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| 22. |
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| 23. |
- Olafsson, S, et al.
(författare)
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Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
- 2017
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 2, s. 24-
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Tidskriftsartikel (refereegranskat)abstract
- A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10−7, 4.3 × 10−9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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| 24. |
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| 25. |
- Sigurdsson, S, et al.
(författare)
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Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus
- 2005
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 76:3, s. 528-37
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms ( SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes - the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes - we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P < 10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.
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| 26. |
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| 27. |
- Urowitz, M. B., et al.
(författare)
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Atherosclerotic Vascular Events in a Multinational Inception Cohort of Systemic Lupus Erythematosus
- 2010
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 62:6, s. 881-887
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To describe vascular events during an 8-year followup in a multicenter systemic lupus erythematosus (SLE) inception cohort and their attribution to atherosclerosis. Methods. Clinical data, including comorbidities, were recorded yearly. Vascular events were recorded and attributed to atherosclerosis or not. All of the events met standard clinical criteria. Factors associated with atherosclerotic vascular events were analyzed using descriptive statistics, t-tests, and chi-square tests. Stepwise multivariate logistic regression was used to assess the association of factors with vascular events attributed to atherosclerosis. Results. Since 2000, 1,249 patients have been entered into the cohort. There have been 97 vascular events in 72 patients, including: myocardial infarction (n = 13), angina (n = 15), congestive heart failure (n = 24), peripheral vascular disease (n = 8), transient ischemic attack (n = 13), stroke (n = 23), and pacemaker insertion (n = 1). Fifty of the events were attributed to active lupus, 31 events in 2
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| 28. |
- Urowitz, M. B., et al.
(författare)
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Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort
- 2016
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. Methods The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. Results 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. Conclusions In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.
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| 29. |
- Urowitz, M B, et al.
(författare)
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Clinical manifestations and coronary artery disease risk factors at diagnosis of systemic lupus erythematosus: data from an international inception cohort
- 2007
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 16:9, s. 731-735
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Tidskriftsartikel (refereegranskat)abstract
- Systemic Lupus International Collaborating Clinics (SLICC) comprises 27 centres from 11 countries. An inception cohort of 918 SLE patients has been assembled according to a standardized protocol between 2000 and 2006. Clinical features, classic coronary artery disease (CAD) risk factors, as well as other potential risk factors were collected. Of the 918 patients 89% were females, and of multi racial origin. Less than half the patients were living in a permanent relationship, 58% had post secondary education and 51% were employed. Eight percent had family history of SLE. At enrolment, with at mean age of diagnosis of 34.5 years, a significant number of patients already had CAD risk factors, such as hypertension (33%) and hypercholesterolemia (36%). Only 15% of the patients were postmenopausal, 16% were current smokers and 3.6% had diabetes at entry to the SLICC-RAS (Registry for Atherosclerosis). A number of patients in this multi-racial, multi-ethnic inception cohort of lupus patients have classic CAD risk factors within a mean of 5.4 months from diagnosis. This cohort will be increased to 1500 patients to be followed yearly for 10 years. This will provide a unique opportunity to evaluate risk factors for accelerated atherosclerosis in SLE.
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| 30. |
- Urowitz, M. B., et al.
(författare)
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Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort
- 2012
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 64:1, s. 132-137
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Tidskriftsartikel (refereegranskat)abstract
- Objective We describe disease activity, damage, and the accrual of key autoantibodies in an inception systemic lupus erythematosus (SLE) cohort. Methods. The Systemic Lupus International Collaborating Clinics (SLICC) International Research Network, comprising 27 centers from 11 countries, has followed an inception cohort of SLE patients yearly according to a standardized protocol. Of these patients, 298 were followed for a minimum of 5 years and constitute the study population. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) and damage was assessed using the SLICC/American College of Rheumatology Damage Index (SDI). Antinuclear antibody (ANA), anti-DNA, and anticardiolipin antibody (aCL) levels and lupus anticoagulant were assessed yearly. Descriptive statistics were generated and repeated-measures general linear models were used to evaluate SLEDAI-2K and SDI over time between whites and nonwhites. Results. Of the 298 patients, 87% were women, 55% were white, 12% were African American, 14% were Asian, 16% were Hispanic, and 2% were categorized as "other." At enrollment, the mean age was 35.3 years, the mean SLEDAI-2K score was 5.9, and the mean disease duration was 5.5 months. Mean SLEDAI-2K scores decreased in the first year and then remained low. SLEDAI-2K scores were significantly lower at each year in whites compared to nonwhites. Mean SDI scores increased progressively over 5 years; there was no significant difference between whites and nonwhites. As expected, ANA positivity was high and anti-DNA positivity was relatively low at enrollment, and both increased over 5 years. Although lupus anticoagulant increased slightly over 5 years, aCL positivity did not. Conclusion. Disease activity in newly diagnosed patients decreases over their first 5 years, while damage increases. Antibody positivity ran variable courses over this period.
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