Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou X, Chen WV, Assassi S, Ying J, Tan FK, Arnett FC, Reveille JD, Guerra S, Terue M, Carmona FD, Gregersen PK, Lee AT, Lopez-Isac E, Ochoa E, Carreira P, Simeon CP, Castellvi I, Angel Gonzalez-Gay M, Zhernakova A, Padyukov L, Aarcon-Riquelme M, Wijmenga C, Brown M, Beretta L, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler J, Voskuy AE, Schuerwegh AJ, Hesselstrand R, Nordin A, Airo P, Lunardi C, Shiels P, Van Laar JM, Herrick A, Worthington J, Denton C, Wigley FM, Hummers LK, Varga J, Hinchcliff ME, Baron M, Hudson M, Pope JE, Furst DE, Khanna D, Phillips K, Schiopu E, Segal BM, Molitor JA, Silver RM, Steen VD, Simms RW, Lafyatis RA, Fessler BIJ, Frech TM, Alkassab F, Docherty P, Kaminska E, Khalidi N, Jones HN, Markland J, Robinson D, Broen J, Radstake TRDJ, Fonseca C, Koeleman BP, Martin J (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Book Volume: 94

Pages Range: 47-61

Journal Issue: 1

DOI: 10.1016/j.ajhg.2013.12.002

Abstract

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Authors with CRIS profile

Involved external institutions

University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Spanish National Research Council / Consejo Superior de Investigaciones Científicas (CSIC) Spain (ES) University of Texas MD Anderson Cancer Center United States (USA) (US) University College London (UCL) United Kingdom (GB) Northwell Health United States (USA) (US) Hospital Universitario 12 de Octubre Spain (ES) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Hospital de la Santa Creu i Sant Pau Spain (ES) Marqués de Valdecilla University Hospital / Hospital Universitario de Marqués de Valdecilla (HUMV) Spain (ES) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Karolinska Institute Sweden (SE) Universidad de Granada Spain (ES) University of Queensland Australia (AU) Charité - Universitätsmedizin Berlin Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Universität zu Köln Germany (DE) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Leiden University Netherlands (NL) Lund University / Lunds universitet Sweden (SE) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia Italy (IT) University of Verona / Università degli Studi di Verona Italy (IT) University of Glasgow United Kingdom (GB) Newcastle University United Kingdom (GB) University of Manchester United Kingdom (GB) Johns Hopkins University (JHU) United States (USA) (US) Northwestern University United States (USA) (US) McGill University Canada (CA) Western University Canada (CA) University of California Los Angeles (UCLA) United States (USA) (US) University of Michigan United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Medical University of South Carolina (MUSC) United States (USA) (US) Georgetown University United States (USA) (US) HELIOS Kliniken Germany (DE) Boston University United States (USA) (US) University of Alabama at Birmingham (UAB) United States (USA) (US) University of Utah United States (USA) (US) Carolinas HealthCare System United States (USA) (US) Moncton Hospital Canada (CA) Alberta Health Services (AHS) Canada (CA) McMaster University Canada (CA) University of Alberta Canada (CA) University of Saskatchewan Canada (CA) University of Manitoba Canada (CA) Radboud University Nijmegen Netherlands (NL) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT)

How to cite

APA:

Mayes, M.D., Bossini-Castillo, L., Gorlova, O., Martin, J.E., Zhou, X., Chen, W.V.,... Martin, J. (2014). Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. American Journal of Human Genetics, 94(1), 47-61. https://doi.org/10.1016/j.ajhg.2013.12.002

MLA:

Mayes, Maureen D., et al. "Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis." American Journal of Human Genetics 94.1 (2014): 47-61.

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