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Hum Mol Genet. 2018 Jul 1;27(13):2392-2404. doi: 10.1093/hmg/ddy140.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Author information

1
Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
2
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
3
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
4
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
5
Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
7
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
8
Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China.
9
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
10
Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
11
Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
12
Servicio de Reumatología, Sanatorio Parque, Rosario 2000, Santa Fe, Argentina.
13
Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
14
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
15
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, United States of America.
16
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
17
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18001-18016, Spain.
18
Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
19
Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota 111711, Colombia.
20
Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, United States of America.
21
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
22
Department of Medicine, Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA 94143-0500, USA.
23
Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA.
24
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
25
United States Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
26
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
27
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea.
28
Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
29
Divisions of Genetics/Molecular Medicine and Immunology, King's College London, Guy's Hospital, London SE1 9RT, UK.
30
Division of Rheumatology, Department of Pathology, New York University, New York, NY 10016, USA.
31
Division of Rheumatology, The Hospital for Sick Children, Hospital for Sick Research Institute, University of Toronto, Toronto, ON M5G 1X8, Canada.
32
Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
33
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
34
Unit of Chronic Inflammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17167, Sweden.
35
Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucia, Parque Tecnológica de la Salud, Granada 18016, Spain.
36
United States Department of Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
37
Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Abstract

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

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