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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.


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.

SUBMITTER: Gomez-Fernandez P 

PROVIDER: S-EPMC7017210 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The Rare <i>IL22RA2</i> 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 P   Lopez de Lapuente Portilla Aitzkoa A   Astobiza Ianire I   Mena Jorge J   Urtasun Andoni A   Altmann Vivian V   Matesanz Fuencisla F   Otaegui David D   Urcelay Elena E   Antigüedad Alfredo A   Malhotra Sunny S   Montalban Xavier X   Castillo-Triviño Tamara T   Espino-Paisán Laura L   Aktas Orhan O   Buttmann Mathias M   Chan Andrew A   Fontaine Bertrand B   Gourraud Pierre-Antoine PA   Hecker Michael M   Hoffjan Sabine S   Kubisch Christian C   Kümpfel Tania T   Luessi Felix F   Zettl Uwe K UK   Zipp Frauke F   Alloza Iraide I   Comabella Manuel M   Lill Christina M CM   Vandenbroeck Koen K  

Cells 20200110 1


The <i>IL22RA2</i> 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 (<i>p</i> = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by <i>IL22RA2</i> (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 a  ...[more]

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