Borrego-Yaniz, G. and Ortiz-Fernández, L. and Madrid-Paredes, A. and Kerick, M. and Hernández-Rodríguez, J. and Mackie, S.L. and Vaglio, A. and Castañeda, S. and Solans, R. and Mestre-Torres, J. and Khalidi, N. and Langford, C.A. and Ytterberg, S. and Beretta, L. and Govoni, M. and Emmi, G. and Cimmino, M.A. and Witte, T. and Neumann, T. and Holle, J. and Schönau, V. and Pugnet, G. and Papo, T. and Haroche, J. and Mahr, A. and Mouthon, L. and Molberg, Ø. and Diamantopoulos, A.P. and Voskuyl, A. and Daikeler, T. and Berger, C.T. and Molloy, E.S. and Blockmans, D. and van Sleen, Y. and Iles, M. and Sorensen, L. and Luqmani, R. and Reynolds, G. and Bukhari, M. and Bhagat, S. and Ortego-Centeno, N. and Brouwer, E. and Lamprecht, P. and Klapa, S. and Salvarani, C. and Merkel, P.A. and Cid, M.C. and González-Gay, M.A. and Morgan, A.W. and Martin, J. and Márquez, A. and Callejas, J.L. and Caminal-Montero, L. and Corbera-Bellalta, M. and de Miguel, E. and Díaz-López, J.B. and García-Villanueva, M.J. and Gómez-Vaquero, C. and Guijarro-Rojas, M. and Hidalgo-Conde, A. and Marí-Alfonso, B. and Martínez-Berriochoa, A. and Morado, I.C. and Narváez, J. and Ramentol-Sintas, M. and Martínez-Zapico, A. and Martínez-Taboada, V.M. and Miranda-Filloy, J.A. and Monfort, J. and Pérez-Conesa, M. and Prieto-González, S. and Raya, E. and Ríos-Fenández, R. and Sánchez-Martín, J. and Sopeña, B. and Tío, L. and Unzurrunzaga, A. and Wordsworth, O. and Whitwell, I. and Brock, J. and Douglas, V. and Hettiarachchi, C. and Bartholomew, J. and Jarrett, S. and Smithson, G. and Green, M. and Brown, P.C. and Lawson, C. and Gordon, E. and Lane, S. and Francis, R. and Dasgupta, B. and Masunda, B. and Calver, J. and Patel, Y. and Thompson, C. and Gregory, L. and Levy, S. and Menon, A. and Thompson, A. and Dyche, L. and Martin, M. and Li, C. and Laxminarayan, R. and Wilcox, L. and de Guzman, R. and Isaacs, J. and Lorenzi, A. and Farley, R. and Hinchcliffe-Hume, H. and Bejarano, V. and Hope, S. and Nandi, P. and Stockham, L. and Wilde, C. and Durrant, D. and Lloyd, M. and Ye, C.-S. and Stevens, R. and Jilani, A. and Collins, D. and Pegler, S. and Rivett, A. and Price, L. and McHugh, N. and Skeoch, S. and O'Kane, D. and Kirkwood, S. and Vadivelu, S. and Pugmire, S. and Sultan, S. and Dooks, E. and Armstrong, L. and Sadik, H. and Nandagudi, A. and Abioye, T. and Ramos, A. and Gumus, S. and Sofat, N. and Harrison, A. and Seward, A. and Mollan, S. and Rahan, R. and Hawkins, H. and Emsley, H. and Bhargava, A. and Fleming, V. and Hare, M. and Raj, S. and George, E. and Allen, N. and Hunter, K. and O'Sullivan, E. and Bird, G. and Magliano, M. and Manzo, K. and Sanghera, B. and Hutchinson, D. and Hammonds, F. and Sharma, P. and Cooper, R. and McLintock, G. and Al-Saffar, Z.S. and Elliott, K. and Neale, T. and Mallinson, J. and Lanyon, P. and Pradere, M.-J. and Jordan, N. and Htut, E.P. and Mushapaidzi, T. and Abercrombie, D. and Wright, S. and Rowlands, J. and Mukhtyar, C. and Kennedy, J. and Makkuni, D. and Wilhelmsen, E. and Kouroupis, M. and John, L. and Hughes, R. and Walsh, M. and Buckley, M. and Mackay, K. and Camden-Woodley, T. and Redome, J. and Pearce, K. and Marianayagam, T. and Cruz, C. and Warner, E. and Atchia, I. and Walker, C. and Black, K. and Duffy, S. and Fothergill, L. and Jefferey, R. and Toomey, J. and Rhys-Dillon, C. and Pothecary, C. and Green, L. and Toms, T. and Maher, L. and Davis, D. and Sayan, A. and Thankachen, M. and Abusalameh, M. and Record, J. and Khan, A. and Stafford, S. and Hussein, A. and Williams, C. and Fletcher, A. and Johson, L. and Burnett, R. and Moots, R. and Frankland, H. and Dale, J. and Moar, K. and Hollas, C. and Parker, B. and Ridings, D. and Eapen, S. and John, S. and Robson, J. and Guthrie, L.B. and Fyfe, R. and Tait, M. and Marks, J. and Gunter, E. and Hernandez, R. and Bhat, S. and Johnston, P. and Khurshid, M. and Barclay, C. and Kapur, D. and Jeffrey, H. and Hughes, A. and Slack, L. and Thomas, E. and Royon, A. and Hall, A. and King, J. and Nyathi, S. and Morris, V. and Castelino, M. and Hawkins, E. and Tomson, L. and Singh, A. and Nunag, A. and O'Connor, S. and Rushby, N. and Hewitson, N. and O'Sunmboye, K. and Lewszuk, A. and Boyles, L. and Perry, M. and Williams, E. and Graver, C. and Defever, E. and Kamanth, S. and Kay, D. and Ogor, J. and Winter, L. and Horton, S. and Welch, G. and Hollinshead, K. and Peters, J. and Labao, J. and Dmello, A. and Dawson, J. and Graham, D. and De Lord, D. and Deery, J. and Hazelton, T. and Carette, S. and Chung, S. and Cuthbertson, D. and Forbess, L.J. and Gewurz-Singer, O. and Hoffman, G.S. and Koening, C.L. and Maksimowicz-McKinnon, K.M. and McAlear, C.A. and Moreland, L.W. and Pagnoux, C. and Seo, P. and Specks, U. and Spiera, R.F. and Sreih, A. and Warrington, K.J. and Monach, P.A. and Weisman, M. (2024) Risk loci involved in giant cell arteritis susceptibility : a genome-wide association study. The Lancet Rheumatology, 6 (6). e374-e383.
Full text not available from this repository.Abstract
Background: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. Methods: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. Findings: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10–8; OR 1·19 [95% CI 1·12–1·26]) and VTN (rs704; p=2·75 × 10–9; OR 0·84 [0·79–0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10–8; OR 1·18 [1·12–1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15–3·82]; p=1·73 × 10–13). Interpretation: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis.