I A Hoppenbrouwers

Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis.

The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 × 10−10). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.

Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis.

A recent genome-wide association study by the International Multiple Sclerosis Genetics Consortium (IMSGC) reported association of 17 single-nucleotide polymorphisms (SNPs) in 14 loci with multiple sclerosis (MS). Only two loci, HLA-DRA and IL2RA, reached genome-wide significance (P<5E−08). In our study, we determined whether we could replicate the results of the IMSGC and whether more SNPs are genome-wide significantly associated with MS. We assessed the association between the 17 IMSGC SNPs and MS in three cohorts (total number of subjects 3981, among these 1853 cases). We performed a meta-analysis of the results of our study, the original IMSGC results and the results of a recent replication study performed in the Australian population. Of the 17 IMSGC SNPs, five SNPs showed genome-wide significant association with MS: HLA-DRA (P=8E−124), IL7R (P=6E−09), IL2RA (P=1E−11), CD58 (P=4E−09) and CLEC16A (P=3E−12). Therefore, genome-wide significance has now been shown for SNPs in different non-HLA MS risk genes. Several of these risk genes, including CD58 and CLEC16A, are shared by different autoimmune diseases. Fine mapping studies will be needed to determine the functional contributions to distinct autoimmune phenotypes.

EVI5 is a risk gene for multiple sclerosis

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P=0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P=0.03 and OR 1.15; P=0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Maternal Transmission of Multiple Sclerosis in a Dutch Population

OBJECTIVE To investigate the parental relationship of patients with multiple sclerosis (MS) from an extended pedigree with extensive genealogical information up to the middle of the 18th century. DESIGN Multiple sclerosis is a complex disease resulting from genetic and environmental factors. Parent-of-origin effect, a phenomenon when the same allele may express differently depending on the sex of the transmitting parent, may influence the risk for MS. We investigated parental relationships between patients with MS using extensive genealogical information available from the Genetic Research in Isolated Populations program. We compared the average kinship of the parents of MS patients. We further explored the distribution of shortest genealogical links between parents of MS patients. Subjects Twenty-four MS patients from the isolated population who could be linked within a large complex pedigree, including 2471 people in total. RESULTS The results consistently indicate a higher prevalence of maternal transmission of MS. The kinship between mothers of patients was 3.8 times higher than that between fathers (bootstrap P = .01). Among the 814 shortest connections between parents, 333 were maternal (40.9%, vs 25.0% expected), 98 were paternal (12.0%, vs 25.0% expected), and 383 were maternal-paternal (47.1%, vs 50.0% expected) (P < .001). CONCLUSIONS Mothers of MS patients were more closely related than their fathers. This skewed relationship shows evidence for a maternal effect in MS. The most likely explanation is a gene-environment effect that takes place in utero.

Cigarette smoking and risk of MS in multiplex families

Recent studies suggest that a history of cigarette smoking is a risk factor for multiple sclerosis (MS). We aimed to test the smoking effect in multiplex families, matching for both environmental and genetic factors. In a matched case-control study, 136 MS patients from 106 multiplex MS families were compared with their 204 healthy siblings as controls. Participants completed self-report questionnaires. Conditional logistic regression was used to analyse smoking and MS risk association while controlling for confounding by age and sex. Smoking history was classified in different variables. Within our survey the smoking history of MS patients and the controls did not differ. The odds of MS were comparable for different smoking levels. However, more intense exposure and women showed higher odds ratios, although non-significant. Association studies in families with relatively high genetic loading are unlikely to be confounded by smoking history.

Genetics of Multiple Sclerosis

A genetic contribution to the pathogenesis of MS has been proven by discovery of HLA-DR2 locus over 40 years ago and description of familial aggregation of MS. Novel array technologies in parallel with analytical tools, improved central sample collection in MS centres and intensified international collaborations have led to the identification of a number of new MS risk alleles, all with a minor effect. The odds ratios of most genes are within the range of 1.1 tot 1.2. Individually these alleles are dwarfs compared to the HLA giant. It should be noted that most of these identifications relate to SNPs around best matched candidate genes and for most cases the exact genetic variation involved still needs to be identified. Nevertheless one can already predict that most MS risk genes are linked to both adaptive and innate immune functions. This underscores the autoimmune character of the disease. Genes with presumed function in the central nervous system are under-represented. New generation genetics will help to pinpoint the exact functional variants involved and functional studies linking the genetic variants with immune activity are needed to explore how these genes exactly contribute to the pathogenesis of MS.

Familial clustering of multiple sclerosis in a Dutch genetic isolate.

Multiple sclerosis (MS) is a complex disease with a substantial, yet poorly identified, genetic influence. We estimated the pattern of familial aggregation of MS in a recent genetically isolated population in the Netherlands. Forty-eight MS patients were identified. Their relationship was evaluated by tracing extended pedigrees, making use of municipal and church records. Of the 48 MS patients, 24 could be linked to a common ancestor in 14 generations. However, multiple relationships exist between patients and, to take these into account, we calculated inbreeding and kinship coefficients. We found that MS patients from the isolate were significantly more often related to each other and significantly more often inbred than a non-MS control group, drawn from the same isolate. There was no clustering of Type 1 diabetes and autoimmune thyroid diseases in families of MS patients from this isolate. Finally, HLA typing was performed. Although there was a trend towards a higher prevalence of the HLA DRB1*15 allele in patients compared to controls, differences did not reach significance. This study suggests familial aggregation in the genetically isolated population. The high level of inbreeding makes this population valuable for finding novel genes involved in MS.

Infectious mononucleosis-linked HLA class i single nucleotide polymorphism is associated with multiple sclerosis

Background: Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Objectives: Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Methods: Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. Results: HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10 -5). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A. Conclusions: HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.