An MIF promoter polymorphism is associated with susceptibility to pulmonary arterial hypertension in diffuse cutaneous systemic sclerosis
Bossini-Castillo, Lara; Campillo-Davo, Diana; Lopez-Isac, Elena; Carmona, Francisco David; Simeon, Carmen P.; Carreira, Patricia; Callejas-Rubio, Jose Luis; Castellvi, Ivan; Fernandez-Nebro, Antonio; Rodriguez-Rodriguez, Luis; Rubio-Rivas, Manel; Garcia-Hernandez, Francisco J.; Madronero, Ana Belen; Beretta, Lorenzo; Santaniello, Alessandro; Lunardi, Claudio; Airo, Paolo; Hoffmann-Vold, Anna-Maria; Kreuter, Alexander; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Vonk, Madelon C.; Voskuyl, Alexandre E.; de Vries-Bouwstra, Jeska; Shiels, Paul; Herrick, Ariane; Worthington, Jane; Radstake, Timothy R.D.J.; Martin, Javier; Spanish Scleroderma Group
(2017) Journal of Rheumatology, volume 44, issue 10, pp. 1453 - 1457
(Article)
Abstract
Objective. Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene,
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which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. Methods.A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. Results. A statistically significant increase of the MIF rs755622C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). Conclusion. We reviewed the association of the MIF rs755622∗C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.
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Keywords: Mif, Pulmonary arterial hypertension, Systemic sclerosis, rs755622, Rheumatology, Immunology and Allergy, Immunology, Journal Article
ISSN: 0315-162X
Publisher: Journal of Rheumatology
Note: Funding Information: From the Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC; Unidad de Enfermedades Sistémicas Autoinmunes, Department of Internal Medicine, Hospital Clínico Universitario San Cecilio, Granada; Department of Internal Medicine, Hospital Valle de Hebron; Department of Rheumatology, Hospital de la Santa Creu i de Sant Pau; Department of Internal Medicine, Hospital Universitario de Bellvitge, Barcelona; Department of Rheumatology, Hospital Universitario 12 de Octubre; Department of Rheumatology, Hospital Clínico San Carlos, Madrid; Department of Rheumatology, Hospital Carlos Haya, Málaga; Servicio de Medicina Interna, Hospital Virgen del Rocio, Seville; Department of Internal Medicine, Hospital General San Jorge, Huesca, Spain; Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Milan; Department of Medicine, Università degli Studi di Verona, Verona; Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia, Italy; Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway; Department of Dermatology, Josefs-Hospital, Ruhr University Bochum, Bochum; Clinic of Rheumatology, University of Lübeck, Lübeck; Klinik für Immunologie und Rheumatologie, Hannover Medical School, Hannover; Department of Dermatology, University of Cologne, Cologne, Germany; Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen; VU University Medical Center, Amsterdam; Department of Rheumatology, Leiden University Medical Center, Leiden; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Supported by the following grants: JM was funded by SAF2015-66761-P from the Spanish Ministry of Economy and Competitiveness. This study was also funded by PI-0590-2010, from Consejería de Salud y Bienestar Social, Junta de Andalucía, Spain. ELI was supported by Ministerio de Educación, Cultura y Deporte through the program FPU. L. Bossini-Castillo, PhD, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC; D. Campillo-Davó, PhD, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC; E. López-Isac, PhD, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC; F.D. Carmona, PhD, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC; C.P. Simeon, MD, Department of Internal Medicine, Hospital Valle de Hebron; P. Carreira, MD, Department of Rheumatology, Hospital Universitario 12 de Octubre; J.L. Callejas-Rubio, MD, Unidad de Enfermedades Sistémicas Autoinmunes, Department of Internal Medicine, Hospital Clínico Universitario San Cecilio; I. Castellví, MD, Department of Rheumatology, Hospital de la Santa Creu i de Sant Pau; A. Fernández-Nebro, MD, Department of Rheumatology, Hospital Carlos Haya; L. Rodríguez-Rodríguez, MD, Department of Rheumatology, Hospital Clínico San Carlos; M. Rubio-Rivas, MD, Department of Internal Medicine, Hospital Universitario de Bellvitge; F.J. García-Hernández, MD, Servicio de Medicina Interna, Hospital Virgen del Rocio; A.B. Madroñero, MD, Department of Internal Medicine, Hospital General San Jorge; L. Beretta, MD, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan; A. Santaniello, MD, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan; C. Lunardi, MD, Department of Medicine, Università degli Studi di Verona; P. Airó, MD, Servizio di Reumatologia ed Immunologia Clinica Spedali Civili; A.M. Hoffmann-Vold, MD, Department of Rheumatology, Rikshospitalet, Oslo University Hospital; A. Kreuter, MD, Department of Dermatology, Josefs-Hospital, Ruhr University Bochum; G. Riemekasten, MD, Clinic of Rheumatology, University of Lübeck; T. Witte, MD, Klinik für Immunologie und Rheumatologie, Hannover Medical School; N. Hunzelmann, MD, Department of Dermatology, University of Cologne; M.C. Vonk, MD, Department of Rheumatology, Radboud University Nijmegen Medical Centre; A.E. Voskuyl, MD, VU University Medical Center; J. de Vries-Bouwstra, MD, Department of Rheumatology, Leiden University Medical Center; P. Shiels, MD, Glasgow Biomedical Research Centre, University of Glasgow; A. Herrick, MD, Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre; J. Worthington, PhD, Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre; T.R. Radstake, MD, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht; J. Martin, MD, PhD, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC. L. Bossini-Castillo, D. Campillo-Davó, and E. López-Isac contributed equally to this study. Address correspondence to E. López-Isac, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18016-Armilla (Granada), Spain. E-mail: elenalopezisac@ipb.csic.es Accepted for publication May 5, 2017. Publisher Copyright: © Copyright 2017 The Journal of Rheumatology. All rights reserved.
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