Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.
ABSTRACT 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.
- SourceAvailable from: Sunil K Narayan[Show abstract] [Hide abstract]
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 · 2.26 Impact Factor
- [Show abstract] [Hide abstract]
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 · 4.87 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Increasing evidence shows that oxidative stress plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of the human disease, multiple sclerosis (MS). Heme oxygenase-1 (HO-1) is a heat shock protein induced by oxidative stress. HO-1 metabolizes heme to the antioxidant bilirubin and carbon monoxide, and represents a powerful endogenous defensive mechanism against free radicals in many diseases. However, the role of this important enzyme in EAE remains unknown. In this study, we showed high expression of HO-1 in lesions of EAE, and demonstrated that hemin, an inducer of HO-1, inhibited EAE effectively. In contrast, tin mesoporphyrin, an inhibitor of HO-1, markedly exacerbated EAE. Our results suggest that endogenous HO-1 plays an important protective role in EAE, and that targeted induction of HO-1 overexpression may represent a new therapy for the treatment of multiple sclerosis.Neuroreport 08/2001; 12(9):1841-5. DOI:10.1097/00001756-200107030-00016 · 1.64 Impact Factor