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
Gómez-Fernández, Paloma (University of the Basque Country)
Lopez de Lapuente Portilla, Aitzkoa (Lund University)
Astobiza, Ianire (University of the Basque Country)
Mena, Jorge (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Urtasun, Andoni (University of the Basque Country)
Altmann, Vivian (University of Lübeck)
Matesanz, Fuencisla (Instituto de Parasitología y Biomedicina "López-Neyra")
Otaegui, David (Biodonostia Osasun Ikerketako Institutura (País Basc))
Urcelay, Elena (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Antigüedad, Alfredo (Hospital Universitario de Cruces (Barakaldo, País Basc))
Malhotra, Sunny (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Montalban, Xavier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Castillo-Triviño, Tamara (Biodonostia Osasun Ikerketako Institutura (País Basc))
Espino-Paisan, Laura (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Aktas, Orhan (Heinrich-Heine University Düsseldorf)
Buttmann, Mathias (Caritas Hospital)
Chan, Andrew (Bern University Hospital)
Fontaine, Bertrand (University Hospital Pitié-Salpêtrière)
Gourraud, Pierre-Antoine (CHU de Nantes)
Hecker, Michael (University of Rostock)
Hoffjan, Sabine (Ruhr-University Bochum)
Kubisch, Christian (University Medical Center Hamburg-Eppendorf)
Kümpfel, Tania (Ludwig-Maximilians University)
Luessi, Felix (University Medical Center of the Johannes Gutenberg University Mainz)
Zettl, Uwe K. (University of Rostock)
Zipp, Frauke (University Medical Center of the Johannes Gutenberg University Mainz)
Alloza, Iraide (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Comabella, Manuel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Lill, Christina M. (Imperial College)
Vandenbroeck, Koen (Ikerbasque)
Universitat Autònoma de Barcelona

Date:	2020
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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	IL22RA2 ; IL-22 binding protein isoform ; Mutation ; Signal peptide ; Multiple sclerosis ; Autoimmune
Published in:	Cells, Vol. 9 (january 2020) , ISSN 2073-4409

DOI: 10.3390/cells9010175
PMID: 31936765

23 p, 7.5 MB

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