{"title":"Identification of Genetic Predisposition to Sjogren's Syndrome by Whole Exome Sequencing","authors":"Qiwei Guo, Qiaowei Li, Huiqin Lu, Yingying Shi, Jintao Guo, Hao Wang, Qiuxiao Deng, Yihang Li, Yuan Liu, Guixiu Shi, Shiju Chen","doi":"10.1101/2024.03.14.24304128","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304128","url":null,"abstract":"A comprehensive understanding of the genetic predisposition associated with the initiation and development of Sjogren's syndrome (SjS) is imperative. This would not only enrich our knowledge of the pathogenesis underlying this autoimmune disease but also address the long-standing clinical challenges of more timely diagnosis and effective treatment to retain organ function and improve prognosis. In this study, we used whole exome sequencing analysis of 50 patients with SjS to investigate the predisposing variants, genes, and their associated biological functions. Hundreds of predisposing genes were identified, and numerous biological processes and pathways were highlighted; suggesting a heterogeneity of genetic predisposition to SjS. Female patients carrying a greater number of enriched variants tended to have higher levels of serum IgG and corresponding systemic involvement, demonstrating the pivotal role of genetic predisposition in the pathogenesis of SjS. Biological function analysis indicated that a subset of SjS and neuropathies may share a similar genetic predisposition. Our results showed that extracellular matrix-receptor interactions, macrophage-associated biological functions, and motor proteins may play important roles in the pathogenesis of SjS, and macrophage-associated biological functions may be associated with early onset SjS in female patients. Furthermore, the identification of highly enriched variants in the patient cohort provides the possibility of advancing the diagnosis of SjS. In conclusion, our study provides an extensive framework for analysis of the genetic predisposition to SjS which can facilitate further focused and in-depth investigation of the pathogenetic mechanisms of specific genes, biological processes, and pathways; thereby contributing to the pathophysiology, diagnosis, and therapeutics of SjS.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140168063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhe Ding, Fumin Qi, Li Liu, Zhouming Wang, Na Zhang, Xing Lyu, Wenwen Sun, Jun Du, Haoming Haoming, Hou Hou, Ying Guo, Xiaomei Wang, Ming-Lin Liu, Wei Wei
{"title":"Circulating microvesicles as novel biomarkers for pulmonary arterial hypertension in patients with systemic lupus erythematosus","authors":"Zhe Ding, Fumin Qi, Li Liu, Zhouming Wang, Na Zhang, Xing Lyu, Wenwen Sun, Jun Du, Haoming Haoming, Hou Hou, Ying Guo, Xiaomei Wang, Ming-Lin Liu, Wei Wei","doi":"10.1101/2024.03.10.24304030","DOIUrl":"https://doi.org/10.1101/2024.03.10.24304030","url":null,"abstract":"Pulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Microvesicles (MVs) are known to be associated with thrombosis. Here, we investigated circulating MVs and their associations with SLE-PAH. Eighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating MVs from leukocytes (LMVs), red blood cells (RMVs), platelets (PMVs), endothelial cells (EMVs), and Annexin V+ MVs with phosphatidylserine (PS) exposure. Plasma levels of all MV subgroups were elevated in SLE patients with or without PAH compared to HCs. Furthermore, plasma Annexin V+ MVs, LMVs, PMVs, RMVs, EMVs, and Annexin V+ RMVs were significantly elevated in SLE-PAH patients compared to SLE-non-PAH patients. Additionally, PAH patients with moderate/high SLE showed a significant increase in LMVs, PMVs, RMVs, Annexin V+ MVs, and Annexin V+ RMVs compared to SLE-non-PAH patients. However, PAH patients with inactive/mild SLE only exhibited elevations in Annexin V+ MVs, RMVs, and Annexin V+ RMVs. In the SLE-PAH patients, EMVs were positively correlated with pulmonary arterial systolic pressure, while PMVs and EMVs were positively correlated with right ventricular diameter. Moreover, the receiver operating characteristic curve indicated that Annexin V+ MVs, LMVs, PMVs, RMVs, EMVs and Annexin V+ RMVs can predict the presence of PAH in SLE patients. Importantly, multivariate logistic regression analysis showed that circulating levels of LMVs or RMVs, anti-nRNP antibody, and serositis were independent risk factors for PAH in SLE patients. Finally, our findings reveal that specific subgroups of circulating MVs contribute to the hypercoagulation state and the severity of SLE-PAH. Higher plasma levels of LMVs or RMVs may serve as biomarkers for SLE-PAH.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariana Correia Marques, Danielle Rubin, Emily Shuldiner, Mallika Datta, Elizabeth Schmitz, Gustavo Gutierrez Cruz, Andrew Patt, Elizabeth Bennett, Alexei Grom, Dirk Foell, Marco Gattorno, John Bohnsack, Rae S. M. Yeung, Sampath Prahalad, Elizabeth Mellins, Jordi Anton, Claudio Arnaldo Len, Sheila Oliveira, Patricia Woo, Seza Ozen, INCHARGE Consortium, Zuoming Deng, Michael J. Ombrello
{"title":"Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis","authors":"Mariana Correia Marques, Danielle Rubin, Emily Shuldiner, Mallika Datta, Elizabeth Schmitz, Gustavo Gutierrez Cruz, Andrew Patt, Elizabeth Bennett, Alexei Grom, Dirk Foell, Marco Gattorno, John Bohnsack, Rae S. M. Yeung, Sampath Prahalad, Elizabeth Mellins, Jordi Anton, Claudio Arnaldo Len, Sheila Oliveira, Patricia Woo, Seza Ozen, INCHARGE Consortium, Zuoming Deng, Michael J. Ombrello","doi":"10.1101/2024.03.13.24304215","DOIUrl":"https://doi.org/10.1101/2024.03.13.24304215","url":null,"abstract":"Objective: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS).\u0000Methods: Targeted sequencing of HLH genes (<em>LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D</em>) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations.\u0000Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of <em>STXBP2</em> (p=0.020), and ultra-rare variants (MAF<0.001) of <em>STXBP2</em> (p=0.007) and <em>UNC13D</em> (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare <em>UNC13D</em> variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving <em>LYST</em>. Conclusion: We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Geier, Haani Qudsi, Jihad Ben Gabr, Robert J Winchester, Andras Perl
{"title":"CD1c Dendritic Cells are depleted and accompanied by new HLA-DRhi Phenotypes in Rheumatoid Arthritis Blood","authors":"Christian Geier, Haani Qudsi, Jihad Ben Gabr, Robert J Winchester, Andras Perl","doi":"10.1101/2024.03.13.24304213","DOIUrl":"https://doi.org/10.1101/2024.03.13.24304213","url":null,"abstract":"Rheumatoid arthritis (RA) in an autoimmune disease that leads to inflammation of synovial joints and other organs. Many RA patients \"share\" a common peptide sequence within the HLA-DR (DR) molecule expressed on antigen-presenting cells (APC), suggesting that DRhi cells are important in RA. Here, we use DRhi to broadly define and immunophenotype RA APC, including potential APC not meeting standard definitions for lymphocytes, monocytes, dendritic cells (DC) from RA patients and healthy controls (HC). We measured mean fluorescence intensities (MFI) of molecules associated with DC (CD141, CD1c, CD11c, CD123, CD303), monocytes (CD14, CD16); granulocytic markers (CD15, CCR3), co-stimulatory molecules and chemokine receptors. DC2 (CD1c+) showed higher CD56, CD86, CD275, and CCR7 in RA. DC2 frequencies were much lower in RA: 3.2% of DRhi [IQR 2.41 to 4.46] in RA vs. 6.9% [IQR 3.96 to 9.08] in HC; p=0.005. CD15 was increased in all RA APC subsets (p<0.01). A distinct CD15+CD16+ population appeared in RA, representing 1.5% of leukocytes [IQR 0.68 to 3.32] (vs 0.1% in HC [IQR 0.08 to 0.46]; p<0.001) and contributed a mean of 2.34% to overall DRhi. The CD15+CD16+ subset was CD303+, CD83+ and CD275+ with much less CD123 relative to reference plasmacytoid DC (p<0.01). In conclusion, APC alterations in RA include depletion of DC2 and increased CD15. Moreover, the APC (DRhi) compartment in RA contains cells with shared dendritic cell and granulocytic features; this phenotype suggests these apparent APC may participate in the pathophysiology of rheumatoid arthritis via the presentation of self-antigen(s) to CD4+ T lymphocytes.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Malin C Erlandsson, Lauri Weman, Eric Malmhall-Bah, Venkataragavan Chandrasekaran, Mahomud Tuameh, Karin ME Andersson, Sofia T Silfversward, Lisa Nilsson, Tatiana Zverkova Sandstrom, Rille Pullerits, Mats Dehlin, Tuulikki Sokka-Isler, Maria I Bokarewa
{"title":"Hyperinsulinemia counteracts inflammation by suppressing IFNg and inducing senescence in CD4+ T cells of patients with rheumatoid arthritis","authors":"Malin C Erlandsson, Lauri Weman, Eric Malmhall-Bah, Venkataragavan Chandrasekaran, Mahomud Tuameh, Karin ME Andersson, Sofia T Silfversward, Lisa Nilsson, Tatiana Zverkova Sandstrom, Rille Pullerits, Mats Dehlin, Tuulikki Sokka-Isler, Maria I Bokarewa","doi":"10.1101/2024.03.08.24303970","DOIUrl":"https://doi.org/10.1101/2024.03.08.24303970","url":null,"abstract":"Background. Clinical evidence connects hyperinsulinemia with obesity, and development of type 2 diabetes (T2D). However, its role in autoimmune conditions was questioned. We investigated consequences of hyperinsulinemia for development of T2D and CD4+T cell function in rheumatoid arthritis (RA).\u0000Methods. Incident T2D was prospectively studied in two independent RA cohorts and in gout patients matched to RA by age and gender, for 10 years. Effect of hyperinsulinemia and JAK-STAT signaling inhibition (JAKi) in CD4+T cells was studied by integrating transcriptional sequencing with direct effect of insulin, and JAKi on cell proliferation, DNA enrichment, and cytokine production. Results. T2D was 3.2-2.5 times less prevalent in RA compared to gout, particularly in females. Hyperinsulinemia predicted the development of T2D, regardless of metabolic parameters and insulin resistance. Additionally, hyperinsulinemia correlated with the senescence-associated high serum levels of IL6, IL8, and VEGF. Hyperinsulinemia, along with ex-vivo exposure of CD4+ cells to insulin, inhibited cell cycle progression and induced DNA enrichment through the suppression of the PI3K-Src kinases and cell cycle promoting genes. It also reduced IFNg production. JAKi-treated CD4+ cells regained insulin sensitivity, which activated glucose metabolism and facilitated senescence. This insulin-dependent mechanism promoted the accumulation of naive CD4+ cells in JAKi-treated patients.\u0000Conclusions. This study shows that insulin has important immunosuppressive ability controlling the adaptive immunity by suppressing IFNg production and inducing senescence in the effector CD4+ T cells. Inhibition of JAK-STAT signaling enhances insulin sensitivity and rejuvenates CD4+ cell population in RA patients.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140099415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nils Burgisser, Denis Mongin, Samia Mehouachi, Clement P Buclin, Romain Guemara, Pauline Darbellay Farhoumand, Olivia Braillard, Kim Lauper, Delphine Sophie Courvoisier
{"title":"Enhancing gout management by creating a register using automated queries in electronic health records","authors":"Nils Burgisser, Denis Mongin, Samia Mehouachi, Clement P Buclin, Romain Guemara, Pauline Darbellay Farhoumand, Olivia Braillard, Kim Lauper, Delphine Sophie Courvoisier","doi":"10.1101/2024.03.08.24303964","DOIUrl":"https://doi.org/10.1101/2024.03.08.24303964","url":null,"abstract":"Objective: To develop an automatic gout register to improve gout management. Methods: We analysed the electronic health records (EHR) of all patients >18 years old from a tertiary academic hospital (2013-2022) based on six criteria: International Classification of Diseases 10 (ICD-10) gout diagnosis, urate-lowering therapy (ULT) prescription, uric acid crystal in joint aspiration and gout-related terms in problem lists, clinical or imaging reports. We assessed the positive and negative predictive value (PPV and NPV) of the query by chart reviews. Results: Of 2,110,902 out- and inpatients, 10,289 had at least one criterion for gout. The combination of joint aspiration OR diagnostic in the problem list OR ≥ 2 other criteria created a register of 5,138 patients, with a PPV of 92.4% (95%CI: 88.5 to 95.0), and an NPV of 94.3% (95%CI: 91.9 to 96.0). PPV and NPV were similar amongst outpatients and inpatients. Incidence was 2.9 per 1000 person-year and dropped by 30% from the COVID-19 pandemic onward. Patients with gout were on average 71.2 years old (SD 14.9), mainly male (76.5%), overweight (69.5%) and polymorbid (mean number of comorbidities of 3, IQR 1-5). More than half (57.4%) had received a urate lowering treatment, 6.7% had a gout that led to a hospitalisation or ≥2 flares within a year, and 32.9% received a rheumatology consultation. Conclusion: An automatic EHR-based gout register is feasible, valid and could be used to evaluate and improve gout management. Interestingly, the register uncovered a marked underdiagnosis or underreporting of gout since the COVID-19 pandemic.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140075554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eduardo Patino Martinez, Shuichiro Nakabo, Kan Jiang, Carmelo Carmona- Rivera, Wanxia Li Tsai, Dillon Claybaugh, Zu-Xi Yu, Aracely Romero, Eric Bohrnsen, Benjamin Schwarz, Miguel A. Solis Barbosa, Luz P. Blanco, Mohammad Naqi, Yenealem Temesgen-Oyelakim, Michael Davis, Nehal Mehta, Faiza Naz, Stephen Brooks, Stefania dell Orso, Sarfaraz Hasni, Mariana J. Kaplan
{"title":"The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE.","authors":"Eduardo Patino Martinez, Shuichiro Nakabo, Kan Jiang, Carmelo Carmona- Rivera, Wanxia Li Tsai, Dillon Claybaugh, Zu-Xi Yu, Aracely Romero, Eric Bohrnsen, Benjamin Schwarz, Miguel A. Solis Barbosa, Luz P. Blanco, Mohammad Naqi, Yenealem Temesgen-Oyelakim, Michael Davis, Nehal Mehta, Faiza Naz, Stephen Brooks, Stefania dell Orso, Sarfaraz Hasni, Mariana J. Kaplan","doi":"10.1101/2024.02.20.24303097","DOIUrl":"https://doi.org/10.1101/2024.02.20.24303097","url":null,"abstract":"Abstract\u0000Objective\u0000The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE. Methods\u0000We characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/- mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity. Results\u0000ACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. Consistent with these results, Acod1-/- BMDM exposed to IMQ showed higher proinflammatory features in vitro. Itaconate levels were decreased in SLE serum compared to healthy control sera, in association with specific perturbed cardiometabolic parameters and subclinical vascular disease. Conclusion\u0000These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in SLE, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139956785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin G Faber, Monika Frysz, Jiayi Zheng, Huandong Lin, Kaitlyn Flynn, Raja Ebsim, Fiona R Saunders, Rhona A Beynon, Jenny S Gregory, Richard M Aspden, Nicholas C Harvey, Claudia Lindner, Tim Cootes, David Evans, George Davey Smith, Xin Gao, Sijia Wang, John Kemp, Jon Tobias
{"title":"Hip shape shows a causal effect on hip fracture but not hip osteoarthritis: findings from a GWAS meta-analysis and causal analyses","authors":"Benjamin G Faber, Monika Frysz, Jiayi Zheng, Huandong Lin, Kaitlyn Flynn, Raja Ebsim, Fiona R Saunders, Rhona A Beynon, Jenny S Gregory, Richard M Aspden, Nicholas C Harvey, Claudia Lindner, Tim Cootes, David Evans, George Davey Smith, Xin Gao, Sijia Wang, John Kemp, Jon Tobias","doi":"10.1101/2024.01.26.24301811","DOIUrl":"https://doi.org/10.1101/2024.01.26.24301811","url":null,"abstract":"Objectives\u0000Hip shape is thought to be an important causal risk factor for hip osteoarthritis and fracture. We aimed to identify genetic determinants of hip shape and use these to assess causal relationships with hip osteoarthritis. Methods\u0000Statistical hip shape modelling was used to derive 10 hip shape modes (HSMs) from DXA images in UK Biobank and Shanghai Changfeng cohorts (n<sub>total</sub>=43,485). Genome-wide association study meta-analyses were conducted for each HSM. Two-sample Mendelian randomisation (MR) was used to estimate causal effects between HSM and hip osteoarthritis using hip fracture as a positive control.\u0000Results\u0000Analysis of the first 10 HSMs identified 290 independent association signals (P<5×10<sup>-8</sup>). Hip shape SNPs were also associated (P<1.7×10<sup>-4</sup>) with hip osteoarthritis (n=29) and hip fracture (n=4). Fine mapping implicated SMAD3 and PLEC as candidate genes that may be involved in the development of hip shape and hip osteoarthritis. MR analyses suggested there was no causal effect between any HSM and hip osteoarthritis, however there was evidence that HSM2 (higher neck-shaft angle) and HSM4 (wider femoral neck) have a causal effect on hip fracture (OR<sub>IVW</sub> 1.27 [95% CI 1.12-1.44], P=1.79×10<sup>-4</sup> and OR<sub>IVW</sub> 0.74 [0.65-0.84], P=7.60×10<sup>-6</sup> respectively)\u0000Conclusions We report the largest hip shape GWAS meta-analysis that identifies hundreds of novel loci, some of which are also associated with hip osteoarthritis and hip fracture. MR analyses suggest hip shape may not cause hip osteoarthritis but is implicated in hip fractures. Consequently, interventions aimed at modifying hip shape in older adults to prevent hip osteoarthritis may prove ineffective.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139578046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Georgina Nunn, Genevieve Glenister, Kathryn Hird, Kelly Beer, Ian Cooper, Merrilee Needham
{"title":"Depression is a more significant predictor for wellbeing in Inclusion Body Myositis than physical disability.","authors":"Georgina Nunn, Genevieve Glenister, Kathryn Hird, Kelly Beer, Ian Cooper, Merrilee Needham","doi":"10.1101/2024.01.22.24301628","DOIUrl":"https://doi.org/10.1101/2024.01.22.24301628","url":null,"abstract":"Objectives: (1) determine if there is a correlation between disability, depression, and wellbeing in people with IBM, (2) determine if disability and depression can predict wellbeing in people with IBM, and (3) identify the prevalence of depression and impaired wellbeing in participants with IBM.\u0000Methods: In this cross-sectional study, 101 participants with IBM completed the Neuromuscular Symptom Score (NSS), Personal Wellbeing Index (PWI), and Patient Health Questionnaire-9 (PHQ-9) surveys to serve as surrogate measures of physical disability, wellbeing, and depression respectively.\u0000Results: Linear regression identified that PHQ-9 significantly predicts PWI, however NSS does not, with a negative predictive value of depression for wellbeing (-2.7513, p < 0.001) and a positive predictive value of disability for wellbeing (0.0575, p = 0.764). Moderate to severe depression was reported in 78.2% of participants, and all but one participant reported reduced wellbeing.\u0000Conclusions: Depression is a more significant predictor of wellbeing than disability in participants diagnosed with IBM. There was a high prevalence of depression and reduced wellbeing in participants, highlighting the importance of assessing these factors to optimise treatment in IBM.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139552832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Analysis of dietary vitamin C intake levels and the risk of hyperuricemia and gout based on cross-sectional studies and bi-directional Mendelian randomisation","authors":"Zi-Ning Peng, Xing-Qiang Wang, Qian Deng, Wei-Tian Yan, Wei-Qing Zhao, Yong-Bin Pu, Nian Liu, Ling-Li Gu, Jiang-Yun Peng","doi":"10.1101/2024.01.18.24301481","DOIUrl":"https://doi.org/10.1101/2024.01.18.24301481","url":null,"abstract":"<strong>Background</strong> Vitamin C, a common antioxidant, may be useful for treating hyperuricemia and gout. The aim of this study was to investigate the risk association between dietary vitamin C intake and hyperuricemia/gout and to test for causality using the bi-directional Mendelian randomisation method.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"175 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139518634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}