A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs
Wouter J. Venema,
Sanne Hiddingh,
Jorg van Loosdregt,
John Bowes,
Brunilda Balliu,
Joke H. de Boer,
Jeannette Ossewaarde-van Norel,
Susan D. Thompson,
Carl D. Langefeld,
Aafke de Ligt,
Lars T. van der Veken,
Peter H.L. Krijger,
Wouter de Laat,
Jonas J.W. Kuiper
Affiliations
Wouter J. Venema
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Sanne Hiddingh
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Jorg van Loosdregt
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
John Bowes
Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
Brunilda Balliu
Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Joke H. de Boer
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Jeannette Ossewaarde-van Norel
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Susan D. Thompson
Department of Pediatrics, University of Cincinnati College of Medicine, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Carl D. Langefeld
Department of Biostatistics and Data Science, and Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Aafke de Ligt
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Lars T. van der Veken
Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Peter H.L. Krijger
Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands
Wouter de Laat
Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands
Jonas J.W. Kuiper
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Corresponding author
Summary: Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
