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.
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.
['Gómez-Fernández|Paloma|P|0000-0002-2086-0652', 'Lopez de Lapuente Portilla|Aitzkoa|A|', 'Astobiza|Ianire|I|', 'Mena|Jorge|J|', 'Urtasun|Andoni|A|', 'Altmann|Vivian|V|0000-0002-7320-2012', 'Matesanz|Fuencisla|F|', 'Otaegui|David|D|0000-0002-6625-5976', 'Urcelay|Elena|E|', 'Antigüedad|Alfredo|A|', 'Malhotra|Sunny|S|', 'Montalban|Xavier|X|', 'Castillo-Triviño|Tamara|T|', 'Espino-Paisán|Laura|L|', 'Aktas|Orhan|O|0000-0002-2020-9210', 'Buttmann|Mathias|M|0000-0001-8309-7685', 'Chan|Andrew|A|', 'Fontaine|Bertrand|B|', 'Gourraud|Pierre-Antoine|PA|', 'Hecker|Michael|M|0000-0001-7015-3094', 'Hoffjan|Sabine|S|', 'Kubisch|Christian|C|', 'Kümpfel|Tania|T|', 'Luessi|Felix|F|0000-0003-4334-4199', 'Zettl|Uwe K|UK|', 'Zipp|Frauke|F|', 'Alloza|Iraide|I|', 'Comabella|Manuel|M|', 'Lill|Christina M|CM|', 'Vandenbroeck|Koen|K|0000-0002-6967-6485']
D000328:Adult D000595:Amino Acid Sequence D003198:Computer Simulation D030541:Databases, Genetic D005787:Gene Frequency D020022:Genetic Predisposition to Disease D057809:HEK293 Cells D006801:Humans D008875:Middle Aged D009103:Multiple Sclerosis D020641:Polymorphism, Single Nucleotide D020033:Protein Isoforms D021382:Protein Sorting Signals D018123:Receptors, Interleukin D012307:Risk Factors
IL22RA2 signal peptide multiple sclerosis IL-22 binding protein isoform autoimmune mutation