Genetics of multiple sclerosis

Abstract

Introduction A genetic contribution to MS pathogenesis has been proven ever since the association with the HLA-DR2 locus was discovered more than 30 years ago. The search for additional MS risk genes has been frustrated by a significant lack of reproducibility. This was until recently. In the last two years there have been tremendous breakthroughs in the search for novel risk genes. The main reasons for this progress has been the introduction of novel techniques, improved statistical methods and an awareness that nothing can be solved without extensive international collaboration, including data from high numbers of patients. As anticipated the effects of these novel genes are small. In relation with the old stable giant of the associated HLA locus, the novel dwarfs have woken up, with odds ratios that generally are below 1.4. A. Current knowledge The genetic component in MS Although familial aggregation of MS has long been recognised, systematic ageadjusted recurrence risks for relatives of persons with MS were first published in 1988 (1). Subsequent studies showed that first-, second-and third-degree relatives of patients with MS were more likely to have the disease than the general population. Studies in twins showed a significant excess of concordance in monozygotic as compared to dizygotic twins (2-6). In a study of individuals with MS who were adopted an excess of risk in the genetically related family was found, whereas no excess of risk in the adopting family was found (7). Affected husband and wife couples do not occur more frequently than would be expected by chance. However the risk for their offspring is greater than if just one parent is affected (8). For halfsiblings the risk is approximately half the risk for full siblings, regardless whether they were raised together or apart (9, 10). Together these data suggest that living with someone who has MS only increases your risk on MS if you are a relative of that person, in which case your risk increases with relatedness. Mode of inheritance in MS Although, as discussed above, data confirm that genetic factors are unequivocally relevant in MS, most MS families contain no more than two or three affected individuals and no clear mode of inheritance can be inferred from segregation analysis. However the nonlinear relationship between familial recurrence risk and

Preferential Use of Public TCR during Autoimmune Encephalomyelitis

“…For example, homozygosity for HLA-DRB1*15:01 increases the probability of developing multiple sclerosis ~7-fold (1, 2). In contrast, few non-MHC polymorphisms impart more than a 1.2-fold increase in risk (3).…”

Lack of Correlation between CCL5 -28C/G Functional Polymorphism and Multiple Sclerosis in Tunisian Patients

“…In addition, interactions with other polymorphisms may be of great importance to understand the genetic mechanisms controlling development of multiple sclerosis. In fact, analysis of polymorphisms in candidate genes has established that, at least in some populations, variations in for example, nucleotide variation in the HLADRB1, interleukin 7 receptor (IL7RA), the interleukin 2 receptor (IL2RA), the CD58 and the c-type lectin domain family 16 member A (CLEC16A) genes [46][47][48].…”

The A Allele of the Single-Nucleotide Polymorphism rs630923 Creates a Binding Site for MEF2C Resulting in Reduced CXCR5 Promoter Activity in B-Cell Lymphoblastic Cell Lines

“…A significant role of genetic predisposition in MS pathogenesis is well established, with MS risk alleles identified for a range of immunologically relevant loci including HLA, IL7R, IL2RA, and CD40 (11). Recent genome-wide association studies (GWAS) produced dozens of additional loci associated with MS (12, 13).…”