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The Rare IL22RA2 Si...
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
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- Gómez-Fernández, Paloma (author)
- University of the Basque Country
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- Lopez de Lapuente Portilla, Aitzkoa (author)
- Lund 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
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- Astobiza, Ianire (author)
- University of the Basque Country
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- Mena, Jorge (author)
- University of the Basque Country
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- Urtasun, Andoni (author)
- University of the Basque Country
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- Altmann, Vivian (author)
- University Heart Center Lübeck
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- Matesanz, Fuencisla (author)
- Uppsala University
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- Otaegui, David (author)
- Biodonostia Health Research Institute
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- Urcelay, Elena (author)
- Hospital Clinico San Carlos de Madrid
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- Antigüedad, Alfredo (author)
- Hospital de Cruces
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- Malhotra, Sunny (author)
- Vall d'Hebron University Hospital
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- Montalban, Xavier (author)
- Vall d'Hebron University Hospital
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- Castillo-Triviño, Tamara (author)
- Biodonostia Health Research Institute
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- Espino-Paisán, Laura (author)
- Hospital Clinico San Carlos de Madrid
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- Aktas, Orhan (author)
- Heinrich Heine University Düsseldorf
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- Buttmann, Mathias (author)
- Julius Maximilian University of Würzburg
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- Chan, Andrew (author)
- Bern University Hospital
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- Fontaine, Bertrand (author)
- University of Paris III: Sorbonne Nouvelle
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- Gourraud, Pierre-Antoine (author)
- University of Nantes
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- Hecker, Michael (author)
- Universitätsmedizin Rostock
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- Hoffjan, Sabine (author)
- Ruhr-University Bochum
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- Kubisch, Christian (author)
- University Medical Center Hamburg-Eppendorf
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- Kümpfel, Tania (author)
- Ludwig-Maximilian University of Munich
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- Luessi, Felix (author)
- Johannes-Gutenberg University Mainz
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- Zettl, Uwe K (author)
- Universitätsmedizin Rostock
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- Zipp, Frauke (author)
- Johannes-Gutenberg University Mainz
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- Alloza, Iraide (author)
- University of the Basque Country
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- Comabella, Manuel (author)
- Vall d'Hebron University Hospital
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- Lill, Christina M (author)
- University Heart Center Lübeck
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- Vandenbroeck, Koen (author)
- University of the Basque Country
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(creator_code:org_t)
- 2020-01-10
- 2020
- English.
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In: Cells. - : MDPI AG. - 2073-4409. ; 9:1
- Related links:
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https://www.mdpi.com...
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Abstract
Subject headings
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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 × 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
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- Adult
- Amino Acid Sequence
- Computer Simulation
- Databases, Genetic
- Gene Frequency/genetics
- Genetic Predisposition to Disease
- HEK293 Cells
- Humans
- Middle Aged
- Multiple Sclerosis/genetics
- Polymorphism, Single Nucleotide/genetics
- Protein Isoforms/genetics
- Protein Sorting Signals/genetics
- Receptors, Interleukin/chemistry
- Risk Factors
Publication and Content Type
- art (subject category)
- ref (subject category)
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Gómez-Fernández, ...
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Lopez de Lapuent ...
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Astobiza, Ianire
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Mena, Jorge
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Urtasun, Andoni
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Altmann, Vivian
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show more...
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Matesanz, Fuenci ...
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Otaegui, David
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Urcelay, Elena
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Antigüedad, Alfr ...
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Malhotra, Sunny
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Montalban, Xavie ...
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Castillo-Triviño ...
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Espino-Paisán, L ...
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Aktas, Orhan
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Buttmann, Mathia ...
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Chan, Andrew
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Fontaine, Bertra ...
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Gourraud, Pierre ...
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Hecker, Michael
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Hoffjan, Sabine
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Kubisch, Christi ...
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Kümpfel, Tania
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Luessi, Felix
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Zettl, Uwe K
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Zipp, Frauke
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Alloza, Iraide
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Comabella, Manue ...
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Lill, Christina ...
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Vandenbroeck, Ko ...
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Cells
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