The complex genetics of multiple sclerosis: pitfalls and prospects

The genetics of complex disease is entering a new and exciting era. The exponentially growing knowledge and technological capabilities emerging from the human genome project have finally reached the point where relevant genes can be readily and affordably identified. As a result, the last 12 months has seen a virtual explosion in new knowledge with reports of unequivocal association to relevant genes appearing almost weekly. The impact of these new discoveries in Neuroscience is incalculable at this stage but potentially revolutionary. In this review, an attempt is made to illuminate some of the mysteries surrounding complex genetics. Although focused almost exclusively on multiple sclerosis all the points made are essentially generic and apply equally well, with relatively minor addendums, to any other complex trait, neurological or otherwise

Investigation of a Neuronal Nitric Oxide Synthase Gene (NOS1) Polymorphism in a Multiple Sclerosis Population

Multiple Sclerosis (MS) is a chronic neurological disease characterized by demyelination associated with infiltrating white blood cells in the central nervous system (CNS). Nitric oxide synthases (NOS) are a family of enzymes that control the production of nitric oxide. It is possible that neuronal NOS could be involved in MS pathophysiology and hence the nNOS gene is a potential candidate for involvement in disease susceptibility. The aim of this study was to determine whether allelic variation at the nNOS gene locus is associated with MS in an Australian cohort. DNA samples obtained from a Caucasian Australian population affected with MS and an unaffected control population, matched for gender, age and ethnicity, were genotyped for a microsatellite polymorphism in the promoter region of the nNOS gene. Allele frequencies were compared using chi-squared based statistical analyses with significance tested by Monte Carlo simulation. Allelic analysis of MS cases and controls produced a chi-squared value of 5.63 with simulated P=0.96 (OR(max)=1.41, 95% CI: 0.926-2.15). Similarly, a Mann-Whitney U analysis gave a non-significant P-value of 0.377 for allele distribution. No differences in allele frequencies were observed for gender or clinical course subtype (P>0.05). Statistical analysis indicated that there is no association of this nNOS variant and MS and hence the gene does not appear to play a genetically significant role in disease susceptibility

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

OBJECTIVE: to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients. METHODS: We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed. RESULTS: HLA-DRB1*15 is associated with OCB+: p\u200a=\u200a0.03, Odds Ratio (OR)\u200a=\u200a1.6, 95% Confidence Limits (CL)\u200a=\u200a1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p\u200a=\u200a0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p\u200a=\u200a9.4 710(-7)) outside the HLA region (65 Mb). DISCUSSION: genetic factors predispose to the development of OCB

Multiple Sclerosis and Demyelinating Diseases

© 2016 John Wiley & Sons, Ltd. This chapter outlines the features of multiple sclerosis as one understand them today, and reviews current practice in diagnosis and management. Other demyelinating diseases are also reviewed. Multiple sclerosis is the most common cause of neurological disability in young adults and health care costs result in considerable financial burden to society. The aetiology of multiple sclerosis is complex and cannot be ascribed to a single genetic or environmental factor. The characteristic pathological feature of multiple sclerosis is the focal plaque or lesion. Neuromyelitis optica (NMO) lesions show peri-vascular inflammation with prominent complement and immunoglobulin deposition in keeping with a role for humoral immunity. Acute para-infectious encephalopathies are typically monophasic encephalitides characterised by multifocal inflammatory lesions, principally affecting the white matter of the CNS. There are two consistently distinguishable pathological subdivisions: acute disseminated encephalomyelitis (ADEM) and acute haemorrhagic leukoencephalitis (AHL)

Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach

International audienceThe immune system is involved in the pathophysiology of multiple sclerosis MS but the initiating antigen s is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after Ž. U stratification of the analysis on the basis of sharing or not of the HLA-DRB1 1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients