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  • 1
    Online Resource
    Online Resource
    Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study
    BMJ ; 2022
    In:  Annals of the Rheumatic Diseases Vol. 81, No. 9 ( 2022-09), p. 1273-1280
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. 9 ( 2022-09), p. 1273-1280
    Abstract: Genome-wide association studies (GWAS) have identified 〉 100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p 〈 1.0×10 –5 ); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p 〈 7.7×10 –8 ). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 –9 ) around CD83 . For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1 , and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2022-222345
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1481557-6
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  • 2
    Online Resource
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    Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus
    BMJ ; 2021
    In:  Annals of the Rheumatic Diseases Vol. 80, No. 5 ( 2021-05), p. 632-640
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 80, No. 5 ( 2021-05), p. 632-640
    Abstract: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. Methods We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. Results We identified 113 genetic regions including 46 novel loci at genome-wide significance (p 〈 5×10 −8 ). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r g =−0.242) and non-albumin protein (r g =0.238). Conclusion This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-219209
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 1481557-6
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  • 3
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    Prostaglandin E 2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation
    BMJ ; 2021
    In:  Gut Vol. 70, No. 12 ( 2021-12), p. 2249-2260
    Details
    In: Gut, BMJ, Vol. 70, No. 12 ( 2021-12), p. 2249-2260
    Abstract: Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive. Design We investigated the role of the prostaglandin E 2 (PGE 2 ) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. We studied mucosal healing and intestinal epithelial barrier regeneration in Csf1r-iCre Ptger4 fl/fl mice during dextran sulfate sodium (DSS)-induced colitis. The effect of PTGER4 + macrophage secreted molecules was investigated on epithelial organoid differentiation. Results Here, we describe a subset of PTGER4-expressing intestinal macrophages with mucosal healing properties both in humans and mice. Csf1r-iCre Ptger4 fl/fl mice showed defective mucosal healing and epithelial barrier regeneration in a model of DSS colitis. Mechanistically, an increased mucosal level of PGE 2 triggers chemokine (C-X-C motif) ligand 1 (CXCL1) secretion in monocyte-derived PTGER4 + macrophages via mitogen-activated protein kinases (MAPKs). CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during colitis. Specific therapeutic targeting of macrophages with liposomes loaded with an MAPK agonist augmented the production of CXCL1 in vivo in conditional macrophage PTGER4-deficient mice, restoring their defective epithelial regeneration and favouring mucosal healing. Conclusion PTGER4 + intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium. Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favour remission in patients with IBD.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2020-322146
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 1492637-4
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  • 4
    Online Resource
    Online Resource
    New-onset paroxysmal atrial fibrillation in acute myocardial infarction: increased risk of stroke
    BMJ ; 2020
    In:  BMJ Open Vol. 10, No. 9 ( 2020-09), p. e039600-
    Details
    In: BMJ Open, BMJ, Vol. 10, No. 9 ( 2020-09), p. e039600-
    Abstract: To investigate the long-term prognostic implications of transient new-onset atrial fibrillation (AF) in patients with acute myocardial infarction (AMI). Design Retrospective observational study. Setting Single tertiary centre. Participants This study included 2523 patients who presented with AMI from 3 June 2003 to 24 February 2015, after the exclusion of those with prior AF or in-hospital death. Outcome measures Patients were divided into three groups according to the occurrence and type of new-onset AF: (1) sinus rhythm (SR) group; (2) paroxysmal AF (PaAF: AF converted to SR prior to discharge) group and (3) persistent AF (PeAF: AF persisted during the hospitalisation) group. Post-discharge all-cause mortality and stroke incidences were compared between the groups. Results New-onset AF was observed in 271 patients (10.7%; PaAF: 230, PeAF: 41). The median follow-up period was 7.2 years (IQR: 5.2–9.4). The incidence of all-cause death and stroke was highest in the PeAF group, followed by the PaAF and SR groups (all-cause mortality: 48.8% vs 26.5% vs 14.7%, p 〈 0.001; stroke 22.0% vs 8.3% vs 4.4%, p 〈 0.001). In the multivariable analysis, PaAF and PeAF were associated with an increased risk of stroke (PaAF, HR: 1.972, 95% CI: 1.162–3.346; PeAF, HR: 5.160, CI: 2.242–11.873) compared with SR. The PaAF group showed a higher incidence of post-discharge AF than the SR group (29.1% vs 4.2%, p 〈 0.001). Conclusions New-onset AF following AMI is associated with poor long-term outcomes. Even when AF episodes are brief and are converted to SR, new-onset AF remains associated with an increased risk of recurrent AF and stroke.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    DOI: 10.1136/bmjopen-2020-039600
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2599832-8
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