Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Maureen D. Mayes, Lara Bossini-Castillo, Olga Gorlova, José Ezequiel Martin, Xiaodong Zhou, Wei V. Chen, Shervin Assassi, Jun Ying, Filemon K. Tan, Frank C. Arnett, John D. Reveille, Sandra Guerra, María Teruel, Francisco David Carmona, Peter K. Gregersen, Annette T. Lee, Elena López-Isac, Eguzkine Ochoa, Patricia Carreira, Carmen Pilar SimeónIván Castellví, Miguel Ángel González-Gay, Alexandra Zhernakova, Leonid Padyukov, Marta Alarcón-Riquelme, Cisca Wijmenga, Matthew Brown, Lorenzo Beretta, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg H W Distler, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Roger Hesselstrand, Annika Nordin, Paolo Airó, Claudio Lunardi, Paul Shiels, Jacob M. Van Laar, Ariane Herrick, Jane Worthington, Christopher Denton, Fredrick M. Wigley, Laura K. Hummers, John Varga, Monique E. Hinchcliff, Murray Baron, Marie Hudson, Janet E. Pope, Daniel E. Furst, Dinesh Khanna, Kristin Phillips, Elena Schiopu, Barbara M. Segal, Jerry A. Molitor, Richard M. Silver, Virginia D. Steen, Robert W. Simms, Robert A. Lafyatis, Barri J. Fessler, Tracy M. Frech, Firas Alkassab, Peter Docherty, Elzbieta Kaminska, Nader Khalidi, Henry Niall Jones, Janet Markland, David Robinson, Jasper Broen, Timothy R D J Radstake, Carmen Fonseca, Bobby P. Koeleman, Javier Martin

Research output: Contribution to journalArticlepeer-review

164 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)47-61
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - Jan 2 2014

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Centers of Research Translation (CORT) grant P50AR054144, NIH grant KL2RR024149-04, NIH NIAMS grant N01-AR02251, and NIH National Center for Research Resources grant 3UL1RR024148. This study was supported by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 and SAF2012-34435 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucia, and RD08/0075 and RD12/0009/0004 from the Redes Temáticas de Investigación Cooperativa en Salud (Red de Investigación en Inflamación y Enfermedades Reumáticas). We are indebted to the Immunochip Consortium for provision of the control data. We are grateful to Julio Charles, Marilyn Perry, Suzanne S. Taillefer (National Study Coordinator for the Canadian Scleroderma Research Group), Sofia Vargas, Sonia García, and Gema Robledo. We also thank the Scleroderma Foundation, the Spanish Scleroderma Patient Group, the Canadian Scleroderma Patient Group, the Federation of European Scleroderma Associations, National DNA Bank Carlos III (University of Salamanca), the European League against Rheumatism Scleroderma Trials and Research group, the German Network of Systemic Sclerosis, and the affected individuals, friends, spouses, and others who generously provided the samples for these studies.


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