PMID- 24387989 OWN - NLM STAT- MEDLINE DCOM- 20140224 LR - 20221207 IS - 1537-6605 (Electronic) IS - 0002-9297 (Print) IS - 0002-9297 (Linking) VI - 94 IP - 1 DP - 2014 Jan 2 TI - Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. PG - 47-61 LID - S0002-9297(13)00571-5 [pii] LID - 10.1016/j.ajhg.2013.12.002 [doi] AB - 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. CI - Copyright (c) 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. FAU - Mayes, Maureen D AU - Mayes MD AD - The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: maureen.d.mayes@uth.tmc.edu. FAU - Bossini-Castillo, Lara AU - Bossini-Castillo L AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. Electronic address: larabossc@gmail.com. FAU - Gorlova, Olga AU - Gorlova O AD - Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Martin, Jose Ezequiel AU - Martin JE AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. FAU - Zhou, Xiaodong AU - Zhou X AD - The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. FAU - Chen, Wei V AU - Chen WV AD - Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Assassi, Shervin AU - Assassi S AD - The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. FAU - Ying, Jun AU - Ying J AD - Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Tan, Filemon K AU - Tan FK AD - The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. FAU - Arnett, Frank C AU - Arnett FC AD - The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. FAU - Reveille, John D AU - Reveille JD AD - The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. FAU - Guerra, Sandra AU - Guerra S AD - Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK. FAU - Teruel, Maria AU - Teruel M AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. FAU - Carmona, Francisco David AU - Carmona FD AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. FAU - Gregersen, Peter K AU - Gregersen PK AD - The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA. FAU - Lee, Annette T AU - Lee AT AD - The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA. FAU - Lopez-Isac, Elena AU - Lopez-Isac E AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. FAU - Ochoa, Eguzkine AU - Ochoa E AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. FAU - Carreira, Patricia AU - Carreira P AD - Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid 28041, Spain. FAU - Simeon, Carmen Pilar AU - Simeon CP AD - Department of Internal Medicine, Hospital Valle de Hebron, Barcelona 08035, Spain. FAU - Castellvi, Ivan AU - Castellvi I AD - Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain. FAU - Gonzalez-Gay, Miguel Angel AU - Gonzalez-Gay MA AD - Department of Rheumatology, Hospital Universitario Marques de Valdecilla, Instituto de Formacion e Investigacion Marques de Valdecilla, Santander 39008, Spain. CN - Spanish Scleroderma Group FAU - Zhernakova, Alexandra AU - Zhernakova A AD - Department of Genetics, University Medical Center Groningen, Groningen 9700, the Netherlands. FAU - Padyukov, Leonid AU - Padyukov L AD - Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, 171 76 Stockholm, Sweden. FAU - Alarcon-Riquelme, Marta AU - Alarcon-Riquelme M AD - Area de Variabilidad del ADN Humano, Centro Pfizer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion Oncologica, Granada 18016, Spain; Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. FAU - Wijmenga, Cisca AU - Wijmenga C AD - Department of Genetics, University Medical Center Groningen, Groningen 9700, the Netherlands. FAU - Brown, Matthew AU - Brown M AD - University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4072, Australia. FAU - Beretta, Lorenzo AU - Beretta L AD - Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan 20122, Italy. FAU - Riemekasten, Gabriela AU - Riemekasten G AD - Department of Rheumatology and Clinical Immunology, Charite University Hospital, Berlin 10117, Germany. FAU - Witte, Torsten AU - Witte T AD - Department of Clinical Immunology, Hannover Medical School, Hannover 30625, Germany. FAU - Hunzelmann, Nicolas AU - Hunzelmann N AD - Department of Dermatology, University of Cologne, Cologne 50924, Germany. FAU - Kreuter, Alexander AU - Kreuter A AD - Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital, Oberhausen 46045, Germany. FAU - Distler, Jorg H W AU - Distler JH AD - Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen 91054, Germany. FAU - Voskuyl, Alexandre E AU - Voskuyl AE AD - Department of Rheumatology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands. FAU - Schuerwegh, Annemie J AU - Schuerwegh AJ AD - Department of Rheumatology and Pathology and Central Medical Immunology Laboratory, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. FAU - Hesselstrand, Roger AU - Hesselstrand R AD - Department of Rheumatology, Lund University, Lund 221 85, Sweden. FAU - Nordin, Annika AU - Nordin A AD - Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, 171 76 Stockholm, Sweden. FAU - Airo, Paolo AU - Airo P AD - Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia 25123, Italy. FAU - Lunardi, Claudio AU - Lunardi C AD - Department of Medicine, Universita degli Studi di Verona, Verona 37134, Italy. FAU - Shiels, Paul AU - Shiels P AD - Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G61 1BD, UK. FAU - van Laar, Jacob M AU - van Laar JM AD - Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. FAU - Herrick, Ariane AU - Herrick A AD - Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK. FAU - Worthington, Jane AU - Worthington J AD - Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK. FAU - Denton, Christopher AU - Denton C AD - Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK. FAU - Wigley, Fredrick M AU - Wigley FM AD - Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA. FAU - Hummers, Laura K AU - Hummers LK AD - Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA. FAU - Varga, John AU - Varga J AD - Division of Rheumatology, Northwestern University, Chicago, IL 60611, USA. FAU - Hinchcliff, Monique E AU - Hinchcliff ME AD - Division of Rheumatology, Northwestern University, Chicago, IL 60611, USA. FAU - Baron, Murray AU - Baron M AD - Department of Rheumatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada. FAU - Hudson, Marie AU - Hudson M AD - Department of Rheumatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada. FAU - Pope, Janet E AU - Pope JE AD - Division of Rheumatology, University of Western Ontario, London, ON N6A 4V2, Canada. FAU - Furst, Daniel E AU - Furst DE AD - Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA 90095-1670, USA. FAU - Khanna, Dinesh AU - Khanna D AD - Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Phillips, Kristin AU - Phillips K AD - Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Schiopu, Elena AU - Schiopu E AD - Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Segal, Barbara M AU - Segal BM AD - Division of Rheumatology, University of Minnesota, Minneapolis, MN 55455, USA. FAU - Molitor, Jerry A AU - Molitor JA AD - Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN 55455, USA. FAU - Silver, Richard M AU - Silver RM AD - Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA. FAU - Steen, Virginia D AU - Steen VD AD - Division of Rheumatology, Georgetown University Medical Center, Washington, DC 20007, USA. FAU - Simms, Robert W AU - Simms RW AD - Division of Rheumatology, Boston University, Boston, MA 02118, USA. FAU - Lafyatis, Robert A AU - Lafyatis RA AD - Division of Rheumatology, Boston University, Boston, MA 02118, USA. FAU - Fessler, Barri J AU - Fessler BJ AD - Division of Rheumatology, University of Alabama Birmingham, Birmingham, AL 35294-3408, USA. FAU - Frech, Tracy M AU - Frech TM AD - Division of Rheumatology, University of Utah, Salt Lake City, UT 84132-2101, USA. FAU - Alkassab, Firas AU - Alkassab F AD - Department of Rheumatology, Carolinas Healthcare System, Charlotte, NC 28211, USA. FAU - Docherty, Peter AU - Docherty P AD - Department of Rheumatology, The Moncton Hospital, Moncton, NB E1C 6Z8, Canada. FAU - Kaminska, Elzbieta AU - Kaminska E AD - Rheumatology Section, Department of Medicine, Alberta Health Services, Calgary, AB T2N 2T9, Canada. FAU - Khalidi, Nader AU - Khalidi N AD - Division of Rheumatology, Department of Medicine, McMaster University, Hamilton, ON L8N 1Y2, Canada. FAU - Jones, Henry Niall AU - Jones HN AD - Department of Rheumatology, University of Edmonton, Edmonton, AB T5M 0H4, Canada. FAU - Markland, Janet AU - Markland J AD - Department of Rheumatology, University of Saskatchewan, Saskatoon, SK S7K 0H6, Canada. FAU - Robinson, David AU - Robinson D AD - Department of Rheumatology, Arthritis Center, University of Manitoba, Winnipeg, MB R3A 1M4, Canada. FAU - Broen, Jasper AU - Broen J AD - 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. FAU - Radstake, Timothy R D J AU - Radstake TR AD - 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. FAU - Fonseca, Carmen AU - Fonseca C AD - Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK. FAU - Koeleman, Bobby P AU - Koeleman BP AD - Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands. FAU - Martin, Javier AU - Martin J AD - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18016, Spain. LA - eng GR - R01 AR051089/AR/NIAMS NIH HHS/United States GR - UL1 RR024148/RR/NCRR NIH HHS/United States GR - 3UL1RR024148/RR/NCRR NIH HHS/United States GR - UL1 TR000371/TR/NCATS NIH HHS/United States GR - P50 AR054144/AR/NIAMS NIH HHS/United States GR - N01-AR02251/AR/NIAMS NIH HHS/United States GR - U01 AI090909/AI/NIAID NIH HHS/United States GR - K23 AR060241/AR/NIAMS NIH HHS/United States GR - KL2 RR024149/RR/NCRR NIH HHS/United States GR - KL2RR024149-04/RR/NCRR NIH HHS/United States GR - P50 AR060780/AR/NIAMS NIH HHS/United States GR - K23 AR059763/AR/NIAMS NIH HHS/United States GR - N01AR02251/AR/NIAMS NIH HHS/United States GR - P50AR054144/AR/NIAMS NIH HHS/United States GR - R01 AR055258/AR/NIAMS NIH HHS/United States GR - 20385/ARC_/Arthritis Research UK/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Hum Genet JT - American journal of human genetics JID - 0370475 RN - 0 (ATG5 protein, human) RN - 0 (Autophagy-Related Protein 5) RN - 0 (Carrier Proteins) RN - 0 (HLA Antigens) RN - 0 (IL12A protein, human) RN - 0 (Interleukin-12 Subunit p35) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (SCHIP1 protein, human) RN - EC 3.1.- (DNASE1L3 protein, human) RN - EC 3.1.- (Endodeoxyribonucleases) RN - EC 3.6.1.- (DDX6 protein, human) RN - EC 3.6.4.13 (DEAD-box RNA Helicases) SB - IM MH - Alleles MH - Autophagy-Related Protein 5 MH - Carrier Proteins/genetics MH - Case-Control Studies MH - Chromosomes, Human, Pair 11/*genetics MH - Chromosomes, Human, Pair 3/*genetics MH - DEAD-box RNA Helicases/genetics MH - Endodeoxyribonucleases/genetics MH - Female MH - *Genetic Loci MH - *Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - Genotype MH - HLA Antigens/genetics MH - Humans MH - Interleukin-12 Subunit p35/genetics MH - Linkage Disequilibrium MH - Logistic Models MH - Male MH - Microchip Analytical Procedures MH - Microtubule-Associated Proteins/genetics MH - Polymorphism, Single Nucleotide MH - Proto-Oncogene Proteins/genetics MH - Risk Factors MH - Scleroderma, Systemic/*genetics MH - White People/genetics PMC - PMC3882906 FIR - Ortego-Centeno, Norberto IR - Ortego-Centeno N FIR - Rios, Raquel IR - Rios R FIR - Callejas, Jose Luis IR - Callejas JL FIR - Navarrete, Nuria IR - Navarrete N FIR - Garcia Portales, Rosa IR - Garcia Portales R FIR - Camps, Maria Teresa IR - Camps MT FIR - Fernandez-Nebro, Antonio IR - Fernandez-Nebro A FIR - Gonzalez-Escribano, Maria F IR - Gonzalez-Escribano MF FIR - Sanchez-Roman, Julio IR - Sanchez-Roman J FIR - Garcia-Hernandez, Francisco Jose IR - Garcia-Hernandez FJ FIR - Castillo, Maria Jesus IR - Castillo MJ FIR - Aguirre, Maria Angeles IR - Aguirre MA FIR - Gomez-Gracia, Inmaculada IR - Gomez-Gracia I FIR - Fernandez-Gutierrez, Benjamin IR - Fernandez-Gutierrez B FIR - Rodriguez-Rodriguez, Luis IR - Rodriguez-Rodriguez L FIR - Vicente, Esther IR - Vicente E FIR - Andreu, Jose Luis IR - Andreu JL FIR - Fernandez de Castro, Monica IR - Fernandez de Castro M FIR - Garcia de la Pena, Paloma IR - Garcia de la Pena P FIR - Lopez-Longo, Francisco Javier IR - Lopez-Longo FJ FIR - Martinez, Lina IR - Martinez L FIR - Fonollosa, Vicente IR - Fonollosa V FIR - Espinosa, Gerard IR - Espinosa G FIR - Tolosa, Carlos IR - Tolosa C FIR - Pros, Anna IR - Pros A FIR - Rodriguez Carballeira, Monica IR - Rodriguez Carballeira M FIR - Narvaez, Francisco Javier IR - Narvaez FJ FIR - Rubio Rivas, Manel IR - Rubio Rivas M FIR - Ortiz Santamaria, Vera IR - Ortiz Santamaria V FIR - Diaz, Bernardino IR - Diaz B FIR - Trapiella, Luis IR - Trapiella L FIR - Freire, Maria Del Carmen IR - Freire Mdel C FIR - Sousa, Adrian IR - Sousa A FIR - Egurbide, Maria Victoria IR - Egurbide MV FIR - Fanlo Mateo, Patricia IR - Fanlo Mateo P FIR - Saez-Comet, Luis IR - Saez-Comet L FIR - Diaz, Federico IR - Diaz F FIR - Hernandez, Vanesa IR - Hernandez V FIR - Beltran, Emma IR - Beltran E FIR - Roman-Ivorra, Jose Andres IR - Roman-Ivorra JA FIR - Grau, Elena IR - Grau E FIR - Alegre Sancho, Juan Jose IR - Alegre Sancho JJ FIR - Blanco Garcia, Francisco J IR - Blanco Garcia FJ FIR - Oreiro, Natividad IR - Oreiro N FIR - Fernandez Sueiro, Luis IR - Fernandez Sueiro L EDAT- 2014/01/07 06:00 MHDA- 2014/02/25 06:00 PMCR- 2014/07/02 CRDT- 2014/01/07 06:00 PHST- 2013/07/19 00:00 [received] PHST- 2013/12/03 00:00 [accepted] PHST- 2014/01/07 06:00 [entrez] PHST- 2014/01/07 06:00 [pubmed] PHST- 2014/02/25 06:00 [medline] PHST- 2014/07/02 00:00 [pmc-release] AID - S0002-9297(13)00571-5 [pii] AID - 10.1016/j.ajhg.2013.12.002 [doi] PST - ppublish SO - Am J Hum Genet. 2014 Jan 2;94(1):47-61. doi: 10.1016/j.ajhg.2013.12.002.