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- Almlöf, Jonas Carlsson, et al.
(författare)
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Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
- 2019
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Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 138:2, s. 141-150
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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.
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- Bengtsson, Anders A., et al.
(författare)
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Role of interferons in SLE
- 2017
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Ingår i: Baillière's Best Practice & Research. - : Elsevier BV. - 1521-6942 .- 1532-1770. ; 31:3, s. 415-428
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects many different organ systems, with excessive production of type I interferons (IFNs) and auto antibodies against nucleic acids as hallmarks. Activation of the type I IFN system in SLE is due to continuous stimulation of plasmacytoid dendritic cells by endogenous nucleic acids, leading to sustained type I IFN production. This is reflected by an over expression of type I IFN-regulated genes or an IFN signature. Type I IFNs have effects on both the innate and adaptive immune systems, which contribute to both loss of tolerance and the autoimmune disease process. In this review, we discuss the current understanding of IFNs in SLE, focusing on their regulation, the influence of genetic background, and environmental factors and therapies that are under development aiming to inhibit the type I IFN system in SLE.
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- Bengtsson, Anders, et al.
(författare)
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Systemic lupus erythematosus : Still a challenge for physicians
- 2017
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 281:1, s. 52-64
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Forskningsöversikt (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.
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- Carlsson Almlöf, Jonas, et al.
(författare)
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Novel risk genes for systemic lupus erythematosus predicted by random forest classification
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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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.
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- Cesarini, Monica, et al.
(författare)
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Predicting the Individual Risk of Acute Severe Colitis at Diagnosis
- 2017
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Ingår i: Journal of Crohn's & Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 11:3, s. 335-341
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. Methods: The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. Results: The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] >10 mg/l, or haemoglobin < 12 g/dl F or < 14 g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. Conclusions: An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy.
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- Farias, Fabiana H. G., et al.
(författare)
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A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27, s. 432-441
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.
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