilizing a short tandem repeat (STR) polymorphism, which is composed of tetranucleotide repeats (TGGA)n and located 1 kilobase (kb) upstream of the MBP gene (Boylan et al., 1990b). In Finnish data-sets we found association and also evidence for linkage between MS and this polymorphism (Tienari et al., 1992a). However, subsequent reports in other populations have failed to demonstrate linkage or association between MS and the MBP gene (Graham et al., 1993; Rose et al., 1993; Eoli et al., 1994; Vandevyver et al., 1994; Wood et al., 1994). This gene has been recently discovered to form part of a larger gene complex, the Golli-MBP gene (Pribyl et al., 1993; Golli=gene expressed in oligodendrocyte lineage). Here we have identified new polymorphisms in the Golli-MBP locus and carried out multipoint association and haplotype studies in case-control and family data-sets to further analyze the role of this genomic region in MS susceptibility.

Section snippets

Case-control study

Association analyses were carried out in 74 unrelated Finnish MS patients and 85 Finnish control subjects. Compared to our previous study (Tienari et al., 1992a), two patients were included and 10 controls were changed. One of the patients could not be typed in the previous study due to a poor DNA sample; the other patient was the index patient of a newly identified multiplex family. The 10 controls were changed because the previous DNA samples were already used up. The patients satisfied the

Screening for nucleotide variations in the Golli-MBP gene

The MBP coding regions, exon-intron boundaries, as well as 600 bp of the MBP promoter and an enhancer region, approximately 4 kb upstream of MBP exon 1 were analysed for polymorphisms using PCR from genomic DNA, detection of SSCP and subsequent sequencing. The index patient of each Finnish family (n=22) and four unrelated controls were included in this initial screening. Additionally, the Golli exons 1, 2, and 3 were directly sequenced from the genomic DNA of 8 patients and 2 controls, and the

Discussion

We have studied the role of the Golli-MBP gene region in MS susceptibility using multipoint association and haplotype analyses in a case-control and a family data-set. (i) Using two independent data-sets we have provided evidence for an association between MS and the STR-1.27 allele at the tetranucleotide repeat element just 5′ to the MBP gene. (ii) We did not detect allelic association with MS using five biallelic markers within Golli-MBP gene or three extremely polymorphic subunits of the

Acknowledgements

We are indebted to the patients and their families for cooperation, to Ms Hannele Pihlaja and Ms Kaija Lindberg for technical assistance, to Drs. John Kamholz, Anthony Campagnoni, Bernard Pessac for sharing unpublished sequence data, to Dr. Joseph D. Terwilliger for many discussions, and to Dr. Marion Carson for reading the manuscript. This study has been supported by the Sigrid Juselius Foundation, the Finnish Neurology Foundation, the Finnish Medical Society Duodecim, the Oskar Öflund

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