P. S. Sørensen

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified—1q11–24, 2q24–32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21–22, 6q21, 9q34.3, 10p15, 10p12–13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12–13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Familial effects on the clinical course of multiple sclerosis

Background: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. Method: We evaluated 1,083 families with ≥2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. Results: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa −0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent–child pairs and no evidence for anticipation or effects of genetic loading. Conclusion: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.

Safety and immunogenicity of a new formulation of interferon β-1a (Rebif® New Formulation) in a Phase IIIb study in patients with relapsing multiple sclerosis: 96-week results

Background A new formulation of subcutaneous (s.c.) interferon-β-1a has been developed (Rebif® New Formulation, RNF), produced without fetal bovine serum and without human serum albumin as an excipient, with the aim of improving injection tolerability, and reducing immunogenicity. Objectives This article reports 96-week analyses of a Phase IIIb, open-label study of the safety and immunogenicity of RNF compared with historical (EVIDENCE study) and recent (REGARD study) data on the original formulation. Methods Patients with relapsing multiple sclerosis (McDonald criteria) and an Expanded Disability Status Scale score < 6.0 received RNF, 44 μg s.c. three times weekly. Results The proportion of neutralizing antibody-positive (NAb+) patients (serum NAb status ≥20 neutralizing units/mL) at week 96 (last observation carried forward; primary endpoint) was 17.4% (exact 95% confidence interval [CI]: 13.0–22.5), compared with 21.4% (95% CI: 17.2–26.2) in the EVIDENCE study, and 27.3% (95% CI: 22.8–32.1) in the REGARD study. The proportion of patients NAb+ at any time during the 96 weeks was 18.9% (95% CI: 14.4–24.2), compared with 27.1% (95% CI: 22.4–32.2) and 33.7% (95% CI: 28.9–38.7), respectively. Most pre-specified categories of adverse events were reported by patients in the RNF study at a similar or lower proportion than in the EVIDENCE and REGARD studies. Injection-site reactions were experienced by fewer patients than in the EVIDENCE and REGARD studies. Conclusions RNF has improved overall immunogenicity and safety profiles compared with the original formulation.

The T cell regulator gene SH2D2A contributes to the genetic susceptibility of multiple sclerosis

The T cell specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the control of T cell activation. The gene is located in the 1q21 region, which has been implicated in susceptibility to experimental allergic encephalomyelitis in the mouse. We therefore evaluated whether a polymorphic GA repeat (GA13–GA33) within the promoter region of the SH2D2A gene shows association to multiple sclerosis (MS). The frequency of the short alleles GA13–16 was increased among 313 Norwegian MS patients compared to 277 healthy controls (0.332 vs 0.249, OR 1.5, Pc = 0.03). Transmission disequilibrium analysis in 146 Scandinavian families with at least two affected sibs showed increased transmission of GA16 to MS patients. No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed. After activation of naive CD4+ T cells, T cells homozygous for MS associated short alleles displayed lower level of TSAd ex vivo than T cells carrying at least one long allele, which were not associated to MS. Since the SH2D2A protein modulates T cell activation, this may be a mechanism for how short SH2D2A alleles confer susceptibility to develop MS.

IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 × 10−9), IL12A (P=3.08 × 10−8) and MPHOSPH9/CDK2AP1 (P=3.96 × 10−8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 × 10−5) and in peripheral blood mononuclear cells from subjects with MS (P=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

Health-related quality of life in secondary progressive multiple sclerosis.

Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-β1a (IFN-β1a), 22 μg subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-β1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS

Linkage analysis of a candidate region in Scandinavian sib pairs with multiple sclerosis reveals linkage to chromosome 17q.

To date, four genome screens have been completed in the demyelinating autoimmune disease multiple sclerosis (MS). Although these screens failed to identify any loci with major effects on susceptibility, several novel regions of potential linkage were suggested, including the long arm of chromosome 17. In order to further pursue this promising region we have investigated six highly polymorphic microsatellite markers in 115 Scandinavian families with MS affected sib pairs. Multipoint linkage analysis revealed a peak maximum likelihood score (MLS) of 0.9 in the region of marker D17S787. Stratifying the results on the basis of HLA-DR2 status showed that the linkage was not limited to families segregating for the HLA-DR2 allele as has previously been suggested. In conclusion, our results further support the proposal that a multiple sclerosis susceptibility locus is contained on chromosome 17q.

Early safety and efficacy of fingolimod treatment in Denmark

Initiation of fingolimod treatment is associated with a transient decrease of heart rate, and atrioventricular (AV) conduction block may occur.

Gender effects on treatment response to interferon-beta in multiple sclerosis

Gender appears to play a role in incidence and disease course of multiple sclerosis (MS).

Linkage analysis suggests a region of importance for multiple sclerosis in 3p14–13

Four genomic screens for linkage in multiple sclerosis (MS) have been reported. They confirmed the established role of the human leucocyte antigen (HLA) complex genes in MS and, in addition, suggested the importance of a few other chromosomal segments. Here we report evidence for the importance of 3p14–13 region identified by suggestive linkage in genomic screens from Canada and the United Kingdom. When studying 146 Nordic MS multiplex families, mostly affected sib-pairs, with eight microsatellite markers, spanning a 36-cM region, we observed a two-point non-parametric linkage (NPL) score of 2.39 (P = 0.007) by the GENEHUNTER package for marker D3S1285 and a multipoint NPL score of 1.20 in the same region. Association studies in Swedish MS patients revealed modest allelic associations of uncertain significance not supported by transmission analysis. Analysis of the trinucleotide repeat sequence of the SCA7 gene in Swedish index cases did not reveal expansions. We conclude that support was obtained for the location of a gene or genes with importance for MS susceptibility in 3p14–13 region.