The main research interest of the Ebers group at the Wellcome Trust Centre for Human Genetics is to investigate the epidemiology and genetics of the complex neurological disease multiple sclerosis (MS).
The Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) was initiated in 1993 in collaboration with neurologists from 19 different MS clinics across Canada. The study has ascertained over 35,000 MS patients since its inception and DNA has been collected from over 3,000 families with at least two family members with MS. We also have a large database of clinical, epidemiological and environmental data which has been able to answer many questions about MS.
Twin studies have shown that susceptibility is partly genetic and partly environmental, indicating that MS is complex trait. Investigations in adopted family members, half-siblings and conjugal pairs have shown that familial clustering of MS is entirely genetic and thus the environment must act at a broad population level. We have also detected a maternal effect in MS, and a modest month of birth effect where MS is more common in those born in May compared to those born in November.
Since 1973, MS has been known to be strongly associated with the Major Histocompatibility Complex (MHC), later pinpointed to a specific allele, HLA-DRB1*15, of the class II gene HLA-DRB1. We have since found that allelic heterogeneity at this locus exerts the single strongest genetic effect in MS and a hierarchy of disease associated HLA-DRB1 alleles in MS has been identified. Briefly, HLA-DRB1*15 and HLA-DRB1*17 increase disease risk and HLA-DRB1*11 and HLA-DRB1*14 are protective. These and other alleles at HLA-DRB1, HLA-DQA1 and HLA-DQB1 interact to determine disease risk. In addition, HLA-DRB1*01 has been shown to influence clinical outcome being under-represented in patients with severe disease.
MS incidence also increases with distance from the equator which is thought to implicate sunlight or vitamin D as a key environmental factor in aetiology. Recently, we have been able to demonstrate a direct link between HLA-DRB1*15 and a vitamin D response element present nearby. This element was shown to bind vitamin D, up-regulating HLA-DRB1*15 expression. The process by which this increases MS risk is as yet unknown but may be related to a lack of tolerance to self antigens.
The main focus of the Ebers research group is to further understand how the MHC contributes to the ultimate development of MS.

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