| 51. |
- Lekman, Magnus, et al.
(författare)
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The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder : an explorative study
- 2014
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Ingår i: BioData Mining. - : Springer Science and Business Media LLC. - 1756-0381. ; 7, s. 19-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. Results: Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e. g. additive dominant model P-uncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with P-uncorrected = 6.95E-5 with odds ratio (OR estimated from beta 3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15). Conclusions: We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied.
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| 52. |
- Lindahl, Hannes, et al.
(författare)
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IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis
- 2019
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 203:4, s. 888-898
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have mapped the specific sequence variants that predispose for multiple sclerosis (MS). The pathogenic mechanisms that underlie these associations could be leveraged to develop safer and more effective MS treatments but are still poorly understood. In this article, we study the genetic risk variant rs17066096 and the candidate gene that encodes IL-22 binding protein (IL-22BP), an antagonist molecule of the cytokine IL-22. We show that monocytes from carriers of the risk genotype of rs17066096 express more IL-22BP in vitro and cerebrospinal fluid levels of IL-22BP correlate with MS lesion load on magnetic resonance imaging. We confirm the pathogenicity of IL-22BP in both rat and mouse models of MS and go on to suggest a pathogenic mechanism involving lack of IL-22-mediated inhibition of T cell-derived IFN-gamma expression. Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization, suggesting a therapeutic potential of IL-22 in the context of MS.
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| 53. |
- Lindberg, Bengt, et al.
(författare)
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Prevalence of β-cell and Thyroid Autoantibody Positivity in Schoolchildren during Three-Year Follow-up
- 1999
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 31:3, s. 175-185
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65Ab), insulin (IAA), islet cells (ICA), thyroid peroxidase (TPOAb) and thyroglob-ulin (TgAb), in relation to HLA-DR types, was assessed in 310 (HLA in 280) twelve-year-old children during three-year follow-up. Altogether, 26.8% (83?10) of the children were found to carry at least one autoantibody. The HLA-DR3/DR4 genotype was significantly more prevalent in the subgroup of children GAD65Ab-positive on at least one occasion than among GAD65Ab-negative children |33% (2/6) vs. 5% (12/274);? = 0.03|, as was the HLA-DR4/x genotype among children seropositive for at least one thyroid autoantibody, compared to the corresponding seronegative subgroup [52% (34/65) vs. 34% (74/215); p = 0.01]. The proportion of children seropositive in at least one of the three tests was 1.9% (6?10) for GAD65Ab, 2.6% (8?10) for IAA, 5.2% (16?10) for ICA, 11.3% (35?10) for TPOAb and 19.4% (60?10) for TgAb. All autoantibodies except GAD65Ab tended to disappear during follow-up, and at the three-year follow-up IAA had disappeared in 50% (2/4) of cases, ICA in 67% (6/9), TPOAb in 30% (6/20) and TgAb in 38% (18/47) of cases. The turnover of seropositive subjects and the large proportion of children seropositive for at least one islet or thyroid autoantibody during a three-year follow-up suggest transient autoantibodies to be more common than is discernible in cross-sectional investigations
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| 54. |
- Ludvigsson, Johnny, et al.
(författare)
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Decline of C-peptide during the first year after diagnosis of Type 1 diabetes in children and adolescents
- 2013
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier. - 0168-8227 .- 1872-8227. ; 100:2, s. 203-209
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: We studied the decline of C-peptide during the first year after diagnosis of Type 1 diabetes (T1D), and its relation to various factors. less thanbrgreater than less thanbrgreater thanMethods: 3824/4017 newly diagnosed patients (95%) were classified as T1D in a national study. In a non-selected subgroup of 1669 T1D patients we determined non-fasting C-peptide both at diagnosis and after 1 year, and analyzed decline in relation to clinical symptoms and signs, initial C-peptide and occurrence of auto-antibodies. less thanbrgreater than less thanbrgreater thanResults: Younger children lost more C-peptide (p andlt; 0.001) and the higher the C-peptide at diagnosis the larger the decline during the first year (p andlt; 0.0000). Patients with higher BMI had higher C-peptide at diagnosis but lost more (p andlt; 0.01), and those with lower HbA1c, without symptoms and signs at diagnosis, and with higher BMI, had higher C-peptide at diagnosis, but lost more during the first year (p andlt; 0.001). Finally, patients diagnosed during autumn had higher C-peptide at diagnosis, but lost more during the coming year (p andlt; 0.001). Occurrence of auto-antibodies did not correlate with C-peptide decline, except possibly for a more rapid loss in IAA-positive patients. less thanbrgreater than less thanbrgreater thanConclusions/interpretation: Even in a restricted geographical area and narrow age range (andlt; 18 years), the natural course of Type 1 diabetes is heterogeneous. This should be considered in clinical trials.
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| 55. |
- Lundtoft, Christian, et al.
(författare)
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Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD–CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.Author summaryGenetic association studies have been very successful in identifying disease-associated single nucleotide polymorphisms (SNPs), but it has been challenging to define the molecular mechanisms underlying these associations. As interferons (IFNs) have a central role in the immune system, we hypothesized that some of the SNPs associated to immune-mediated diseases would affect the IFN system. By combining genetic data with characterization of interferon receptor levels and their responses on the protein level in immune cells from 303 genotyped healthy individuals, we show that two SNPs tagging the HLA class I alleles A*02/A*68 and B*44 are associated with a decreased response to type I IFN stimulation in B cells and T cells. Notably, both HLA-A*02 and HLA-B*44 confer protection from developing multiple sclerosis (MS), which is a chronic inflammatory neurologic disease. In addition to suggesting a pathogenic role of enhanced type I interferon signalling in B cells and T cells in MS, our data emphasize the fact that genetic associations in the HLA locus can affect functions not directly associated to antigen presentation, which conceptually may be important for other diseases genetically associated to the HLA locus.
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| 56. |
- Magnusson, Rasmus, et al.
(författare)
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RNA-sequencing and mass-spectrometry proteomic time-series analysis of T-cell differentiation identified multiple splice variants models that predicted validated protein biomarkers in inflammatory diseases
- 2022
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Profiling of mRNA expression is an important method to identify biomarkers but complicated by limited correlations between mRNA expression and protein abundance. We hypothesised that these correlations could be improved by mathematical models based on measuring splice variants and time delay in protein translation. We characterised time-series of primary human naive CD4(+) T cells during early T helper type 1 differentiation with RNA-sequencing and mass-spectrometry proteomics. We performed computational time-series analysis in this system and in two other key human and murine immune cell types. Linear mathematical mixed time delayed splice variant models were used to predict protein abundances, and the models were validated using out-of-sample predictions. Lastly, we re-analysed RNA-seq datasets to evaluate biomarker discovery in five T-cell associated diseases, further validating the findings for multiple sclerosis (MS) and asthma. The new models significantly out-performing models not including the usage of multiple splice variants and time delays, as shown in cross-validation tests. Our mathematical models provided more differentially expressed proteins between patients and controls in all five diseases. Moreover, analysis of these proteins in asthma and MS supported their relevance. One marker, sCD27, was validated in MS using two independent cohorts for evaluating response to treatment and disease prognosis. In summary, our splice variant and time delay models substantially improved the prediction of protein abundance from mRNA expression in three different immune cell types. The models provided valuable biomarker candidates, which were further validated in MS and asthma.
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| 57. |
- Malmeström, Clas, 1965, et al.
(författare)
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Serum levels of LIGHT in MS
- 2013
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:7, s. 871-876
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently, a polymorphism in the LIGHT gene was shown to increase the risk of multiple sclerosis (MS) in a genome-wide association study (GWAS). OBJECTIVE: Our aim was to investigate if serum levels of LIGHT were affected by this polymorphism and by the disease itself. METHODS: Serum levels of LIGHT were investigated in four cohorts; 1) MS (n = 159) and controls (n = 160) in relation to rs1077667 genotype; 2) MS at relapse (n = 30) vs. healthy controls (n = 26); 3) MS (n = 27) vs. other neurological disease (OND, n = 33); and 4) MS patients before and after one year of treatment with natalizumab (n = 30). RESULTS: Carriers of the GG genotype had the lowest serum levels of LIGHT (p=0.02). Serum levels of LIGHT were increased in MS at relapse in two separate cohorts: vs. healthy controls (p=0.00005) and vs. remission (p=0.00006), other neurological disease (OND) (p=0.002) and OND with signs of inflammation (iOND; p=0.00005). Furthermore, serum levels of LIGHT were decreased by natalizumab treatment (p=0.001). CONCLUSION: Soluble LIGHT is an inhibitor of T-cell activation and GG carriers of rs1077667, with the highest risk for MS, had the lowest serum levels. The increased levels of LIGHT at times of increased MS activity suggest that soluble LIGHT is protective and may act to limit inflammation.
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| 58. |
- Meisgen, Sabrina, et al.
(författare)
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The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence
- 2014
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:6, s. 640-651
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block.SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases, and 95 unaffected siblings).RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n=1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of p<2.59×10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (p<0.03 and p<0.05, respectively), while HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (p<0.04 and p<0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (p<0.02).CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, while DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.
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| 59. |
- Mofors, Johannes, et al.
(författare)
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Cigarette smoking patterns preceding primary Sjögren's syndrome
- 2020
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjogren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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| 60. |
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