The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis

Research output: Contribution to journalArticle

Abstract

The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.

Details

Authors
  • Paloma Gómez-Fernández
  • Ianire Astobiza
  • Jorge Mena
  • Andoni Urtasun
  • Vivian Altmann
  • Fuencisla Matesanz
  • David Otaegui
  • Elena Urcelay
  • Alfredo Antigüedad
  • Sunny Malhotra
  • Xavier Montalban
  • Tamara Castillo-Triviño
  • Laura Espino-Paisán
  • Orhan Aktas
  • Mathias Buttmann
  • Andrew Chan
  • Bertrand Fontaine
  • Pierre-Antoine Gourraud
  • Michael Hecker
  • Sabine Hoffjan
  • Christian Kubisch
  • Tania Kümpfel
  • Felix Luessi
  • Uwe K Zettl
  • Frauke Zipp
  • Iraide Alloza
  • Manuel Comabella
  • Christina M Lill
  • Koen Vandenbroeck
Organisations
External organisations
  • University Heart Center Lübeck
  • Uppsala University
  • Biodonostia Health Research Institute
  • Hospital Clinico San Carlos de Madrid
  • Hospital de Cruces
  • Vall d'Hebron University Hospital
  • Heinrich Heine University Düsseldorf
  • Julius Maximilian University of Würzburg
  • Bern University Hospital
  • University of Paris III: Sorbonne Nouvelle
  • University of Nantes
  • Universitätsmedizin Rostock
  • Ruhr-University Bochum
  • University Medical Center Hamburg-Eppendorf
  • Ludwig-Maximilian University of Munich
  • University of the Basque Country
  • University of Mainz
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Endocrinology and Diabetes

Keywords

  • Adult, Amino Acid Sequence, Computer Simulation, Databases, Genetic, Gene Frequency/genetics, Genetic Predisposition to Disease, HEK293 Cells, Humans, Middle Aged, Multiple Sclerosis/genetics, Polymorphism, Single Nucleotide/genetics, Protein Isoforms/genetics, Protein Sorting Signals/genetics, Receptors, Interleukin/chemistry, Risk Factors
Original languageEnglish
JournalCells
Volume9
Issue number1
Publication statusPublished - 2020 Jan 10
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

These authors contributed equally to this paper: Paloma Gómez-Fernández; Aitzkoa Lopez de Lapuente Portilla