Search

Multiple sclerosis (MS) is a complex disease with a substantial, yet poorly identified, genetic influence. We estimated the pattern of familial aggregation of MS in a recent genetically isolated population in the Netherlands. Forty-eight MS patients were identified. Their relationship was evaluated by tracing extended pedigrees, making use of municipal and church records. Of the 48 MS patients, 24 could be linked to a common ancestor in 14 generations. However, multiple relationships exist between patients and, to take these into account, we calculated inbreeding and kinship coefficients. We found that MS patients from the isolate were significantly more often related to each other and significantly more often inbred than a non-MS control group, drawn from the same isolate. There was no clustering of Type 1 diabetes and autoimmune thyroid diseases in families of MS patients from this isolate. Finally, HLA typing was performed. Although there was a trend towards a higher prevalence of the HLA DRB1*15 allele in patients compared to controls, differences did not reach significance. This study suggests familial aggregation in the genetically isolated population. The high level of inbreeding makes this population valuable for finding novel genes involved in MS. [ABSTRACT FROM AUTHOR]

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P=0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P=0.03 and OR 1.15; P=0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.