Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.
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.
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. Electronic address: guthridgej@omrf.org.
Joel M
JM
Guthridge
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.
Rufei
R
Lu
Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA.
Harry
H
Sun
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Celi
C
Sun
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Graham B
GB
Wiley
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Nicolas
N
Dominguez
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Susan R
SR
Macwana
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Christopher J
CJ
Lessard
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Xana
X
Kim-Howard
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Beth L
BL
Cobb
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
Kenneth M
KM
Kaufman
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Jennifer A
JA
Kelly
Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27106, USA.
Carl D
CD
Langefeld
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Adam J
AJ
Adler
Division of Molecular Immunology and Graduate Program in Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Isaac T W
IT
Harley
Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Joan T
JT
Merrill
Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
Gary S
GS
Gilkeson
Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
Diane L
DL
Kamen
Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN 55902, USA.
Timothy B
TB
Niewold
Department of Epidemiology, University of Alabama-Birmingham, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama-Birmingham, Birmingham, AL 35294, USA.
Elizabeth E
EE
Brown
Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294, USA.
Jeffery C
JC
Edberg
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Michelle A
MA
Petri
Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Rosalind
R
Ramsey-Goldman
Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX.77030, USA.
John D
JD
Reveille
Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan 00921, Puerto Rico.
Luis M
LM
Vilá
Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294, USA.
Robert P
RP
Kimberly
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
Barry I
BI
Freedman
Division of Rheumatology, Department of Pediatrics, University of Washington Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Anne M
AM
Stevens
Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.
Susan A
SA
Boackle
Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA 94143, USA.
Lindsey A
LA
Criswell
Division of Medicine, Imperial College of London, London SW7 2AZ, UK.
Tim J
TJ
Vyse
Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA.
Timothy W
TW
Behrens
Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Chaim O
CO
Jacob
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.
Marta E
ME
Alarcón-Riquelme
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Kathy L
KL
Sivils
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea.
Jiyoung
J
Choi
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea.
Young Bin
YB
Joo
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea.
So-Young
SY
Bang
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea.
Hye-Soon
HS
Lee
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea.
Sang-Cheol
SC
Bae
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.
Nan
N
Shen
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.
Xiaoxia
X
Qian
Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Betty P
BP
Tsao
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.
R Hal
RH
Scofield
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
John B
JB
Harley
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.
Carol F
CF
Webb
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Edward K
EK
Wakeland
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.
Judith A
JA
James
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Swapan K
SK
Nath
Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA.
Robert R
RR
Graham
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Patrick M
PM
Gaffney
D000483:Alleles; D002898:Chromosomes, Human, Pair 8; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D019061:src-Family Kinases / Q000235:genetics*
C584409:BLK protein, human; D019061:src-Family Kinases