Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.

Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
The Lancet (Impact Factor: 45.22). 07/1996; 347(9017):1728-30.
Source: PubMed


BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the contributions of genes and environment is to study half-sibs. METHODS In a Canadian population-based sample of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was reported by 939 index cases. By interview we elicited information on family structure and an illness in half-sibs and any full brothers or sisters. FINDINGS The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32 percent compared with 3.46 percent for the 1395 full sibs of the same cases (p<0.001; likelihood ratio test). There were no significant differences in risk for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for those raised together versus those raised apart from the index case (1.17 percent vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the feasibility of using half-sib studies to throw light on the aetiology of complex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as intrauterine and perinatal factors, breastfeeding, and genomic imprinting) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an observation consistent with a polygenic hypothesis.

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    • "Adopted relatives, although raised from infancy with the MS patients, do not develop MS more frequently than it would be expected for the general population [9]. Half-siblings raised apart (different environments) or together (same environment) with MS patients have similar risk to develop the disease and, the recurrence risk for half-siblings is significantly lower than that for full-siblings raised in the same family (1.32% vs. 3.46%) [10]. These studies made clear that the excess of the disease in biological relatives results from the sharing of genetic material, but does not follow a simple Mendelian mode of inheritance. "
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    ABSTRACT: Genetic and environmental factors jointly determine the susceptibility to develop Multiple Sclerosis (MS). Collaborative efforts during the past years achieved substantial progress in defining the genetic architecture, underlying susceptibility to MS. Similar to other autoimmune diseases, HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are the highest-risk-conferring genes. Less-robust susceptibility effects have been identified for MHC class I alleles and for non-MHC regions. The role of environmental risk factors and their interaction with genetic susceptibility alleles are much less well defined, despite the fact that infections have long been associated with MS development. Current data suggest that infectious triggers are most likely ubiquitous, i.e., highly prevalent in the general population, and that they require a permissive genetic trait which predisposes for MS development. In this review article, we illustrate mechanisms of infection-induced immunopathologies in experimental animal models of autoimmune CNS inflammation, discuss challenges for the translation of these experimental data into human immunology research, and provide future perspectives on how novel model systems could be utilized to better define the role of viral pathogens in MS.
    Biochimica et Biophysica Acta 02/2011; 1812(2):132-40. DOI:10.1016/j.bbadis.2010.06.012 · 4.66 Impact Factor
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    • "Recurrence risk in siblings of MS patients in a genetically homogeneous, inbred, very stable, isolated population with a high MS frequency in Sardinia, Italy, is 4.7%, and the risk ratio compared with the general population is 31 [8]. The major international studies on FMS include the Spanish [9], the French [10], the American [11] and the Canadian [12] "
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    ABSTRACT: To report Multiple Sclerosis (MS) in two migrant Indian siblings in the Middle East. MS was thought to be rare in the Indian subcontinent, but, of late, with ready availability of Magnetic Resonance Imaging (MRI) scan, evoked potential studies and immunoglobulin estimation in this part of the developing world, there have been several reports of definite cases of MS from India. However familial MS remains hitherto unreported from the Indian subcontinent. A 39-year-old South Indian Hindu female presented with an episode of hemiparesis which remitted with treatment. Three months later she had a relapse in an acute disseminated form, with residual deficits in gait, vision and mental faculties. MRI revealed discrete and confluent plaques in the centrum semiovale. Four years later, her brother was diagnosed to have central demyelinating disease with discrete and confluent plaques in the cervical cord and corona radiata when he presented at age 39 with neck pain and episodic tonic spasms in the lower limbs. Leucodystrophies were ruled out through appropriate biochemical tests. Cases satisfied diagnostic criteria for MS and were confirmed by follow up. HLA associations were studied. Starting a decade after migration from the South Indian state of Kerala to the Middle East, the disease had slow secondary progression in the female but a stable benign course, so far, in the male sibling. This is the first case report of familial MS from the Indian subcontinent. Onset of MS in South Indian siblings after several years of stay in the Middle East may support aetiological postulations of gene-environment interactions.
    Journal of the Neurological Sciences 10/2007; 260(1-2):244-8. DOI:10.1016/j.jns.2007.03.025 · 2.47 Impact Factor
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    • "The development of better treatment strategies requires the specification of crucial disease mechanisms and thus a better understanding of the causes of MS. It is well established that susceptibility to MS is determined by multiple genes acting in concert with the environment (Ebers et al. 1986, 1995; Sadovnick et al. 1996; Willer et al. 2003). An unbiased identification of susceptibility genes would therefore provide new insights into disease pathophysiology and facilitate the identification of suitable drug targets. "
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    ABSTRACT: Unbiased identification of susceptibility genes might provide new insights into pathogenic mechanisms that govern complex inflammatory diseases such as multiple sclerosis. In this study we fine mapped Eae18a, a region on rat chromosome 10 that regulates experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We utilized two independent approaches: (1) in silico mapping based on sequence similarity between human multiple sclerosis susceptibility regions and rodent EAE quantitative trait loci and (2) linkage mapping in an F10 (DA x PVG.AV1) rat advanced intercrossed line. The linkage mapping defines Eae18a to a 5-Mb region, which overlaps one intergenomic consensus region identified in silico. The combined approach confirms experimentally, for the first time, the accuracy of the in silico method. Moreover, the shared intersection between the results of both mapping techniques defines a 1.06-Mb region containing 13 candidate genes for the regulation of neuroinflammation in humans, rats, and mice.
    Genetics 08/2006; 173(3):1539-45. DOI:10.1534/genetics.106.057406 · 5.96 Impact Factor
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