[Show abstract][Hide abstract] ABSTRACT: Background:
Mental disorders and suicidal behavior are common in patients with multiple sclerosis (MS), they also carry a higher risk of disability pension (DP). Our aim was to investigate if DP and other factors are associated with psychiatric disorders and suicidal behavior among MS patients, and whether DP is a stronger risk indicator among certain groups.
A prospective population-based cohort study with six-year follow-up (2005-2010), including 11 346 MS patients who in 2004 were aged 16-64 and lived in Sweden. Incidence rate ratios (IRR) with 95 % confidence intervals (CI) were calculated.
MS patients on DP had a modestly higher risk of requiring psychiatric healthcare, IRR: 1.36 (95 % CI: 1.18-1.58). MS patients with previous psychiatric healthcare had a higher IRR for both psychiatric healthcare and suicidal behavior; 2.32 (2.18-2.47) and 1.91 (1.59-2.30), respectively. DP moderated the association between sex and psychiatric healthcare, where women on DP displayed higher risk than men, X(2) 4.74 (p = 0.03).
The findings suggest that losing one's role in work life aggravates rather than alleviates the burden of MS, as MS patients on DP seem to have a higher need for psychiatric healthcare, especially among women; which calls for extra awareness among clinicians.
[Show abstract][Hide abstract] ABSTRACT: Background:
The national strategy for treatment of chronic diseases - including MS - and changes in the Swedish welfare system, call for analyses of the use of, and patient satisfaction with, care in a long-term perspective. The aim was therefore to explore the use of care and the predictive value of personal factors, disease-specific factors and functioning on the use of care and to explore patient satisfaction with care in a 10-year perspective.
Information regarding personal factors, disease-specific factors, functioning and satisfaction with care was collected by home-visits; use of care was collected from the Stockholm County Council computerised register.
Data from 121 people with MS (PwMS) was collected. Primary care accounted for the majority of all care. Neurology and Rehabilitation Departments together accounted for two-thirds of all hospital outpatient care. Rehabilitation Departments accounted for one-third of the total number of inpatient days. Lower coping capacity, impaired manual dexterity and activity of daily living dependency at baseline, together with progress in MS disability predicted a higher use of care. Overall, patient satisfaction with care was stable over time.
The extensive use of care offers challenges to care coordination. Implementation of person-centred care could be a strategy to increase efficacy/outcome of care.
BMC Health Services Research 10/2015; 15(1):480. DOI:10.1186/s12913-015-1144-1 · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted.
The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands.
Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program.
A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008).
This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Importance:
Smoking tobacco is a well-established risk factor for multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system usually characterized by bouts and remissions and typically followed by a secondary progressive (SP) course. However, it is not clear whether smoking after diagnosis is detrimental.
To determine whether smoking after MS diagnosis is associated with a change in time to SP disease.
Design, setting, and participants:
Cross-sectional study of patients with prevalent MS who smoked at diagnosis (n = 728) taken from the Genes and Environment in Multiple Sclerosis Study, which consists of patients from the Swedish National MS Registry. The study entrance date was at time of first-year smoking. The study was conducted between November 2008 and December 2011, with patient environmental data collected from November 2009 to March 2011 via questionnaire. Study participants were from all counties in Sweden diagnosed as having MS at the time of the Genes and Environment in Multiple Sclerosis Study and registered in the Swedish National MS Registry. Patients with MS with relapsing-remitting disease course or SP were included. These patients' conditions were diagnosed according to the McDonald criteria and the patients responded to recruitment letters with detailed questionnaires.
Smoking, considered yearly after diagnosis and combined into a time-invariant covariate before diagnosis.
Main outcomes and measures:
Time to SPMS, measured using an accelerated failure time model, with smoking as a time-varying covariate. Other covariates included sex, age at diagnosis, snuff use, and smoking before diagnosis.
The optimized model illustrated that each additional year of smoking after diagnosis accelerated the time to conversion to SPMS by 4.7% (acceleration factor, 1.047; 95% CI, 1.023-1.072; P < .001). Kaplan-Meier plots demonstrated that those who continued to smoke continuously each year after diagnosis converted to SPMS faster than those who quit smoking, reaching SP disease at 48 and 56 years of age, respectively.
Conclusions and relevance:
This study provides evidence that continued smoking is associated with an acceleration in time to SPMS and that those who quit fare better. Therefore, we propose that patients with MS should be advised to stop smoking once a diagnosis has been made, not only to lessen risks for comorbidities, but also to avoid aggravating MS-related disability.
[Show abstract][Hide abstract] ABSTRACT: Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
[Show abstract][Hide abstract] ABSTRACT: Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multiple sclerosis (MS) (n=43 879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16 731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.
[Show abstract][Hide abstract] ABSTRACT: Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 x 10-16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 x 10-7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 x 10-37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 x 10-22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 x 10-6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
[Show abstract][Hide abstract] ABSTRACT: Background and purposeThe possible interaction between adolescent obesity and past infectious mononucleosis (IM) was investigated with regard to multiple sclerosis (MS) risk.Methods
This report is based on two population-based case–control studies, one with incident cases (1780 cases, 3885 controls) and one with prevalent cases (4502 cases, 4039 controls). Subjects were categorized based on adolescent body mass index (BMI) and past IM and compared with regard to occurrence of MS by calculating odds ratios with 95% confidence intervals (CIs) employing logistic regression. A potential interaction between adolescent BMI and past IM was evaluated by calculating the attributable proportion due to interaction.ResultsRegardless of human leukocyte antigen (HLA) status, a substantial interaction was observed between adolescent obesity and past IM with regard to MS risk. The interaction was most evident when IM after the age of 10 was considered (attributable proportion due to interaction 0.8, 95% CI 0.6–1.0 in the incident study, and attributable proportion due to interaction 0.7, 95% CI 0.5–1.0 in the prevalent study). In the incident study, the odds ratio of MS was 14.7 (95% CI 5.9–36.6) amongst subjects with adolescent obesity and past IM after the age of 10, compared with subjects with none of these exposures. The corresponding odds ratio in the prevalent study was 13.2 (95% CI 5.2–33.6).Conclusions
An obese state both impacts the cellular immune response to infections and induces a state of chronic immune-mediated inflammation which may contribute to explain our finding of an interaction between adolescent BMI and past IM. Measures taken against adolescent obesity may thus be a preventive strategy against MS.
European Journal of Neurology 12/2014; 22(3). DOI:10.1111/ene.12620 · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Large population-based genome-wide association studies have identified several multiple
sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies.
Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible
role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded
Objectives: In this study we investigated the role of consanguinity on MS risk in the relatively isolated
Faroe Islands, which have a presumed high level of inbreeding.
Methods: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients,
number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes
as measures of relatedness. Parametric and non-parametric statistical models were applied.
Results: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding
coefficients, large number of observed homozygotes and many long ROH. However, apart from the
number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed.
Conclusions: Overall, no significant difference between cases and controls were found, indicating that
consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe
[Show abstract][Hide abstract] ABSTRACT: Objective: The objective of this paper is to study comorbidity between multiple sclerosis (MS) and bipolar disorder, schizophrenia and depression in a nationwide cohort and to determine whether shared genetic liability underlies the putative association. Methods: We identified ICD-diagnosed patients with MS , bipolar disorder , schizophrenia and depression in the Swedish National Patient Register and identified their siblings in the Multi-Generation Register. The risk of MS was compared in psychiatric patients and in matched unexposed individuals. Shared familial risk between MS and psychiatric disorders was estimated by sibling comparison. Results: The risk of MS was increased in patients with bipolar disorder (HR 1.8, 95% CI 1.6–2.2, p < 0.0001) and depression (HR 1.9, 95% CI 1.7–2.0, p < 0.0001). MS risk in schizophrenia was decreased (HR 0.6, 95% CI 0.4–0.9, p = 0.005). The association between having a sibling with a psychiatric disorder and developing MS was not significant. Conclusion: We found a strong positive association between MS and bipolar disorder and depression that could not be explained by genetic liability. The unexpected negative association between MS and schizophrenia might be spurious or indicate possible protective mechanisms that warrant further exploration. Background
European congress of neuropsychopharmacology, Berlin, Germany; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Background:
Identification of MS registries and databases that are currently in use in Europe as well as a detailed knowledge of their content and structure is important in order to facilitate comprehensive analysis and comparison of data.
National MS registries or databases were identified by literature search, from the results of the MS Barometer 2011 and by asking 33 national MS societies. A standardized questionnaire was developed and sent to the registries' leaders, followed by telephone interviews with them.
Twenty registries were identified, with 13 completing the questionnaire and seven being interviewed by telephone. These registries differed widely for objectives, structure, collected data, and for patients and centres included. Despite this heterogeneity, common objectives of the registries were epidemiology (n=10), long-term therapy outcome (n=8), healthcare research (n=9) and support/basis for clinical trials (n=8). While physician-based outcome measures (EDSS) are used in all registries, data from patients' perspectives were only collected in six registries.
The detailed information on a large number of national MS registries in Europe is a prerequisite to facilitating harmonized integration of existing data from MS registries and databases, as well as comprehensive analyses and comparison across European populations.