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  • Gómez-Fernández, PalomaUniversity of the Basque Country (author)

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

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2020-01-10
  • MDPI AG,2020

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:cda303bc-6eef-4a68-9a91-975a89df9463
  • https://lup.lub.lu.se/record/cda303bc-6eef-4a68-9a91-975a89df9463URI
  • https://doi.org/10.3390/cells9010175DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Lopez de Lapuente Portilla, AitzkoaLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,University of the Basque Country(Swepub:lu)med-azl (author)
  • Astobiza, IanireUniversity of the Basque Country (author)
  • Mena, JorgeUniversity of the Basque Country (author)
  • Urtasun, AndoniUniversity of the Basque Country (author)
  • Altmann, VivianUniversity Heart Center Lübeck (author)
  • Matesanz, FuencislaUppsala University (author)
  • Otaegui, DavidBiodonostia Health Research Institute (author)
  • Urcelay, ElenaHospital Clinico San Carlos de Madrid (author)
  • Antigüedad, AlfredoHospital de Cruces (author)
  • Malhotra, SunnyVall d'Hebron University Hospital (author)
  • Montalban, XavierVall d'Hebron University Hospital (author)
  • Castillo-Triviño, TamaraBiodonostia Health Research Institute (author)
  • Espino-Paisán, LauraHospital Clinico San Carlos de Madrid (author)
  • Aktas, OrhanHeinrich Heine University Düsseldorf (author)
  • Buttmann, MathiasJulius Maximilian University of Würzburg (author)
  • Chan, AndrewBern University Hospital (author)
  • Fontaine, BertrandUniversity of Paris III: Sorbonne Nouvelle (author)
  • Gourraud, Pierre-AntoineUniversity of Nantes (author)
  • Hecker, MichaelUniversitätsmedizin Rostock (author)
  • Hoffjan, SabineRuhr-University Bochum (author)
  • Kubisch, ChristianUniversity Medical Center Hamburg-Eppendorf (author)
  • Kümpfel, TaniaLudwig-Maximilian University of Munich (author)
  • Luessi, FelixJohannes-Gutenberg University Mainz (author)
  • Zettl, Uwe KUniversitätsmedizin Rostock (author)
  • Zipp, FraukeJohannes-Gutenberg University Mainz (author)
  • Alloza, IraideUniversity of the Basque Country (author)
  • Comabella, ManuelVall d'Hebron University Hospital (author)
  • Lill, Christina MUniversity Heart Center Lübeck (author)
  • Vandenbroeck, KoenUniversity of the Basque Country (author)
  • University of the Basque CountryAvdelningen för hematologi och transfusionsmedicin (creator_code:org_t)

Related titles

  • In:Cells: MDPI AG9:12073-4409

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