title: Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.
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.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: maureen.d.mayes@uth.tmc.edu.
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain. Electronic address: larabossc@gmail.com.
authors.forename: Lara
authors.initials: L
authors.lastname: Bossini-Castillo
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Gorlova
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
authors.forename: José Ezequiel
authors.initials: JE
authors.lastname: Martin
authors.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei V
authors.initials: WV
authors.lastname: Chen
authors.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Filemon K
authors.initials: FK
authors.lastname: Tan
authors.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.affiliation: Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guerra
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Teruel
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
authors.forename: Francisco David
authors.initials: FD
authors.lastname: Carmona
authors.affiliation: The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: López-Isac
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
authors.forename: Eguzkine
authors.initials: E
authors.lastname: Ochoa
authors.affiliation: Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid 28041, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Carreira
authors.affiliation: Department of Internal Medicine, Hospital Valle de Hebrón, Barcelona 08035, Spain.
authors.forename: Carmen Pilar
authors.initials: CP
authors.lastname: Simeón
authors.affiliation: Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Castellví
authors.affiliation: Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, Santander 39008, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: González-Gay
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen 9700, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, 171 76 Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Área de Variabilidad del ADN Humano, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica, Granada 18016, Spain; Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Alarcón-Riquelme
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen 9700, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4072, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan 20122, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beretta
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin 10117, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.affiliation: Department of Clinical Immunology, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50924, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hunzelmann
authors.affiliation: Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital, Oberhausen 46045, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kreuter
authors.affiliation: Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.affiliation: Department of Rheumatology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.affiliation: Department of Rheumatology and Pathology and Central Medical Immunology Laboratory, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
authors.forename: Annemie J
authors.initials: AJ
authors.lastname: Schuerwegh
authors.affiliation: Department of Rheumatology, Lund University, Lund 221 85, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Hesselstrand
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, 171 76 Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Nordin
authors.affiliation: Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia 25123, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Airó
authors.affiliation: Department of Medicine, Universita degli Studi di Verona, Verona 37134, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.affiliation: Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Shiels
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
authors.affiliation: Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
authors.forename: Ariane
authors.initials: A
authors.lastname: Herrick
authors.affiliation: Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Denton
authors.affiliation: Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Wigley
authors.affiliation: Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Hummers
authors.affiliation: Division of Rheumatology, Northwestern University, Chicago, IL 60611, USA.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Division of Rheumatology, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Hinchcliff
authors.affiliation: Department of Rheumatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
authors.forename: Murray
authors.initials: M
authors.lastname: Baron
authors.affiliation: Department of Rheumatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Hudson
authors.affiliation: Division of Rheumatology, University of Western Ontario, London, ON N6A 4V2, Canada.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Pope
authors.affiliation: Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA 90095-1670, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.affiliation: Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Phillips
authors.affiliation: Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Schiopu
authors.affiliation: Division of Rheumatology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Segal
authors.affiliation: Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Molitor
authors.affiliation: Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Silver
authors.affiliation: Division of Rheumatology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Virginia D
authors.initials: VD
authors.lastname: Steen
authors.affiliation: Division of Rheumatology, Boston University, Boston, MA 02118, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Simms
authors.affiliation: Division of Rheumatology, Boston University, Boston, MA 02118, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lafyatis
authors.affiliation: Division of Rheumatology, University of Alabama Birmingham, Birmingham, AL 35294-3408, USA.
authors.forename: Barri J
authors.initials: BJ
authors.lastname: Fessler
authors.affiliation: Division of Rheumatology, University of Utah, Salt Lake City, UT 84132-2101, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Frech
authors.affiliation: Department of Rheumatology, Carolinas Healthcare System, Charlotte, NC 28211, USA.
authors.forename: Firas
authors.initials: F
authors.lastname: Alkassab
authors.affiliation: Department of Rheumatology, The Moncton Hospital, Moncton, NB E1C 6Z8, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Docherty
authors.affiliation: Rheumatology Section, Department of Medicine, Alberta Health Services, Calgary, AB T2N 2T9, Canada.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kaminska
authors.affiliation: Division of Rheumatology, Department of Medicine, McMaster University, Hamilton, ON L8N 1Y2, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: Khalidi
authors.affiliation: Department of Rheumatology, University of Edmonton, Edmonton, AB T5M 0H4, Canada.
authors.forename: Henry Niall
authors.initials: HN
authors.lastname: Jones
authors.affiliation: Department of Rheumatology, University of Saskatchewan, Saskatoon, SK S7K 0H6, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Markland
authors.affiliation: Department of Rheumatology, Arthritis Center, University of Manitoba, Winnipeg, MB R3A 1M4, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Robinson
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HC, the Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Broen
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HC, the Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fonseca
authors.affiliation: Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
authors.forename: Bobby P
authors.initials: BP
authors.lastname: Koeleman
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
mesh_terms: D000483:Alleles; D000071187:Autophagy-Related Protein 5; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D046208:Microchip Analytical Procedures; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D002352:Carrier Proteins; D006680:HLA Antigens; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; C405019:SCHIP1 protein, human; C485421:DNASE1L3 protein, human; D004706:Endodeoxyribonucleases; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases