| アブストラクト | BACKGROUND: We previously identified genetic correlation between pairs of musculoskeletal (MSK) and respiratory conditions. Strategies to prevent or delay their onset remain underexplored in the context of multimorbidity. This study investigated whether MSK-respiratory disease pairs show evidence of potential causal relationships, identified modifiable risk factors, and quantified intervention windows to prevent progression to multimorbidity. METHODS: We examined combinations of one respiratory condition (asthma, COPD) and one MSK condition [rheumatoid arthritis (RA), osteoarthritis (OA), polymyalgia rheumatica (PMR), psoriasis]. Two-sample Mendelian randomisation (MR) evaluated potential causal relationships in both directions. Linked electronic health records from CPRD (N = 11,042,985; age >/= 40 years) were used to assess longitudinal disease trajectories, prognostic consequences, and mediation by potentially modifiable or treatable factors. RESULTS: We found evidence for bidirectional relationships between COPD and RA/OA (ORs 1.10-1.19) and between asthma and RA/OA (ORs 1.03-1.14). COPD genetic liability also increased PMR risk (OR 1.14, 95% CI 1.03-1.25). Psoriasis liability increased risk of COPD (OR 1.04, 95% CI 1.02-1.07) and asthma (OR 1.05, 95% CI 1.03-1.08). Across disease pairs, the median interval between first and second diagnoses was 5-13 years, indicating a substantial window for intervention. Obesity, smoking, hypertension, and thyroid conditions were risk factors common across all studied conditions. Mediation analyses suggested reduced physical activity and lipid changes partially contributed to the onset of respiratory disease following MSK conditions. Colocalisation identified genetic variants causal for specific condition pairs (implicating genes IFIH1, APOE, and CXCR5), highlighting inflammatory and lipid pathways. CONCLUSIONS: MSK and respiratory conditions commonly develop sequentially over many years. Targeted strategies promoting physical function, optimising lipid and cardiovascular risk management may help delay or prevent multimorbidity progression. |
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| 投稿者 | Murrin, Olivia; Voller, Bethany; Woodward, Ruby M; Carrasco-Ribelles, Lucia A; Turkmen, Deniz; Gu, Qingze; Boddy, Kate; Farmer, Leon; Mancini, Mary; Khalid, Sara; Aveyard, Nicholas; Fox, Chris; Bowden, Jack; Dudbridge, Frank; Lamb, Sarah E; Masoli, Jane A H; Violan, Concepcion; Pilling, Luke C; Frayling, Timothy M; Delgado, Joao |
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| 組織名 | Department of Clinical and Biomedical Sciences, Faculty of Health and Life;Sciences, University of Exeter, Exeter, UK. o.murrin@exeter.ac.uk.;Sciences, University of Exeter, Exeter, UK.;Division of Public Health & Epidemiology, School of Medical Sciences, University;of Leicester, Leicester, UK.;Unitat de Suport a La Recerca Metropolitana Nord, Fundacio Institut Universitari;Per a La Recerca a L'Atencio Primaria de Salut Jordi Gol I Gurina (IDIAPJGol),;Barcelona, 08007, Spain.;Grup de Recerca en Impacte de Les Malalties Croniques I Les Seves Trajectories;(GRIMTra) (2021 SGR 01537), Institut Universitari d'Investigacio en Atencio;Primaria Jordi Gol (IDIAPJGol), Mare de Deu de Guadalupe, 2, Barcelona, 08303,;Spain.;Red de Investigacion en Cronicidad, Atencion Primaria y Prevencion y Promocion de;La Salut (RICAPPS), Instituto de Salud Carlos III (ISCIII), Avenida Monforte de;Lemos,5, Madrid, 28029, Spain.;Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences,;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Department of Health and Community Sciences, Faculty of Health and Life Sciences,;University of Exeter, Exeter, UK.;Public and Patient Involvement Representative, Exeter, UK.;Royal Devon University Healthcare NHS Foundation Trust, Barrack Road, Exeter, EX2;5DW, UK.;Novo Nordisk Research Centre, Roosevelt Drive, Headington, Oxford, UK.;Leicester British Heart Foundation Centre of Research Excellence, University of;Leicester, Leicester, UK.;Department of Public Health and Sports Sciences, Faculty of Health and Life;Germans Trias I Pujol Research Institute (IGTP), Barcalona, 08916, Spain.;Department of Medicine, Universitat Autonoma de Barcelona, Placa Civica, 1,;Barcelona, 08193, Spain.;Department of Genetic Medicine and Development, Faculty of Medicine, University;of Geneva, 1 Rue Michel-Servet, Geneva 4, CH-1211, Switzerland. |
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