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Am J Hum Genet. 2014 Jan 2;94(1):47-61. doi: 10.1016/j.ajhg.2013.12.002.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.

Author information

1
The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: maureen.d.mayes@uth.tmc.edu.
2
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain. Electronic address: larabossc@gmail.com.
3
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
5
The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
6
Centre for Rheumatology, University College London Medical School, London WC1E 6BT, UK.
7
The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
8
Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid 28041, Spain.
9
Department of Internal Medicine, Hospital Valle de Hebrón, Barcelona 08035, Spain.
10
Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain.
11
Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, Santander 39008, Spain.
12
Department of Genetics, University Medical Center Groningen, Groningen 9700, the Netherlands.
13
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, 171 76 Stockholm, Sweden.
14
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.
15
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4072, Australia.
16
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan 20122, Italy.
17
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin 10117, Germany.
18
Department of Clinical Immunology, Hannover Medical School, Hannover 30625, Germany.
19
Department of Dermatology, University of Cologne, Cologne 50924, Germany.
20
Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital, Oberhausen 46045, Germany.
21
Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
22
Department of Rheumatology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
23
Department of Rheumatology and Pathology and Central Medical Immunology Laboratory, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
24
Department of Rheumatology, Lund University, Lund 221 85, Sweden.
25
Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia 25123, Italy.
26
Department of Medicine, Universita degli Studi di Verona, Verona 37134, Italy.
27
Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G61 1BD, UK.
28
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
29
Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
30
Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA.
31
Division of Rheumatology, Northwestern University, Chicago, IL 60611, USA.
32
Department of Rheumatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
33
Division of Rheumatology, University of Western Ontario, London, ON N6A 4V2, Canada.
34
Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA 90095-1670, USA.
35
Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA.
36
Division of Rheumatology, University of Minnesota, Minneapolis, MN 55455, USA.
37
Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN 55455, USA.
38
Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
39
Division of Rheumatology, Georgetown University Medical Center, Washington, DC 20007, USA.
40
Division of Rheumatology, Boston University, Boston, MA 02118, USA.
41
Division of Rheumatology, University of Alabama Birmingham, Birmingham, AL 35294-3408, USA.
42
Division of Rheumatology, University of Utah, Salt Lake City, UT 84132-2101, USA.
43
Department of Rheumatology, Carolinas Healthcare System, Charlotte, NC 28211, USA.
44
Department of Rheumatology, The Moncton Hospital, Moncton, NB E1C 6Z8, Canada.
45
Rheumatology Section, Department of Medicine, Alberta Health Services, Calgary, AB T2N 2T9, Canada.
46
Division of Rheumatology, Department of Medicine, McMaster University, Hamilton, ON L8N 1Y2, Canada.
47
Department of Rheumatology, University of Edmonton, Edmonton, AB T5M 0H4, Canada.
48
Department of Rheumatology, University of Saskatchewan, Saskatoon, SK S7K 0H6, Canada.
49
Department of Rheumatology, Arthritis Center, University of Manitoba, Winnipeg, MB R3A 1M4, Canada.
50
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.
51
Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.

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.

PMID:
24387989
PMCID:
PMC3882906
DOI:
10.1016/j.ajhg.2013.12.002
[Indexed for MEDLINE]
Free PMC Article

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