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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

Authors
  • gómez-fernández, paloma
  • de lapuente portilla, aitzkoa lopez
  • astobiza, ianire
  • mena, jorge
  • urtasun, andoni
  • altmann, vivian
  • matesanz, fuencisla
  • otaegui, david
  • urcelay, elena
  • antigüedad, alfredo
  • malhotra, sunny
  • montalban, xavier
  • castillo-triviño, tamara
  • espino-paisán, laura
  • aktas, orhan
  • buttmann, mathias
  • chan, andrew
  • fontaine, bertrand
  • gourraud, pierre-antoine
  • hecker, michael
  • And 10 more
Publication Date
Jan 10, 2020
Source
MDPI
Keywords
Language
English
License
Green
External links

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 &times / 10&minus / 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%&ndash / 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.

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