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 - Centre de Recherche en Transplantation et Immunologie Accéder directement au contenu
Article Dans Une Revue Cells Année : 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

Fuencisla Matesanz
David Otaegui
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  • PersonId : 1139633
Sunny Malhotra
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  • PersonId : 1119227
Xavier Montalban
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  • PersonId : 1119228
Mathias Buttmann
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  • PersonId : 1139636
Andrew Chan
Michael Hecker
Uwe K Zettl
Manuel Comabella
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Résumé

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.

Domaines

Immunologie
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Origine : Publication financée par une institution

Dates et versions

hal-03464472 , version 1 (03-12-2021)

Identifiants

Citer

Paloma Gómez-Fernández, Aitzkoa Lopez de Lapuente Portilla, Ianire Astobiza, Jorge Mena, Andoni Urtasun, et al.. 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 (1), pp.175. ⟨10.3390/cells9010175⟩. ⟨hal-03464472⟩
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