Perspectives on the use of multiple sclerosis risk genes for prediction

Objective

A recent collaborative genome-wide association study replicated a large number of susceptibility loci and identified novel loci. This increase in known multiple sclerosis (MS) risk genes raises questions about clinical applicability of genotyping. In an empirical set we assessed the predictive power of typing multiple genes. Next, in a modelling study we explored current and potential predictive performance of genetic MS risk models.

Materials and Methods

Genotype data on 6 MS risk genes in 591 MS patients and 600 controls were used to investigate the predictive value of combining risk alleles. Next, the replicated and novel MS risk loci from the recent and largest international genome-wide association study were used to construct genetic risk models simulating a population of 100,000 individuals. Finally, we assessed the required numbers, frequencies, and ORs of risk SNPs for higher discriminative accuracy in the future.

Results

Individuals with 10 to 12 risk alleles had a significantly increased risk compared to individuals with the average population risk for developing MS (OR 2.76 (95% CI 2.02–3.77)). In the simulation study we showed that the area under the receiver operating characteristic curve (AUC) for a risk score based on the 6 SNPs was 0.64. The AUC increases to 0.66 using the well replicated 24 SNPs and to 0.69 when including all replicated and novel SNPs (n = 53) in the risk model. An additional 20 SNPs with allele frequency 0.30 and ORs 1.1 would be needed to increase the AUC to a slightly higher level of 0.70, and at least 50 novel variants with allele frequency 0.30 and ORs 1.4 would be needed to obtain an AUC of 0.85.

Conclusion

Although new MS risk SNPs emerge rapidly, the discriminatory ability in a clinical setting will be limited.     

Uncoupling the roles of HLA-DRB1 and HLA-DRB5 genes in multiple sclerosis

Genetic susceptibility to multiple sclerosis (MS) is associated with the MHC located on chromosome 6p21. This signal maps primarily to a 1-Mb region encompassing the HLA class II loci, and it segregates often with the HLA-DQB1*0602, -DQA1*0102, -DRB1*1501, -DRB5*0101 haplotype. However, the identification of the true predisposing gene or genes within the susceptibility haplotype has been handicapped by the strong linkage disequilibrium across the locus. African Americans have greater MHC haplotypic diversity and distinct patterns of linkage disequilibrium, which make this population particularly informative for fine mapping efforts. The purpose of this study was to establish the telomeric boundary of the HLA class II region affecting susceptibility to MS by assessing genetic association with the neighboring HLA-DRB5 gene as well as seven telomeric single nucleotide polymorphisms in a large, well-characterized African American dataset. Rare DRB5*null individuals were previously described in African populations. Although significant associations with both HLA-DRB1 and HLA-DRB5 loci were present, HLA-DRB1*1503 was associated with MS in the absence of HLA-DRB5, providing evidence for HLA-DRB1 as the primary susceptibility gene. Interestingly, the HLA-DRB5*null subjects appear to be at increased risk for developing secondary progressive MS. Thus, HLA-DRB5 attenuates MS severity, a finding consistent with HLA-DRB5's proposed role as a modifier in experimental autoimmune encephalomyelitis. Additionally, conditional haplotype analysis revealed a susceptibility signal at the class III AGER locus independent of DRB1. The data underscore the power of the African American MS dataset to identify disease genes by association in a region of high linkage disequilibrium.     

Apoptosis in multiple sclerosis

Several recent studies have provided evidence that apoptosis is an important feature in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. Apoptosis presumably plays a role in the immunoregulation via activation-induced T-cell death (AICD) and in local processes of tissue damage. In this review the dual role of apoptosis in the MS pathogenesis and its relevance regarding therapeutic concepts is discussed.     

The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration

The autoimmune model of multiple sclerosis (MS) pathogenesis provided for many years a useful but incomplete conceptual framework for understanding the complex array of factors that lead to the loss of immune homeostasis, myelin and axonal injury, and progressive neurological symptoms. The availability of novel tools in molecular neurogenetics and increasingly sophisticated neuroimaging technologies, together with the revitalization of MS neuropathology, has created a new paradigm for the multidisciplinary study of this disease. This is reflected by the growing resolution of the MS genomic map, discovery of delicate inflammatory networks that are perturbed in MS, identification of mediators of demyelination, and recognition that cumulative axonal loss and neuronal injury are the histological correlates of neurological disability. Together, these advances have set the stage for the development of therapeutic approaches designed to target the demyelinating and neurodegenerative components of the disease and promote repair.     

Polymorphic markers of some genes associated with multiple sclerosis in the population of Kazakhstan

Associations of DR2 specificity of the DRB1 gene and single-nucleotide polymorphisms of the tumor necrosis factor gene TNFα (−308 G/A), interleukin genes IL-1β (−511 C/T), IL-2 (−475 A/T and −631 G/A), IL-6 (−634 C/G), paraoxanase gene PON1 (M55L, Q192R), and the mitochondrial protein transport gene UCP2 (−866 G/A) with the development of multiple sclerosis (MS) were studied in two main ethnic groups of Kazakhstan (Kazakhs and Russians). An association of DR2 specificity of the DRB1 gene with MS was found in the combined group of Kazakhs, Russians, and offsprings from mixed marriages. No correlation between DR2 specificity and MS was found in the separately examined groups of Kazakhs and Russians. Statistically significant (p < 0.05) differences between the MS patients and healthy individuals were observed in the distribution of the genotypes at site −634 G/C of the IL-6 gene in the Kazakh group, in the allelic frequencies at site −308 A/G in the promoter region of the TNFα gene in the Russian group, and in the frequencies of alleles at the polymorphic Q192R locus of the PON1 gene in the Kazakh group.. No significant differences were revealed in the distribution of the genotypes and in the frequencies of alleles at the polymorphic sites of the genes IL-1β (−511 C/T), IL-2 (−475 A/T and −631 G/A), PON1 (M55L), and UCP2 (−866 G/A).     

Identification of novel mouse genes conferring posthypoxic pauses

Although central to the susceptibility of adult diseases characterized by abnormal rhythmogenesis, characterizing the genes involved is a challenge. We took advantage of the C57BL/6J (B6) trait of hypoxia-induced periodic breathing and its absence in the C57BL/6J-Chr 1(A/J)/NaJ chromosome substitution strain to test the feasibility of gene discovery for this abnormality. Beginning with a genetic and phenotypic analysis of an intercross study between these strains, we discovered three quantitative trait loci (QTLs) on mouse chromosome 1, with phenotypic effects. Fine-mapping reduced the genomic intervals and gene content, and the introgression of one QTL region back onto the C57BL/6J-Chr 1(A/J)/NaJ restored the trait. mRNA expression of non-synonymous genes in the introgressed region in the medulla and pons found evidence for differential expression of three genes, the highest of which was apolipoprotein A2, a lipase regulator; the apo a2 peptide fragment (THEQLTPLVR), highly expressed in the liver, was expressed in low amounts in the medulla but did not correlate with trait expression. This work directly demonstrates the impact of elements on mouse chromosome 1 in respiratory rhythmogenesis.     

Antigen-specific therapies in multiple sclerosis

Multiple sclerosis is the major neurological disease of young adults in the western world, affecting about 1 per 1,000. It is characterised by chronic or recurrent lesions of inflammatory damage in the white matter of the central nervous system. Within such lesions, the protective myelin sheath is stripped off axons by infiltrated macrophages which leads to impaired conductivity. The inflammatory process most likely starts by activation of helper T cells directed against local myelin antigens. Currently, efforts are directed at specifically blocking such myelin-reactive helper T cells in order to control the disease. In this chapter, immunological features of multiple sclerosis and the experimental animal model for the disease, experimental allergic encephalomyelitis, are discussed. Next, an overview is presented on myelin antigens that have been suggested to play a role as target antigens in MS. Finally, strategies are discussed that are currently employed to selectively block the activation of T-cells reactive against myelin antigens.     

Insulin counter-regulation in multiple sclerosis

Fasting hypoglycemia is frequently observed in patients with Multiple Sclerosis (S.M.) showing orthostatic hypotension and defective thermoregulation, although they never complicate in hypoglycemic coma. The aim of this study was to evaluate glucose homeostasis in S.M. patients. Both insular and counter-insular regulating mechanisms were investigated by determination of glucose, insulin, C-peptide and cortisol plasmatic levels during OGTT, and subsequently by evaluating glucagon plasmatic levels after arginine administration (30 g., i.v.). Our results suggest that the increased susceptibility of S.M. patients to undergo fasting hypoglycemia could be related to some alterations in counter-insular mechanisms, generally included among neurovegetative modifications in S.M. patients and probably due to orthosympathetic function impairment.     

Analysing the effect of candidate genes on complex traits: an application in multiple sclerosis

The conventional approach of candidate gene studies in complex diseases is to look at the effect of one gene at a time. However, as the outcome of chronic diseases is influenced by a large number of alleles, simultaneous analysis is needed. We demonstrate the application of multivariate regression and cluster analysis to a multiple sclerosis (MS) dataset with genotypes for 489 patients at 11 candidate genes selected on their involvement in the immune response. Using multivariate regression, we observed that different sets of genes were associated with different disease characteristics that reflect different aspects of disease. Out of 15 polymorphisms, we identified one that contributed to the severity of disease. In addition, the set of 15 polymorphisms was predictive for yearly increase in lesion volume as seen on T1-weighted MRI (p=0.044). From this set, no individual polymorphisms could be identified after adjustment for multiple hypotheses testing. By means of a cluster analysis, we aimed to identify subgroups of patients with different pathogenic subtypes of MS on the basis of their genetic profile. We constructed genetic profiles from the genotypes at the 11 candidate genes. The approach proved to be feasible. We observed three clusters in the sample of patients. In this study, we observed no significant differences in the usual clinical and MRI outcome measures between the different clusters. However, a number of consistent trends indicated that this clustering might be related to the course of disease. With a larger number of genes regulating the course of disease, we may be able to identify clinically relevant clusters. The analyses are easily implemented and will be applicable to candidate gene studies of complex traits in general.     

Beta-interferon for multiple sclerosis

Interferon beta is widely used as first-line treatment for relapsing remitting multiple sclerosis (RRMS). Several products are marketed world-wide, and biosimilar products are emerging. Interferon beta reduces relapse rates by about 1/3, and reduces the appearance of new MRI lesions by about 2/3, and some studies have shown reduced disability progression, and reduced rates of brain atrophy. The mechanism of action of interferon beta in MS is poorly understood, partly due to the complex nature of the biological response to interferon injections. This mini-review succinctly summarizes clinical effects, possible mechanism of action, physiochemical properties of the different interferon products, issues related to immunogenicity, and biomarkers of the interferon beta response, and proposes important unresolved issues for future research.