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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
    Online Resource
    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
    Online Resource
    Online Resource
    Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis
    BMJ ; 2020
    In:  Annals of the Rheumatic Diseases Vol. 79, No. 11 ( 2020-11), p. 1438-1445
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. 11 ( 2020-11), p. 1438-1445
    Abstract: Genome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population. Methods We newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations. Results We identified six new RA-risk loci ( SLAMF6 , CXCL13 , SWAP70 , NFKBIA , ZFP36L1 and LINC00158 ) with p meta 〈 5×10 −8  and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases. Conclusion This study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-217663
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1481557-6
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  • 4
    Online Resource
    Online Resource
    Tailored antiplatelet therapy in stent assisted coiling for unruptured aneurysms: a nationwide registry study
    BMJ ; 2023
    In:  Journal of NeuroInterventional Surgery
    Details
    In: Journal of NeuroInterventional Surgery, BMJ
    Abstract: Antiplatelet therapy, where regimens are tailored based on platelet function testing, has been introduced into neurointerventional surgery. This nationwide registry study evaluated the effect and safety of tailored antiplatelet therapy in stent assisted coiling for unruptured aneurysms compared with conventional therapy using a standard regimen. Methods This study enrolled 1686 patients in 44 participating centers who received stent assisted coiling for unruptured aneurysms between January 1, 2019 and December 31, 2019. The standard regimen (aspirin and clopidogrel) was used for all patients in the conventional group (924, 19 centers). The regimen was selected based on platelet function testing (standard regimen for clopidogrel responders; adding cilostazol or replacing clopidogrel with other thienopyridines (ticlopidine, prasugrel, or ticagrelor) for clopidogrel non-responders) in the tailored group (762, 25 centers). The primary outcome was thromboembolic events. Secondary outcomes were bleeding and poor outcomes (increase in modified Rankin Scale score). Outcomes within 30 days after coiling were compared using logistic regression analysis. Results The thromboembolic event rate was lower in the tailored group than in the conventional group (30/762 (3.9%) vs 63/924 (6.8%), adjusted OR 0.560, 95% CI 0.359 to 0.875, P=0.001). The bleeding event rate was not different between the study groups (62/762 (8.1%) vs 73/924 (7.9%), adjusted OR 0.790, 95% CI 0.469 to 1.331, P=0.376). Poor outcomes were less frequent in the tailored group (12/762 (1.6%) vs 34 (3.7%), adjusted OR 0.252, 95% CI 0.112 to 0.568, P=0.001). Conclusion Tailored antiplatelet therapy in stent assisted coiling for unruptured aneurysms reduced thromboembolic events and poor outcomes without increasing bleeding.
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    URL: Article
    DOI: 10.1136/jnis-2022-019571
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2506028-4
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