| 1. |
- Almlöf, Jonas Carlsson, et al.
(författare)
-
Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
- 2019
-
Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 138:2, s. 141-150
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.
|
|
| 2. |
- Bolin, Karin, 1982-, et al.
(författare)
-
Variants in BANK1 are associated with lupus nephritis
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Lupus nephritis (LN) is a cause of significant morbidity in SLE. While the genetic background to SLE has been well characterized, less is known about genes predisposing to LN.Methods: The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN, proliferative nephritis, end-stage renal disease and LN negative patients. SNPs with p-value <0.001 in the discovery cohort were analyzed in replication cohort 1. Ten SNPs associated with LN in the discovery cohort (p<0.0002) were genotyped in replication cohort 2. DNA methylation data were available for 180 LN patients from the discovery cohort.Results: In the discovery cohort, six gene loci were associated with LN (p<1x10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y and PHCA). SNPs in BANK1 showed the strongest association with LN in replication cohort 1 (p=9.5x10-4), with a tendency for an association in replication cohort 2 (p=0.052). In a meta-analysis of all three cohorts the association between LN and BANK1 rs4699259, was strengthened (p=1.7x10‑7). There were no associations to proliferative nephritis or ESRD in the meta-analysis. Methylation quantitative trait loci (MeQTL) effects between a CpG site and several SNPs in BANK1 were identified.Conclusion: Genetic variations in BANK1 are associated with LN. There is evidence for genetic regulation of DNA methylation within the BANK1 locus, however, the exact role of BANK1 in LN pathogenesis remains to be elucidated.
|
|
| 3. |
- Bolin, Karin, et al.
(författare)
-
Variants in BANK1 are associated with lupus nephritis of European ancestry
- 2021
-
Ingår i: Genes and Immunity. - : Springer Nature. - 1466-4879 .- 1476-5470. ; 22:3, s. 194-202
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10−4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10−4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10−7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.
|
|
| 4. |
- Carlsson Almlöf, Jonas, et al.
(författare)
-
Contributions of de novo variants to systemic lupus erythematosus
- 2021
-
Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 29:1, s. 184-193
-
Tidskriftsartikel (refereegranskat)abstract
- By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.
|
|
| 5. |
- Carlsson Almlöf, Jonas, et al.
(författare)
-
Novel risk genes for systemic lupus erythematosus predicted by random forest classification
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.
|
|
| 6. |
- Diaz-Gallo, Lina-Marcela, et al.
(författare)
-
Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations
- 2022
-
Ingår i: ACR Open Rheumatology. - : John Wiley & Sons. - 2578-5745. ; 4:1, s. 27-39
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data.Methods: An unsupervised cluster analysis was performed based on detection of 13 SLE-associated autoantibodies (double-stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]-Immunoglobulin G [IgG], CL-Immunoglobulin M [IgM], and β2 glycoprotein I [β2 GPI]-IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA-DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).Results: Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti-SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA-DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52-4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18-2.47). Subgroup 2 (28.7%) was dominated by anti-nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA-DRB1*15 (OR = 1.62, 95% CI = 1.41-1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14-2.26). Subgroup 3 (23.8%) was characterized by anti-ß2 GPI-IgG/anti-CL-IgG/IgM autoantibodies and a higher frequency of HLA-DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2-2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA-DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.Conclusion: Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA-DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.
|
|
| 7. |
- Frodlund, Martina, et al.
(författare)
-
Glucocorticoid treatment in SLE is associated with infections, comorbidities and mortality—a national cohort study
- 2024
-
Ingår i: Rheumatology (United Kingdom). - : OXFORD UNIV PRESS. - 1462-0324 .- 1462-0332. ; 63:4, s. 1104-1112
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Patients with SLE have an increased risk of comorbidities and impaired survival. We aimed to assess whether various thresholds of oral CS (OCS) can predict development of infections, comorbidities, malignancies and survival in SLE using data from national health registries in Sweden. Methods: All incident SLE cases, age >18 years, in Sweden (n ¼ 5309) between 2005 and 2020 and matched population controls (n ¼ 26 545) were included and followed until 2020, a total of 257 942 patient years. Data from national registers were retrieved including information from the National Prescribed Drug Register. Risk factors were analysed using time-dependent Cox regression models. Results: Compared with no OCS, >0 to <5.0 mg/day, 5.0–7.5 mg/day as well as >7.5 mg/day OCS predicted development of infections (pneumonia, influenza, herpes zoster and urinary tract infection), osteoporosis, osteonecrosis, gastroduodenal ulcers, cataracts, hypertension and mortality (all P < 0.05). OCS >0 to <5.0 mg/day was associated with lower hazard ratios for these comorbidities than higher doses of OCS. Fifteen years after diagnosis, 48% of patients were taking OCS at a median dose of 5.7 mg/day. A small reduction of OCS treatment 5 years after diagnosis in patients diagnosed with SLE 2006–10 compared with 2011–15 was observed, 49% vs 46% respectively (P ¼ 0.039). Conclusion: Results highlight the potential harm associated with even low OCS dose treatment in SLE and the need to judiciously use OCS at the lowest possible dose to maximize efficacy and minimize harm.
|
|
| 8. |
- Hedenstedt, Anna, et al.
(författare)
-
B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus.
- 2023
-
Ingår i: Lupus science & medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 10:2
-
Tidskriftsartikel (refereegranskat)abstract
- B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina's Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 -/- (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/- or -/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
|
|
| 9. |
- Imgenberg-Kreuz, Juliana, et al.
(författare)
-
DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
- 2018
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 77:5, s. 736-743
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.
|
|
| 10. |
- Jönsen, Andreas, et al.
(författare)
-
Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts
- 2016
-
Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier BV. - 0049-0172 .- 1532-866X. ; 45:6, s. 684-690
-
Forskningsöversikt (refereegranskat)abstract
- Objectives: The main objectives of this study were to calculate total costs of illness and cost -driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden. Methods: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency. Results: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941(sic)), of which direct cost was 63,672kr ($10,188 = 7004(sic)) and the indirect cost was 144,883 SEK ($23,181 = 15,937(sic)), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs. Conclusion: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (= 129.5 million (sic)). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs. (C) 2016 Elsevier Inc. All rights reserved.
|
|
