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- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 4. |
- Reitsema, R., 1994-, et al.
(författare)
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ABERRANT PHENOTYPE OF CIRCULATING ANTIGEN PRESENTING CELLS IN GIANT CELL ARTERITIS AND POLYMYLAGIA RHEUMATICA
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 1071-1071
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are overlapping diseases occurring exclusively in people older than 50 years. Antigen-presenting cells (APCs), including monocytes and dendritic cells (DCs), are main contributors to the immunopathology of GCA and PMR. In GCA tissues, DCs may be prone to activation, leading to chemokine production and recruitment of CD4+ T-cells and monocytes to the arterial wall. However, little is known about APC phenotypes in the peripheral blood at the time of GCA/PMR diagnosis.Objectives: We aimed to investigate the phenotype of the circulating monocytes and DCs in GCA and PMR patients.Methods: APCs among peripheral blood mononuclear cells (PBMCs) of treatment-naive GCA and PMR patients were compared to those in age- and sex-matched healthy controls (HCs) using flow cytometry (n=15 in each group). Using a 13-colour panel, we identified three monocyte subsets: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14lowCD16+) monocytes. DC subsets were subdivided in CD303+CD11c- plasmacytoid DCs (pDCs), CD11c+CD141+ conventional DCs (cDC1) and CD11c+CD1c+ conventional DCs (cDC2). Each of these subsets was analysed for expression of pattern recognition receptors (Toll-like receptor 4 (TLR4), TLR2) and activation markers (CD86, Programmed Death- Ligand 1 (PD-L1), CD40, HLA-DR, CD11c) by assessing the mean-fluorescence intensity of these markers. Data were analysed by conventional gating strategies and by unsupervised tSNE.Results: GCA and PMR patients displayed a monocytosis, which was due to increases in classical and intermediate monocyte counts, whereas the proportion of non-classical monocytes was reduced. Intermediate monocytes of GCA patients had significantly higher TLR2 expression, a similar trend was observed in non-classical monocytes of GCA and PMR patients. A divergent pattern was observed in the expression of activation markers on classical versus non-classical monocytes: classical monocytes of GCA/PMR patients appeared to be less activated, whereas non-classical monocytes showed an increased marker expression compared to HCs (Figure 1). Even though no differences were observed in DC counts in the peripheral blood, cDC2 counts correlated negatively with CRP levels (r=-0.60 for GCA, r=-0.55 for PMR).Conclusion: Circulating non-classical monocytes, but not DCs, display an activated phenotype in GCA and PMR patients at diagnosis. These cells are thought to be pro-inflammatory, representing the end stage of monocyte maturation in the blood. In contrast, classical monocytes show reduced expression of activation markers in GCA and PMR patients, potentially signalling either an immature or exhausted phenotype. Shown is the mean fluorescence intensity (MFI) of CD11c on the surface of monocyte subsets and CD1c+ conventional dendritic cells (cDC2). Data are shown for patients with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR) and age-matched healthy controls (HCs), n=15 for each group. Statistics by Mann Whitney U. CD11c expression data for pDCs (no CD11c expression) and cDC1 (too small population) are not shown.
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| 5. |
- Weng, Lu Chen, et al.
(författare)
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Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation : The AFGen Consortium
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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