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

doi:10.1016/j.xgen.2023.100460

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Cell Genom. 2024 Jan 10;4(1):100460. doi: 10.1016/j.xgen.2023.100460. Epub 2023 Dec 5.

Affiliations

¹ 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.
² Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
³ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
⁴ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁶ Department of Pediatrics, University of Cincinnati College of Medicine, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ Department of Biostatistics and Data Science, and Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁸ Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁹ Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
¹⁰ 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. Electronic address: j.j.w.kuiper@umcutrecht.nl.

Abstract

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.

Keywords: ERAP2; GWAS; SNP; alternative splicing; autoimmunity; birdshot; eQTL; haplotype; rs2248374.

MeSH terms

Aminopeptidases / genetics
Autoimmune Diseases* / genetics
Genetic Predisposition to Disease / genetics
Humans
Polymorphism, Single Nucleotide* / genetics
Promoter Regions, Genetic / genetics

Substances

ERAP2 protein, human
Aminopeptidases