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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

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
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cells 2020, 9(1), 175;
Received: 10 December 2019 / Revised: 29 December 2019 / Accepted: 3 January 2020 / Published: 10 January 2020
(This article belongs to the Special Issue The Molecular and Cellular Basis for Multiple Sclerosis 2020)
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. View Full-Text
Keywords: IL22RA2; IL-22 binding protein isoform; mutation; signal peptide; multiple sclerosis; autoimmune IL22RA2; IL-22 binding protein isoform; mutation; signal peptide; multiple sclerosis; autoimmune
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Gómez-Fernández, P.; Lopez de Lapuente Portilla, A.; Astobiza, I.; Mena, J.; Urtasun, A.; Altmann, V.; Matesanz, F.; Otaegui, D.; Urcelay, E.; Antigüedad, A.; Malhotra, S.; Montalban, X.; Castillo-Triviño, T.; Espino-Paisán, L.; Aktas, O.; Buttmann, M.; Chan, A.; Fontaine, B.; Gourraud, P.-A.; Hecker, M.; Hoffjan, S.; Kubisch, C.; Kümpfel, T.; Luessi, F.; Zettl, U.K.; Zipp, F.; Alloza, I.; Comabella, M.; Lill, C.M.; Vandenbroeck, K. 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. Cells 2020, 9, 175.

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