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- Kottyan, Leah C., et al.
(författare)
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The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
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Tidskriftsartikel (refereegranskat)abstract
- Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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| 2. |
- Hanly, John G., et al.
(författare)
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Mood Disorders in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study
- 2015
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 67:7, s. 1837-1847
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo examine the frequency, characteristics, and outcome of mood disorders, as well as clinical and autoantibody associations, in a multiethnic/racial, prospective inception cohort of patients with systemic lupus erythematosus (SLE). MethodsPatients were assessed annually for mood disorders (4 types, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 18 other neuropsychiatric events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 subscales, mental and physical component summary scores were collected. Time to event, linear and ordinal regressions, and multi-state models were used as appropriate. ResultsAmong the 1,827 patients with SLE, 88.9% were female, and 48.9% were Caucasian. The mean SD age of the patients was 35.1 +/- 13.3 years, disease duration was 5.6 +/- 4.8 months, and the length of followup was 4.7 +/- 3.5 years. During the course of the study, 863 (47.2%) of the 1,827 patients had 1,627 neuropsychiatric events. Mood disorders occurred in 232 (12.7%) of 1,827 patients, and 98 (38.3%) of 256 mood disorder events were attributed to SLE. The estimated cumulative incidence of any mood disorder after 10 years was 17.7% (95% confidence interval 15.1, 20.2%). A greater risk of mood disorder was associated with concurrent neuropsychiatric events (P0.01), and a lower risk was associated with Asian race/ethnicity (P=0.01) and treatment with immunosuppressive drugs (P=0.003). Mood disorders were associated with lower mental health and mental component summary scores but not with the SLEDAI-2K, SDI, or lupus autoantibodies. Among the 232 patients with depression, 168 (72.4%) were treated with antidepressants. One hundred twenty-six (49.2%) of 256 mood disorders resolved in 117 (50.4%) of 232 patients. ConclusionMood disorders, the second most frequent neuropsychiatric event in patients with SLE, have a negative impact on health-related quality of life and improve over time. The lack of association with global SLE disease activity, cumulative organ damage, and lupus autoantibodies emphasizes the multifactorial etiology of mood disorders and a role for non-lupus-specific therapies.
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| 4. |
- Parker, Ben, et al.
(författare)
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Impact of early disease factors on metabolic syndrome in systemic lupus erythematosus: data from an international inception cohort
- 2015
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:8, s. 1530-1536
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Tidskriftsartikel (refereegranskat)abstract
- Background The metabolic syndrome (MetS) may contribute to the increased cardiovascular risk in systemic lupus erythematosus (SLE). We examined the association between MetS and disease activity, disease phenotype and corticosteroid exposure over time in patients with SLE. Methods Recently diagnosed (< 15 months) patients with SLE from 30 centres across 11 countries were enrolled into the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort from 2000 onwards. Baseline and annual assessments recorded clinical, laboratory and therapeutic data. A longitudinal analysis of factors associated with MetS in the first 2 years of follow-up was performed using random effects logistic regression. Results We studied 1150 patients with a mean (SD) age of 34.9 (13.6) years and disease duration at enrolment of 24.2 (18.0) weeks. In those with complete data, MetS prevalence was 38.2% at enrolment, 34.8% at year 1 and 35.4% at year 2. In a multivariable random effects model that included data from all visits, prior MetS status, baseline renal disease, SLICC Damage Index > 1, higher disease activity, increasing age and Hispanic or Black African race/ethnicity were independently associated with MetS over the first 2 years of follow-up in the cohort. Conclusions MetS is a persistent phenotype in a significant proportion of patients with SLE. Renal lupus, active inflammatory disease and damage are SLE-related factors that drive MetS development while antimalarial agents appear to be protective from early in the disease course.
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| 5. |
- Bourre-Tessier, Josiane, et al.
(författare)
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Electrocardiographic Findings in Systemic Lupus Erythematosus: Data From an International Inception Cohort
- 2015
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 67:1, s. 128-135
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To estimate the early prevalence of various electrocardiographic (EKG) abnormalities in patients with systemic lupus erythematosus (SLE) and to evaluate possible associations between repolarization changes (increased corrected QT [QTc] and QT dispersion [QTd]) and clinical and laboratory variables, including the anti-Ro/SSA level and specificity (52 or 60 kd). Methods. We studied adult SLE patients from 19 centers participating in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Registry. Demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]), disease damage (SLICC/American College of Rheumatology Damage Index [SDI]), and laboratory data from the baseline or first followup visit were assessed. Multivariate logistic and linear regression models were used to asses for any cross-sectional associations between anti-Ro/SSA and EKG repolarization abnormalities. Results. For the 779 patients included, mean +/- SD age was 35.2 +/- 13.8 years, 88.4% were women, and mean +/- SD disease duration was 10.5 +/- 14.5 months. Mean +/- SD SLEDAI-2K score was 5.4 +/- 5.6 and mean +/- SD SDI score was 0.5 +/- 1.0. EKG abnormalities were frequent and included nonspecific ST-T changes (30.9%), possible left ventricular hypertrophy (5.4%), and supraventricular arrhythmias (1.3%). A QTc >= 440 msec was found in 15.3%, while a QTc >= 460 msec was found in 5.3%. Mean +/- SD QTd was 34.2 +/- 14.7 msec and QTd >= 40 msec was frequent (38.1%). Neither the specificity nor the level of anti-Ro/SSA was associated with QTc duration or QTd, although confidence intervals were wide. Total SDI was significantly associated with a QTc interval exceeding 440 msec (odds ratio 1.38 [95% confidence interval 1.06, 1.79]). Conclusion. A substantial proportion of patients with recent-onset SLE exhibited repolarization abnormalities, although severe abnormalities were rare.
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