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.
PLoS genetics, 5 (2), pp. e1000369. View on PubMed2009. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D.
Human molecular genetics, 18 (2), pp. 261-6. View on PubMed2009. Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex.
Proceedings of the National Academy of Sciences of the United States of America, 104 (52), pp. 20896-901. View on PubMed2007. An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus.
Lancet neurology, 5 (11), pp. 932-6. View on PubMed2006. Sex ratio of multiple sclerosis in Canada: a longitudinal study.
Proceedings of the National Academy of Sciences of the United States of America, 106 (18), pp. 7542-7. View on PubMed2009. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility.
Multiple Sclerosis Society of Canada
Multiple Sclerosis Society of UK
multiple sclerosis genetics MHC epidemiology interaction vitamin D environmental