title: Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression.
abstract: Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.
authors: Immunology Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Xiaoming
authors: X
authors: Lu
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Erin E
authors: EE
authors: Zoller
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Matthew T
authors: MT
authors: Weirauch
authors: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Zhiguo
authors: Z
authors: Wu
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Bahram
authors: B
authors: Namjou
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
authors: Adrienne H
authors: AH
authors: Williams
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
authors: Julie T
authors: JT
authors: Ziegler
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
authors: Mary E
authors: ME
authors: Comeau
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
authors: Miranda C
authors: MC
authors: Marion
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Stuart B
authors: SB
authors: Glenn
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Adam
authors: A
authors: Adler
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Joint Molecular Rheumatology Laboratory, Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine in collaboration with Shanghai Institutes for Biological Sciences and Chinese Academy of Sciences, Shanghai 200031, PRC.
authors: Nan
authors: N
authors: Shen
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Swapan K
authors: SK
authors: Nath
authors: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Anne M
authors: AM
authors: Stevens
authors: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
authors: Barry I
authors: BI
authors: Freedman
authors: Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
authors: Betty P
authors: BP
authors: Tsao
authors: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors: Chaim O
authors: CO
authors: Jacob
authors: Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Diane L
authors: DL
authors: Kamen
authors: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Elizabeth E
authors: EE
authors: Brown
authors: Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Gary S
authors: GS
authors: Gilkeson
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Graciela S
authors: GS
authors: Alarcón
authors: Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: John D
authors: JD
authors: Reveille
authors: Center for Autoimmune Diseases Research, Universidad del Rosario, 110010 Bogota, Colombia.
authors: Juan-Manuel
authors: JM
authors: Anaya
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Judith A
authors: JA
authors: James
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Kathy L
authors: KL
authors: Sivils
authors: Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94117, USA.
authors: Lindsey A
authors: LA
authors: Criswell
authors: Division of Rheumatology, Department of Medicine, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
authors: Luis M
authors: LM
authors: Vilá
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucia, Granada 18016, Spain.
authors: Marta E
authors: ME
authors: Alarcón-Riquelme
authors: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors: Michelle
authors: M
authors: Petri
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors: R Hal
authors: RH
authors: Scofield
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Robert P
authors: RP
authors: Kimberly
authors: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors: Rosalind
authors: R
authors: Ramsey-Goldman
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Korea.
authors: Young Bin
authors: YB
authors: Joo
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Korea.
authors: Jeongim
authors: J
authors: Choi
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Korea.
authors: Sang-Cheol
authors: SC
authors: Bae
authors: Division of Rheumatology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors: Susan A
authors: SA
authors: Boackle
authors: Divisions of Genetics and Molecular Medicine and Immunology, King's College London, Strand, London WC2R 2LS, UK.
authors: Deborah Cunninghame
authors: DC
authors: Graham
authors: Divisions of Genetics and Molecular Medicine and Immunology, King's College London, Strand, London WC2R 2LS, UK.
authors: Timothy J
authors: TJ
authors: Vyse
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Joel M
authors: JM
authors: Guthridge
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Patrick M
authors: PM
authors: Gaffney
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
authors: Carl D
authors: CD
authors: Langefeld
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Jennifer A
authors: JA
authors: Kelly
authors: Cancer Biology, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors: Kenneth D
authors: KD
authors: Greis
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
authors: Kenneth M
authors: KM
authors: Kaufman
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
authors: John B
authors: JB
authors: Harley
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA. Electronic address: leah.kottyan@cchmc.org.
authors: Leah C
authors: LC
authors: Kottyan
mesh_terms: D000483:Alleles; D000818:Animals; D044466:Asian People; D001499:Bayes Theorem; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D051379:Mice; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D050794:STAT1 Transcription Factor