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Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

Lookup NU author(s): Professor Jaap Van Laar


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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.

Publication metadata

Author(s): Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou XD, 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, Gonzalez-Gay MA, Zhernakova A, Padyukov L, Aarcon-Riquelme M, Wijmenga C, Brown M, Beretta L, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler JHW, 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, Spanish Scleroderma Grp

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2014

Volume: 94

Issue: 1

Pages: 47-61

Print publication date: 02/01/2014

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2013.12.002


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Funder referenceFunder name
GEN-FER from the Spanish Society of Rheumatology
3UL1RR024148NIH National Center for Research Resources grant
CTS-4977Junta de Andalucia
P50AR054144National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Centers of Research Translation (CORT) grant
SAF2009-11110Spanish Ministry of Science
SAF2012-34435Spanish Ministry of Science
RD08/0075Redes Tematicas de Investigacion Cooperativa en Salud (Red de Investigacion en Inflamacion y Enfermedades Reumaticas)
RD12/0009/0004Redes Tematicas de Investigacion Cooperativa en Salud (Red de Investigacion en Inflamacion y Enfermedades Reumaticas)