| 1. |
- Tesi, B., et al.
(författare)
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Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis
- 2015
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. Methods: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. Results: Analyses revealed a mutation detection sensitivity of 97.3 %, an average coverage per gene of 98.0 %, and adequate coverage over 98.6 % of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38 %). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. Conclusions: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.
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| 2. |
- Olén, Ola, et al.
(författare)
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Increasing Risk of Lymphoma Over Time in Crohn's Disease but Not in Ulcerative Colitis : A Scandinavian Cohort Study
- 2023
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 21:12, s. 3132-3142
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Earlier studies have provided varying risk estimates for lymphoma in patients with inflammatory bowel disease (IBD), but often have been limited by detection biases (especially during the first year of follow-up evaluation), misclassification, and small sample size; and rarely reflect modern-day management of IBD.Methods: We performed a binational register-based cohort study (Sweden and Denmark) from 1969 to 2019. We compared 164,716 patients with IBD with 1,639,027 matched general population reference individuals. Cox regression estimated hazard ratios (HRs) for incident lymphoma by lymphoma subtype, excluding the first year of follow-up evaluation.Results: From 1969 to 2019, 258 patients with Crohn's disease (CD), 479 patients with ulcerative colitis (UC), and 6675 matched reference individuals developed lymphoma. This corresponded to incidence rates of 35 (CD) and 34 (UC) per 100,000 person-years in IBD patients, compared with 28 and 33 per 100,000 person-years in their matched reference individuals. Although both CD (HR, 1.32; 95% CI, 1.16–1.50) and UC (HR, 1.09; 95% CI, 1.00–1.20) were associated with an increase in lymphoma, the 10-year cumulative incidence difference was low even in CD patients (0.08%; 95% CI, 0.02–0.13). HRs have increased in the past 2 decades, corresponding to increasing use of immunomodulators and biologics during the same time period. HRs were increased for aggressive B-cell non-Hodgkin lymphoma in CD and UC patients, and for T-cell non-Hodgkin lymphoma in CD patients. Although the highest HRs were observed in patients exposed to combination therapy (immunomodulators and biologics) or second-line biologics, we also found increased HRs in patients naïve to such drugs.Conclusions: During the past 20 years, the risk of lymphomas have increased in CD, but not in UC, and were driven mainly by T-cell lymphomas and aggressive B-cell lymphomas.
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| 3. |
- Everhov, Åsa H., et al.
(författare)
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Inflammatory bowel disease and pancreatic cancer : a Scandinavian register-based cohort study 1969-2017
- 2020
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Ingår i: Alimentary Pharmacology and Therapeutics. - : John Wiley & Sons. - 0269-2813 .- 1365-2036. ; 52:1, s. 143-154
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with inflammatory bowel disease (IBD) have an increased risk of cancer.Aim: To assess the risk of pancreatic cancer in IBD compared to the general population.Methods: Patients with incident IBD 1969-2017 were identified in Danish and Swedish National Patient Registers and through biopsy data, and were matched to IBD-free reference individuals by sex, age, place of residence and year of IBD diagnosis. We linked data to Cancer and Causes of Death Registers and examined the absolute and relative risks of pancreatic cancer and pancreatic cancer death.Results: Among 161 926 patients followed for 2 000 951 person years, 442 (0.27%) were diagnosed with pancreatic cancer compared to 3386 (0.21%) of the 1 599 024 reference individuals. The 20-year cumulative incidence was 0.34% (95% confidence interval 0.30-0.38) vs 0.29% (0.28-0.30). The incidence rate was 22.1 (20.1-24.2)/100 000 person years in the patients (excluding the first year of follow-up: 20.8 [18.8-23.0]), and 16.6 (16.0-17.2) in the reference individuals. The hazard ratio (HR) for pancreatic cancer was increased overall: 1.43 (1.30-1.58), in subtypes (Crohn's disease: 1.44 [1.18-1.74]; ulcerative colitis: 1.35 [1.19-1.53]; IBD unclassified: 1.99 [1.50-2.64]) and especially in IBD patients with primary sclerosing cholangitis: 7.55 (4.94-11.5). Patients and reference individuals with pancreatic cancer did not differ in cancer stage (P = 0.17) or pancreatic cancer mortality (HR 1.07 [0.95-1.21]).Conclusions: Patients with IBD had an excess risk of pancreatic cancer, in particular patients with primary sclerosing cholangitis. However, the cumulative incidence difference after 20 years was small: 0.05%, that is, one extra pancreatic cancer per 2000 IBD patients.
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| 4. |
- Horn, M. A., et al.
(författare)
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Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease
- 2013
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664. ; 79:3, s. 316-320
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesX-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Study designAmong 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. ResultsEighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 15% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. ConclusionsWe found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids.
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| 5. |
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| 6. |
- Stray-Pedersen, Asbjorg, et al.
(författare)
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Primary immunodeficiency diseases : Genomic approaches delineate heterogeneous Mendelian disorders
- 2017
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Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 139:1, s. 232-245
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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