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

Gomez-Fernandez, Paloma; de Lapuente Portilla, Aitzkoa Lopez; Astobiza, Ianire; Mena, Jorge; Urtasun, Andoni; Altmann, Vivian; Matesanz, Fuencisla; Otaegui, David; Urcelay, Elena; Antiguedad, Alfredo; Malhotra, Sunny; Montalban, Xavier; Castillo-Trivino, Tamara; Espino-Paisan, Laura; Aktas, Orhan; Buttmann, Mathias; Chan, Andrew; Fontaine, Bertrand; Gourraud, Pierre-Antoine; Hecker, Michael; Hoffjan, Sabine; Kubisch, Christian; Kuempfel, Tania; Luessi, Felix; Zettl, Uwe K.; Zipp, Frauke; Alloza, Iraide; Comabella, Manuel; Lill, Christina M. und Vandenbroeck, Koen (2020): 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. In: Cells, Bd. 9, Nr. 1, 175

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 x 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch