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- Saevarsdottir, S., et al.
(author)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Journal article (peer-reviewed)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 4. |
- Lundtoft, Christian, et al.
(author)
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Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
- 2022
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In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:11, s. 1842-1850
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Journal article (peer-reviewed)abstract
- Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.
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| 5. |
- Oster, S., et al.
(author)
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Self-management and hospitalization in 615 Swedish patients with Addison's disease during the coronavirus disease 2019 pandemic: a retrospective study
- 2023
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 188:2
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Journal article (peer-reviewed)abstract
- Objective Autoimmune Addison's disease (AAD) entails a chronic adrenal insufficiency and is associated with an increased risk of severe infections. It is, however, unknown how patients with AAD were affected by the coronavirus disease 2019 (COVID-19) pandemic of 2020-2021. This study was aimed at investigating the incidence of COVID-19 in patients with AAD in Sweden, the self-adjustment of medications during the disease, impact on social aspects, and treatment during hospitalization. Additionally, we investigated if there were any possible risk factors for infection and hospitalization. Design and methods Questionnaires were sent out from April to October 2021 to 813 adult patients with AAD in the Swedish Addison Registry. The questionnaires included 55 questions inquiring about COVID-19 sickness, hospital care, medications, and comorbidities, focusing on the pre-vaccine phase. Results Among the 615 included patients with AAD, COVID-19 was reported in 17% of which 8.5% required hospital care. Glucocorticoid treatment in hospitalized patients varied. For outpatients, 85% increased their glucocorticoid dosage during sickness. Older age (P = .002) and hypertension (P = .014) were associated with an increased risk of hospital care, while younger age (P < .001) and less worry about infection (P = .030) were correlated with a higher risk of COVID-19. Conclusions In the largest study to date examining AAD during the COVID-19 pandemic, we observed that although one-fifth of the cohort contracted COVID-19, few patients required hospital care. A majority of the patients applied general recommended sick rules despite reporting limited communication with healthcare during the pandemic.
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- Hadi, M. A., et al.
(author)
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Chemically stable new MAX phase V2SnC: a damage and radiation tolerant TBC material
- 2020
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In: RSC Advances. - : ROYAL SOC CHEMISTRY. - 2046-2069. ; 10:71, s. 43783-43798
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Journal article (peer-reviewed)abstract
- Using density functional theory, the phase stability and physical properties, including structural, electronic, mechanical, thermal and vibrational with defect processes, of a newly synthesized 211 MAX phase V2SnC are investigated for the first time. The obtained results are compared with those found in the literature for other existing M2SnC (M = Ti, Zr, Hf, Nb, and Lu) phases. The formation of V2SnC is exothermic and this compound is intrinsically stable in agreement with the experiment. V2SnC has potential to be etched into 2D MXene. The new phase V2SnC and existing phase Nb2SnC are damage tolerant. V2SnC is elastically more anisotropic than Ti2SnC and less than the other M2SnC phases. The electronic band structure and Fermi surface of V2SnC indicate the possibility of occurrence of its superconductivity. V2SnC is expected to be a promising TBC material like Lu2SnC. The radiation tolerance in V2SnC is better than that in Lu2SnC.
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| 7. |
- Hallström, Sara, et al.
(author)
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Characteristics of Continuous Glucose Monitoring Metrics in Persons with Type 1 and Type 2 Diabetes Treated with Multiple Daily Insulin Injections
- 2021
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In: Diabetes Technology & Therapeutics. - : Mary Ann Liebert Inc. - 1520-9156 .- 1557-8593. ; 23:6, s. 425-433
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Journal article (peer-reviewed)abstract
- Background: Although guidelines advocate similar continuous glucose monitoring (CGM) targets for insulin-treated persons with type 1 diabetes (T1D) and type 2 diabetes (T2D), it is unclear how these persons differ with respect to hypoglycemia, glucose variability, and other CGM metrics in clinical practice. Methods: We used data from 2 multicenter randomized-controlled trials (GOLD and MDI-Liraglutide) where 161 persons with T1D and 124 persons with T2D treated with multiple daily injections were included and monitored with masked CGM. Results: Persons from both cohorts had similar mean glucose levels, 10.9 mmol/L (196 mg/dL) in persons with T1D and 10.8 mmol/L (194 mg/dL) in persons with T2D. Time in hypoglycemia (<3.9 mmol/L [70 mg/dL]) was 5.1% and 1.0% for persons with T1D and T2D, respectively (P < 0.001). Corresponding estimates for the standard deviations of mean glucose levels were 4.4 mmol/L (79 mg/dL) versus 3.0 (54 mg/dL) (P < 0.001), for coefficient of variation 41% versus 28% (P < 0.001), and for time in range 38.2% versus 45.3%, respectively (P = 0.004). Mean C-peptide levels were 0.05 nmol/L and 0.67 nmol/L (P < 0.001) for persons with T1D and T2D, respectively. Conclusions: Persons with T1D compared with persons with T2D treated with multiple daily insulin injections spend considerably more time in hypoglycemia, have higher glucose variability, and less "time in range." This needs to be taken into account in daily clinical care and in recommended targets for CGM metrics.
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- Papakokkinou, Eleni, et al.
(author)
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Prevalence of Nelson's syndrome after bilateral adrenalectomy in patients with cushing's disease: a systematic review and meta-analysis
- 2021
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In: Pituitary. - : Springer Science and Business Media LLC. - 1386-341X .- 1573-7403.
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Journal article (peer-reviewed)abstract
- Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson's syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22-31%), with moderate to high heterogeneity (I-2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27-50%). The prevalence of treatment for NS was 21% (95% CI 18-26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5-1.6)] or pituitary surgery [0.6 (95% CI 0.4-1.0)]. Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.
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