Ebers group

Research Overview

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). We hope that our work will provide clues towards understanding the specific disease processes and may one day help in developing better treatments and improving the quality of life for individuals afflicted with this disorder.

Professor Ebers leads the Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS). The 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. The study group has also collected a large database of clinical, epidemiological and environmental data which has been able to answer many questions about MS.

It was recognised in the late 19th century that some people with MS have an affected relative. But not until the mid-1980s was it finally established, based on recurrence risks in many categories of relatives of index cases by the CCPGSMS, that disease susceptibility is genetically determined. Studies of twins 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.  Our large database has enabled us to detect 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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Publications

Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, Deluca GC, Herrera BM, Chao MJ, Sadovnick AD, Ebers GC, Knight JC. 2009. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS genetics, 5 (2), pp. e1000369. View on PubMed

Chao MJ, Ramagopalan SV, Herrera BM, Lincoln MR, Dyment DA, Sadovnick AD, Ebers GC. 2009. Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex. Human molecular genetics, 18 (2), pp. 261-6. View on PubMed

DeLuca GC, Ramagopalan SV, Herrera BM, Dyment DA, Lincoln MR, Montpetit A, Pugliatti M, Barnardo MC, Risch NJ, Sadovnick AD, Chao M, Sotgiu S, Hudson TJ, Ebers GC. 2007. An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proceedings of the National Academy of Sciences of the United States of America, 104 (52), pp. 20896-901. View on PubMed

Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, Ebers GC, Canadian Collaborative Study Group. 2006. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet neurology, 5 (11), pp. 932-6. View on PubMed

Lincoln MR, Ramagopalan SV, Chao MJ, Herrera BM, Deluca GC, Orton SM, Dyment DA, Sadovnick AD, Ebers GC. 2009. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility. Proceedings of the National Academy of Sciences of the United States of America, 106 (18), pp. 7542-7. View on PubMed

Funding Sources

Multiple Sclerosis Society of Canada

Multiple Sclerosis Society of UK

Research Area

neurogenetics

Keywords

multiple sclerosis genetics MHC epidemiology interaction vitamin D environmental