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- Saevarsdottir, S., et al.
(författare)
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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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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)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. |
- Tjora, E., et al.
(författare)
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Patient reported exposure to smoking and alcohol abuse are associated with pain and other complications in patients with chronic pancreatitis
- 2020
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Ingår i: Pancreatology. - : Elsevier BV. - 1424-3903. ; 20:5, s. 844-851
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Tidskriftsartikel (refereegranskat)abstract
- Background/objectives: Smoking and alcohol abuse are established risk factors for chronic pancreatitis (CP). Few studies have examined how exposure to smoking and alcohol abuse act as risk factors for complications in CP. Our aim was to examine associations between patient reported exposure to smoking and alcohol abuse and complications in CP in a large cohort of patients from the Scandinavian and Baltic countries. Methods: We retrieved data on demographics, CP related complications and patients' histories of exposure to smoking and alcohol abuse from the Scandinavian Baltic Pancreatic Club database. Associations were investigated by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals. Results: A complete history of smoking and alcohol exposure was available for 932 patients. In multivariate regression analyses, the presence of pain and exocrine pancreatic insufficiency were both significantly associated with history of smoking (OR 1.94 (1.40-2.68), p < 0.001 and OR 1.89 (1.36-2.62), p < 0.001, respectively) and alcohol abuse (OR 1.66 (1.21-2.26), p = 0.001 and 1.55 (1.14-2.11), p = 0.005, respectively). Smoking was associated with calcifications (OR 2.89 (2.09-3.96), p < 0.001), moderate to severe ductal changes (OR 1.42 (1.05-1.92), p = 0.02), and underweight (OR 4.73 (2.23-10.02), p < 0.001). History of alcohol abuse was associated with pseudocysts (OR 1.38 (1.00-1.90) p = 0.05) and diabetes mellitus (OR 1.44 (1.03-2.01), p = 0.03). There were significantly increased odds-ratios for several complications with increasing exposure to smoking and alcohol abuse. Conclusion: Smoking and alcohol abuse are both independently associated with development of complications in patients with CP. There seems to be a dose-dependent relationship between smoking and alcohol abuse and complications in CP. (c) 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.
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- Hauge, Stale Wagen, et al.
(författare)
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Short-term outcome after open-heart surgery for severe chronic rheumatic heart disease in a low-income country, with comparison with an historical control group: an observational study
- 2021
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Ingår i: Open heart. - : BMJ PUBLISHING GROUP. - 2053-3624. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Rheumatic heart disease (RHD) is a major burden in low-income and middle-income countries (LMICs). Cardiac surgery is the only curative treatment. Little is known about patients with severe chronic RHD operated in LMICs, and challenges regarding postoperative follow-up are an important issue. At Tikur Anbessa Specialised Hospital, Addis Ababa, Ethiopia, we aimed to evaluate the course and 12-month outcome of patients with severe chronic RHD who received open-heart surgery, as compared with the natural course of controls waiting for surgery and undergoing only medical treatment. Methods Clinical data and outcome measures were registered in 46 patients operated during five missions from March 2016 to November 2019, and compared with the first-year course in a cohort of 49 controls from the same hospitals waiting list for surgery. Adverse events were death or complications such as stroke, other thromboembolic events, bleeding, hospitalisation for heart failure and infectious endocarditis. Results Survival at 12 months was 89% and survival free from complications was 80% in the surgical group. Despite undergoing open-heart surgery, with its inherent risks, outcome measures of the surgical group were non-inferior to the natural course of the control group in the first year after inclusion on the waiting list (p >= 0.45). All except six surgical patients were in New York Heart Association class I after 12 months and 84% had resumed working. Conclusions Cardiac surgery for severe chronic RHD is feasible in LMICs if the service is structured and planned. Rates of survival and survival free from complications were similar to those of controls at 12 months. Functional level and resumption of work were high in the surgical group. Whether the patients who underwent cardiac surgery will have better long-term prognosis, in line with what is known in high-income countries, needs to be evaluated in future studies.
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