Increased disease severity in non-Western immigrants with multiple sclerosis in Oslo, Norway.

BACKGROUND AND PURPOSE: Non-Western immigrants to Norway acquire an increased risk of multiple sclerosis (MS) after migration. Ethnicity and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) might influence the disease course. The aim of this study was to investigate differences in disease severity and in the presence of OCBs in ethnic Norwegian and immigrant MS patients. METHODS: Clinical data and CSF findings from 47 non-Western immigrants with MS were compared with those from 447 Norwegian and 48 immigrant patients from Western countries. RESULTS: The non-Western immigrants had a higher mean Multiple Sclerosis Severity Score (MSSS) than the Norwegian patients (5.68 vs. 4.13, P = 0.001). Age at onset was 4 years lower amongst the non-Western immigrants (P = 0.001). After adjusting for year of birth, age at onset, gender and disease course, the mean difference in MSSS between the groups was 2.17 (P < 0.001). Amongst the non-Western immigrants, 70% received disease-modifying drugs, compared with 48% of the Norwegian patients (P = 0.005). In both groups, 88% were OCB-positive. CONCLUSIONS: Non-Western immigrants with MS had an increased disease severity compared with native Norwegians and immigrants from Western countries. The presence of OCBs in the CSF was not different between the groups.

Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus.

Genomewide association studies have implicated the CLEC16A gene in several autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes. However, the most associated single-nucleotide polymorphism (SNP) varies, and causal variants are still to be defined. In MS, two SNPs in partial linkage disequilibrium with each other, rs6498169 and rs12708716, have been validated at genomewide significance level. To explore the CLEC16A association in MS in more detail, we genotyped 57 SNPs in 807 Norwegian MS patients and 1027 Norwegian controls. Six highly associated SNPs emerged and were then replicated in two large independent sample sets (Norwegian and British), together including 1153 MS trios, 2308 MS patients and 4044 healthy controls. In combined analyses, SNP rs12708716 gave the strongest association signal in MS (P=5.3 x 10⁻8, odds ratio 1.18, 95% confidence interval=1.11-1.25), and was found to be superior to the other SNP associations in conditional logistic regression analyses. Expression analysis revealed that rs12708716 genotype was significantly associated with the relative expression levels of two different CLEC16A transcripts in thymus (P=0.004), but not in blood, possibly implying a thymus- or cell-specific splice regulation.

Cognitive impairment after three decades of multiple sclerosis.

BACKGROUND: Population-based studies of cognitive impairment in patients with multiple sclerosis (MS) with long disease duration are limited. The aim of this study was to evaluate long-term outcome and the predictors of cognitive impairment in a cohort of patients with MS. METHODS: Patients living in Oslo, Norway, with definite MS and onset in 1940-1980 alive on 1 May 2006 were included. Disability was assessed by Expanded Disability Status Scale (EDSS). Cognitive functioning was assessed in terms of psychomotor speed, attention, learning/memory and executive functions. RESULTS: A total of 123 patients was included. EDSS was < or =3.0 in 26% and > or =6.0 in 60% after mean disease duration of 34.5 years. Cognitive impairment was found in 48% of the patients eligible for neuropsychological evaluation (n = 84). Typical pattern was moderate impairment within areas of information processing, attention and memory. In the univariate analysis, younger onset age was significantly associated with cognitive impairment (P = 0.014). Younger onset age (P = 0.017) and disease course (secondary progressive vs. relapsing-remitting MS, P = 0.049) were significantly associated with cognitive impairment in the multivariate analysis. CONCLUSIONS: After three decades of disease, half of the MS patients experienced reduced cognitive functioning; however, nearly one-third of the patients were only mildly disabled based on the EDSS. Younger onset age was associated with higher prevalence of cognitive impairment. A thorough evaluation of cognitive function in addition to EDSS is essential for evaluating long-term impairment in patients with MS.

RGMA and IL21R show association with experimental inflammation and multiple sclerosis.

Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31. Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA, IL21R and IL4R. We tested the association with multiple sclerosis (MS) in a Nordic case-control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR)=1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-gamma (IFN-gamma) and TNF in cerebrospinal fluid of MS patients. In IL21R, there was one positively associated (OR=1.14) and two protective (OR=0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-gamma expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets.

HLA-DRB1 and month of birth in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) displays a month-of-birth effect, with an excess of individuals being born in the spring and a deficit in the winter. This effect was shown to be more pronounced in familial cases of MS. In the present study, we investigated whether this month-of-birth association has any relation to the principal MS susceptibility gene, HLA-DRB1. METHODS: A total of 4,834 patients with MS, 4,056 controls, and 659 unaffected siblings from Canada, Sweden, and Norway were genotyped for the HLA-DRB1 gene. Month of birth was compared for patients, controls, and unaffected siblings with and without the MS risk allele HLA-DRB1*15. RESULTS: Significantly fewer patients with MS carrying the HLA-DRB1*15 risk allele were born in November compared with patients not carrying this allele (p = 0.02). Additionally, patients with MS carrying HLA-DRB1*15 had a higher number of April births compared with patients with MS not carrying HLA-DRB1*15 (p = 0.004). These differences were not present in controls or unaffected siblings. CONCLUSIONS: Month of birth, HLA-DRB1 genotype, and risk of multiple sclerosis are associated. The interaction of a seasonal risk factor with loci at or near HLA-DRB1 during gestation or shortly after birth is implicated.

Excess mortality and cause of death in a cohort of Norwegian multiple sclerosis patients.

There are few studies of long-term, cause-specific mortality in multiple sclerosis (MS) relating to population mortality. Our objective was to study survival, excess mortality and causes of death in a cohort of patients with a long history of MS. Patients living in Oslo with definite MS and onset during 1940-80 were included in 2006. Causes of death and mortality in the general population were obtained from the Cause of Death Registry of Statistics Norway. Of the 386 patients included in the study, 263 (68%) had died at inclusion. Median survival from onset was 35 years (Kaplan-Meier: 95% confidence interval 33-37). Primary progressive MS was associated with shorter survival, but mean age at death was similar for relapsing-remitting and primary progressive MS patients. The most frequent underlying cause of death was MS (50%), and infection was often registered as a contributory cause (56%). The all-cause standardized mortality ratio was 2.47. Excess mortality was most marked during the second decade after onset of MS. We conclude that infections are probably the main cause of death in patients with MS, but the frequency is underestimated due to misleading information on death certificates. Excess mortality in patients with MS first appeared during the second decade of the disease. Survival seems to be age-dependent rather than related to disease course.

Change in sex ratio, disease course and age at diagnosis in Oslo MS patients through seven decades.

OBJECTIVES: To study changes in sex ratio, disease course, time from onset to diagnosis and age at diagnosis by year of birth in a well-defined population of multiple sclerosis (MS) patients. MATERIALS AND METHODS: Based on the Oslo MS Registry patients born from 1910 to 1980 with residence in Oslo at time of diagnosis were studied. Data were analyzed by 10-year intervals based on year of birth. RESULTS: The female to male ratio increased significantly from 1.48 to 2.30 through seven decades. Also, the ratio of initial relapsing-remitting (RR-MS) to primary progressive (PP-MS) disease course increased significantly from 1.93 to 16.00. The time from onset to diagnosis and the mean age at diagnosis declined significantly during the same period. CONCLUSIONS: This study shows that there has been a change in MS sex ratio, disease course and age at diagnosis through a period of seven decades, suggesting an environmental factor mainly affecting women at a younger age and causing a RR-MS disease course.

X chromosome inactivation in females with multiple sclerosis.

The aetiology of multiple sclerosis (MS) is unknown. Autoimmune mechanisms are most probably involved. Loss of immunological tolerance to self-antigens is a common feature of autoimmune disorders. Response to X-linked self-antigens could be influenced by X-chromosome inactivation, and contribute to the gender bias observed in autoimmune disorders. Previous studies have indicated an association between skewed X inactivation and autoimmune thyroid disease and scleroderma. To investigate a potential role of X inactivation in MS, we compared the X-inactivation pattern in 568 female MS patients with controls. We found no difference in degree of skewing between patients (median 64%) and controls (median 65%) (P = 0.474). The X-inactivation pattern did thus not explain the female predominance of MS patients in general. As the aetiology of different subgroups of MS may differ, patients were grouped according to disease course: relapsing-remitting (RR-MS), secondary progressive (SP-MS) and primary progressive (PP-MS). A comparison of the X-inactivation pattern between subgroups indicated a possible difference in degree of skewing between patients with a progressive versus a relapsing course (P = 0.05).

The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patients.

The human leucocyte antigen (HLA) class II haplotype DRB1*15-DQB1*06 (DR15-DQ6) is associated with susceptibility to multiple sclerosis (MS), and HLA class I associations in MS have also been reported. However, the influence of HLA class I and II alleles on clinical phenotypes in MS has not yet been completely studied. This study aimed at evaluating the impact of HLA-A and -DRB1 alleles on clinical variables in Scandinavian MS patients. The correlation between HLA-A or -DRB1 alleles and age at onset, disease course and Multiple Sclerosis Severity Score (MSSS) were studied in 1457 Norwegian and Swedish MS patients by regression analyses and Kruskal-Wallis rank sum test. Presence of HLA-DRB1*15 was correlated with younger age at onset of disease (corrected P = 0.009). No correlation was found between HLA-A and the variables studied. This study analysed the effect of HLA-A on clinical variables in a large Scandinavian sample set, but could not identify any significant contribution from HLA-A on the clinical phenotype in MS. However, associations between HLA-DRB1*15 and age at onset of MS were reproduced in this extended Scandinavian MS cohort.