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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

  • 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
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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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