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Am J Hum Genet. 2014 Apr 3;94(4):586-98. doi: 10.1016/j.ajhg.2014.03.008.

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Author information

1
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. Electronic address: guthridgej@omrf.org.
2
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
3
Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA.
4
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
5
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
7
Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27106, USA.
8
Division of Molecular Immunology and Graduate Program in Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
9
Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
10
Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
11
Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN 55902, USA.
12
Department of Epidemiology, University of Alabama-Birmingham, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama-Birmingham, Birmingham, AL 35294, USA.
13
Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294, USA.
14
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
15
Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
16
Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX.77030, USA.
17
Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan 00921, Puerto Rico.
18
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
19
Division of Rheumatology, Department of Pediatrics, University of Washington Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
20
Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.
21
Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA 94143, USA.
22
Division of Medicine, Imperial College of London, London SW7 2AZ, UK.
23
Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
24
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Centro de Genómica e Investigaciones Oncológicas (GENYO). Pfizer-Universidad de Granada-Junta de Andalucía, Granada 18016, Spain.
25
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea.
26
Molecular Rheumatology Laboratory, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
27
Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
28
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73105, USA; United States Department of Veterans Affairs Medical Center, Oklahoma City, OK 73105, USA.
29
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Cell Biology and Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
30
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
31
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73105, USA.

Abstract

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

PMID:
24702955
PMCID:
PMC3980411
DOI:
10.1016/j.ajhg.2014.03.008
[Indexed for MEDLINE]
Free PMC Article

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