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Cells. 2020 Jan 10;9(1). pii: E175. doi: 10.3390/cells9010175.

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.

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Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
Department of Laboratory Medicine, Lund University, SE-221 00 Lund, Sweden.
Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain.
Genetic and Molecular Epidemiology Group, Lübeck Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, 23552 Lübeck, Germany.
Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, 18002 Granada, Spain.
Multiple Sclerosis Group, Biodonostia Research Institute, Paseo Doctor Begiristain, s/n, 20014 San Sebastián, Spain.
Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, 28014 Madrid, Spain.
Department of Neurology, Cruces Hospital, S/N, 48903 Barakaldo, Spain.
Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08007 Barcelona, Spain.
Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Department of Neurology, University of Wuerzburg, 97080 Wuerzburg, Germany.
Department of Neurology, Caritas Hospital, 97980 Bad Mergentheim, Germany.
Department of Neurology, Inselspital Bern, Bern University Hospital, University of Bern, 3011 Bern, Switzerland.
INSERM, Sorbonne University, Assistance Publique-Hopitaux de Paris (AP-HP), UMR 974 and Neuro-Myology Service, University Hospital Pitié-Salpêtrière, 75013 Paris, France.
Nantes Université, CHU, INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ATIP-Avenir, Equipe 5, 44093 Nantes, France.
CHU de Nantes, INSERM, CIC 1413, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des données, 44000 Nantes, France.
Department of Neurology, Neuroimmunological Section, University of Rostock, 18147 Rostock, Germany.
Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Institute of Clinical Neuroimmunology, Ludwig-Maximilians University, 80333 Munich, Germany.
Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, 55116 Mainz, Germany.
Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck, 23552 Lübeck, Germany.
Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London SW71, UK.
Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.


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.


IL-22 binding protein isoform; IL22RA2; autoimmune; multiple sclerosis; mutation; signal peptide

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