| 1. |
- Carlsson Almlöf, Jonas, et al.
(författare)
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Contributions of de novo variants to systemic lupus erythematosus
- 2021
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 29:1, s. 184-193
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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.
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| 2. |
- Elbagir, Sahwa, et al.
(författare)
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Associations with thrombosis are stronger for antiphosphatidylserine/prothrombin antibodies than for the Sydney criteria antiphospholipid antibody tests in SLE
- 2021
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Ingår i: Lupus. - : Sage Publications. - 0961-2033 .- 1477-0962. ; 30:8, s. 1289-1299
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Antiphosphatidylserine/prothrombin complex antibodies (aPS/PT) are risk factors for thrombosis, yet further validation of their clinical relevance in different ethnic groups is required. We investigated the performance of aPS/PT of IgA/G/M isotypes among Sudanese and Swedish systemic lupus erythematosus (SLE) patients.Methods: Consecutive SLE patients/matched controls from Sudan (n = 91/102) and Sweden (n = 332/163) were included. All patients fulfilled the 1982 ACR SLE classification criteria. IgA/G/M of aPS/PT, anti-cardiolipin and anti-beta(2)glycoprotein I (anti-beta(2)GPI) were tested in both cohorts, and lupus anticoagulant (LA) also in the Swedish cohort. Clinical antiphospholipid syndrome-related events and atherosclerosis, measured as carotid plaques were assessed for associations. Univariate and multivariate analyses adjusting for cardiovascular risk factors were performed.Results: Sudanese SLE patients had higher levels of IgM aPS/PT, but using national cut-offs, the frequency of positivity was similar to Swedish patients for all isotypes. Among Swedish patients, all isotypes of aPS/PT associated with venous thromboembolism (VTE), while only IgA aPS/PT associated with arterial thrombosis (AT). aPS/PT antibodies associated strongly with LA and they were, independently, the best predictor for VTE. Double positivity for aPS/PT and anti-beta(2)GPI associated with higher VTE risk than the conventional triple positivity. Carotid plaques did not associate with any antiphospholipid antibody.Conclusions: IgA aPS/PT associated with AT, and the association of IgG/M aPS/PT with VTE outperforms LA and criteria antiphospholipid antibodies in Swedish SLE patients. Furthermore, double positivity for aPS/PT and anti-beta(2)GPI performed better than conventional triple positivity. Future studies need to address if aPS/PT can replace LA, as this would simplify clinical procedures.
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| 3. |
- Grosso, Giorgia, et al.
(författare)
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The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies
- 2021
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 121:10, s. 1299-1309
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Tidskriftsartikel (refereegranskat)abstract
- Background Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. Objectives To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. Methods In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N =67), aPL++ individuals without clinical manifestations (aPL carriers, N =15), SLE-aPL++ ( N =118, among them, secondary [s] APS, N =56), aPL negative (-) SLE (SLE-aPL-, N =291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. Results Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) Conclusion Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.
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| 4. |
- Grosso, Giorgia
(författare)
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Thrombotic and cardiac disease in the antiphospholipid syndrome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The antiphospholipid syndrome (APS) is a highly heterogeneous disease that presents with obstetric complications and/or thromboembolic events that can hit any side of the vascular tree in an unpredictable way. The common trait among all patients affected by the syndrome is the persistent presence of the antiphospholipid antibodies (aPL) and/or a prolonged coagulation time in vitro, the lupus anticoagulant (LA) test. The pathogenesis of APS has not yet been clearly defined. Many molecules are involved in the maintenance of the equilibrium called hemostasis, interacting and cross-reacting in an incredibly perfect orchestrated balance that somehow, in APS, is broken. The aim of this thesis has been to try to shed some light on the complex mechanisms behind APS, by focusing on some of the many pieces of the puzzle that characterize the disease. The complement, coagulation and fibrinolytic systems have been the subjects of this fascinating journey, and two proteins in particular have been on focus: C4b-binding protein (C4BP) and Thrombin activatable fibrinolysis inhibitor (TAFI). These are both regulators of complement activation that at the same time play a role in coagulation. Moreover, the link between myocardial infarction (MI) and aPL/LA has been explored. Paper I: TAFI and its activated form, TAFIa, were studied in patients affected by mainly primary APS (i.e. without other autoimmune diseases) and compared with a healthy control group. Moreover, C5a, a marker of complement activation, and markers of fibrinolysis were investigated and correlated with TAFI and TAFIa. Both TAFI and TAFIa are significantly higher in APS compared to controls. TAFIa is increased in APS patients affected by arterial thrombosis compared to other clinical manifestations, independently of traditional cardiovascular risk factors. TAFI is positively correlated with C5a, confirming its increase upon inflammation. TAFIa positively correlates with thrombomodulin, marker of endothelial damage/activation. The values of the clot lysis time (CLT) and of the permeability coefficient confirm impaired fibrinolysis in APS, with clots more resistant to lysis. Paper II: we investigated the prevalence of aPL in a large and well-characterized cohort of patients after 6-10 weeks from a first MI, and compared it with age, gender and region matched controls. We demonstrated ten times higher prevalence of aPL of the IgG isotype in patients versus controls, independently of traditional cardiovascular risk factors, suggesting that IgG aPL positivity may be considered a potential risk factor for MI in the general population. No significant differences were observed for IgM and IgA isotypes. Paper III: C4BP was investigated in a large cohort of patients affected by systemic lupus erythematosus (SLE), in primary APS and in controls. C4BP is lower in patients persistently positive for aPL and in patients treated with warfarin. C4BP correlates with markers of complement activation. Both persistent aPL positivity and warfarin are associated with C4BP reduction, and by means of a mediation analysis we were able to assess the relative contribution of these two variables: aPL have a direct reducing effect on C4BP of 11%, while warfarin contributes to 9% of the observed reduction. Paper IV: After the results of paper III, we decided to study the effect of warfarin on complement and C4BP in the general population, comparing it with the direct oral anticoagulants (DOACs), during and after treatment discontinuation. Warfarin, as opposed to DOACs, is associated with increased markers of complement activation, which persist for at least three weeks after withdrawal. Higher C4BP levels characterize the patients after warfarin discontinuation, as a rebound effect. DOACs have no effect on complement, but, in contrast, we demonstrate that warfarin is associated with complement activation, partly but probably not only through inhibition of C4BP. This study is of relevance in the context of APS, since different anticoagulant mechanisms have been subjects of debate in recent years. In conclusion, as also Ames stated regarding paper I , this thesis has tried to insert other linking pieces in the puzzle of APS. We confirm the presence of impaired fibrinolysis and complement activation in APS, and we have opened the path for a new era of research in the syndrome, where also the treatment with anticoagulants has to be considered for its potential impact on complement activation. Moreover, although causality could not be proven, we demonstrate that the prevalence of aPL after myocardial infarction in the general population is considerable and higher than generally anticipated.
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