Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Hum Mol Genet. 2018 Apr 18. doi: 10.1093/hmg/ddy140. [Epub ahead of print]

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, United States of America.
2
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
3
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, United States of America.
4
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45220, United States of America.
5
Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
6
Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, United States of America.
7
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United States of America.
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, United States of America.
10
Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, WA, 98195, United States of America.
11
Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, United States of America.
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, United States of America.
14
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, United States of America.
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, United States of America.
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, United States of America.
19
Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, 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, United States of America.
22
Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143-0500, United States of America.
23
Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States of America.
24
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, United States of America.
25
United States Department of Veterans Affairs Medical Center, Oklahoma City, OK, 73104, United States of America.
26
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, United States of America.
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, United States of America.
29
Divisions of Genetics/Molecular Medicine and Immunology, King's College London, Guy's Hospital, London, SE1 9RT, United Kingdom.
30
Division of Rheumatology, Department of Pathology, New York University, New York, NY 10016, United States of America.
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, United States of America.
33
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, United States of America.
34
Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucia, Parque Tecnológica de la Salud, Granada, 18016, Spain.
35
United States Department of Veterans Affairs Medical Center, Cincinnati, OH, 45220, United States of America.
36
Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.

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 to 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.

PMID:
29912393
PMCID:
PMC6005081
[Available on 2019-07-01]
DOI:
10.1093/hmg/ddy140

Grant support

Grant support

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center