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
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Controls
2.2. Selection and Genotyping of SNPs
2.3. Statistical Analysis
2.4. Functional Annotation of SNPs
2.5. In silico Analysis of the Effect of the Leu to Pro Transition Coded by rs28385692 on Signal Peptide Characteristics
2.6. p.Leu16Pro Mutagenesis of the Three IL-22BP Isoforms
2.7. Assessment of Effect of p.Leu16Pro Variant on Secretion of IL-22BP Isoforms
2.8. Replacement of the SP of IL-22BPi2 with the IL17A SP
2.9. Flow Cytometry Analysis
3. Results
3.1. The p.Leu16Pro coding SNP rs28385692 is Associated with Risk for Multiple Sclerosis
3.2. In Silico Analysis of the p.Leu16Pro Variant
3.3. The p.Leu16Pro Variant Decreases Secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AP | Acetone precipitate |
CL | Cell lysate |
EAE | Experimental autoimmune encephalomyelitis |
EDSS | Expanded Disability Status Scale |
GWAS | Genome-wide association screen |
IL-22BPi1, 2 or 3 | Interleukin 22 binding protein isoform-1, -2 or -3 |
IL22RA2 | Interleukin 22 receptor subunit alpha 2 |
LD | Linkage disequilibrium |
MAF | Minor allele frequency |
OR | Odds ratio |
PP | Primary progressive |
RAF | Risk allele frequency |
RR | Relapsing-remitting |
ScP | Secondary progressive |
SFM | Serum-free medium |
SNP | Single nucleotide polymorphism |
SP | Signal peptide |
Appendix A
SNP | OR 1 (95% CI 2) | p |
---|---|---|
rs4896239 | 0.95 (0.798–1.131) | 0.5638 |
rs17066096 | 1.059 (0.8746–1.282) | 0.5569 |
rs12194034 | 1.025 (0.8412–1.249) | 0.8055 |
rs1543509 | 0.9821 (0.7719–1.25) | 0.8835 |
rs28366 | 1.047 (0.8594–1.275) | 0.6497 |
rs276466 | 0.9779 (0.7803–1.225) | 0.8458 |
rs10484798 | 0.8452 (0.6874–1.039) | 01105 |
rs13217897 | 0.8249 (0.6608–1.03) | 0.08906 |
rs2064501 | 0.8337 (0.6674–1.041) | 0.109 |
rs11154914 | 1.043 (0.7864–1.384) | 0.7687 |
rs28385692 | 1.799 (0.8654–3.739) | 0.1158 |
rs13197049 | 0.846 (0.6766–1.058) | 0.1423 |
rs6570136 | 0.8669 (0.7018–1.071) | 0.1855 |
rs7745487 | 1.001 (0.7436–1.347) | 0.9947 |
Block | Haplotype | Frequency | Case, Control Frequencies | p |
---|---|---|---|---|
rs4896239 + rs28385692 | TA | 0.501 | 0.479, 0.519 | 0.102 |
CG | 0.267 | 0.273, 0.262 | 0.6031 | |
CA | 0.232 | 0.248, 0.219 | 0.1642 | |
rs12194034 + rs1543509+rs28366 + rs276466 | TTTA | 0.408 | 0.404, 0.411 | 0.763 |
TTTG | 0.22 | 0.216, 0.224 | 0.7026 | |
ATCA | 0.217 | 0.215, 0.218 | 0.8637 | |
TCTA | 0.148 | 0.160, 0.139 | 0.2266 | |
rs132117897 + rs202573 + rs2064501 + rs11154914 + rs13197049 | GGCAA | 0.495 | 0.475, 0.512 | 0.1298 |
AGTAT | 0.193 | 0.178, 0.206 | 0.1565 | |
GATGA | 0.172 | 0.192, 0.156 | 0.0561 | |
GATAA | 0.124 | 0.139, 0.111 | 0.0806 | |
rs6570136 +rs7745487 | GG | 0.551 | 0.543, 0.558 | 0.5396 |
AG | 0.278 | 0.265, 0.289 | 0.2853 | |
AA | 0.171 | 0.192, 0.153 | 0.0373 |
ID Server Name | Individual or Consensus Tool | Website | MLT That Based on | Input Parameters | Deleterious Threshold & Outputs | Ref. |
---|---|---|---|---|---|---|
Meta RL & Meta SVM | Consensus | http://annovar.openbioinformatics.org/en/latest/ | MMAF, linear kernel, radial kernel and polynomial kernel | A score of SIFT, PolyPhen-2, GERPþþ, Mutation Taster, Mutation Assessor, FATHMM, LRT, SiPhy and PhyloP | D (Deleterious), N (Neutral) and U (Unknown) | [50] |
Meta-SNP | Consensus | http://snps.biofold.org/meta-snp/ | RF | A score of PANTHER, PhD-SNP, SIFT, and SNAP | Disease related or Polymorphic non-synonymous SNVs | [32] |
PredictSNP | Consensus | https://loschmidt.chemi.muni.cz/predictsnp/ | Weighted majority vote consensus | A score of PolyPhen-1, PolyPhen-2, SIFT, MAPP, PhD-SNP and SNAP | Confidence scores and neutral or deleterious | [31] |
REVEL | Consensus | https://omictools.com/revel-tool | RF | A score of MutPred, FATHMM, VEST, Poly-Phen, SIFT, PROVEAN, Mutation Assessor, Mutation Taster, LRT, GERP, SiPhy, phyloP, and phastCons | Disease variants or rare neutral variants | [51] |
CADD | Individual | http://cadd.gs.washington.edu/score | A linear kernel support vector machine (SVM) | SNVs | Functional, deleterious, and pathogenic variants | [52] |
MAPP | Individual | http://mendel.stanford.edu/SidowLab/downloads/MAPP/index.html | Physicochemical properties and alignment score | The original amino acid, the position of the substitution and the new amino acid. | Score (0–1). The predicted is damaging if the score <=0.05 and tolerated if the score >0.05 | [53] |
Mutation Assessor | Individual | http://mutationassessor.org/r3/ | Conservation method | Genome build, chromosome position, reference allele and substituted allele or Protein ID and variant | (VC) Variant conservation score and (VS) Variant specificity score. Level of functional impact (high, medium, low, neutral) | [54] |
SIFT | Individual | http://sift.jcvi.org/www/SIFT_help.html#SIFT_OUTPUT | Alignment scores | The original amino acid, the position of the substitution and the new amino acid | Score (0–1). The predicted is damaging if the score <=0.05 and tolerated if the score >0.05 | [55] |
SNAP2 | Individual | https://rostlab.org/services/snap2web/ | ANN | Protein sequence | Non-neutral and neutral, Score and accuracy | [56] |
PANTHER | Individual | http://www.pantherdb.org/about.jsp | Alignment Scores HMM | Protein sequence and substitution | All GO annotations & Phylogenetic annotation | [57] |
PhD-SNPg | Individual | http://snps.biofold.org/phd-snpg/method.html | Gradient boosting algorithm | Chromosome position, and protein variation (position, and first amino acid, and second amino acid variant) | If the probability is >0.5 then the SNV is predicted to be Pathogenic otherwise Benign | [58] |
Polyphen-2 | Individual | http://genetics.bwh.harvard.edu/pph2/ | Empirical rules | Protein, SNP identifier or Protein sequence in FASTA format and positions of the substitution | Probably damaging or Benign, or Possibly damaging, Sensitivity, specificity, Multiple sequence alignment and 3D Visualization | [59] |
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Population | Number (% Female) | Age, Average ± SD 1 | RR 2 & ScP 3/PP 4/Other/ND 5 | Age at Onset, Average ± SD | EDSS 6, Mean ± SD | |
---|---|---|---|---|---|---|
Bilbao | Cases | 647 (72.3) | 42.5 ± 12.01 | 79.6/9/1.4/10 | 30.42 ± 10.17 | 2.9 ± 2.3 |
Controls | 573 (60.3) | 44.2 ± 9 | - | - | - | |
Donostia | Cases | 572 (64.8) | 46.4 ± 4.8 | 84.8/3.8/4.8/6.6 | 33.01 ± 11.05 | 2.79 ± 2.7 |
Controls | 250 (66) | 50.52 ± 13.26 | - | - | - | |
Barcelona | Cases | 676 (63.3) | 40.17 ± 12.93 | 81.5/14.8/3.7 | 31.6 ± 9.9 | 3.91 ± 2.5 |
Controls | 910 (52.7) | 40.2 ± 12.9 | - | - | - | |
Madrid | Cases | 899 (63.7) | 44.8 ± 10.55 | 79.7/6.9/4.7/8.7 | 29.8 ± 8.65 | 2.56 ± 2.13 |
Controls | 697 (55.1) | 40.96 ± 16.71 | - | - | - | |
Andalucía | Cases | 1474 (61) | 43 ± 12 | 47.4/1/9/42.6 | 28.87 ± 10.25 | ND |
Controls | 1777 (64.4) | 40.22 ± 12.9 | - | - | - | |
Germany | Cases | 3762 (70.2) | 42.2 ± 13.6 | ND | ND | ND |
Controls | 2972 (60.1) | 41.1 ± 14.05 | - | - | - | |
France | Cases | 1344 (63.6) | 44.3 ± 11.8 | ND | ND | ND |
Controls | 768 (60.4) | 39.6 ± 13 | - | - | - |
SNP | Position 1 | Risk Allele | RAF 2 Cases | RAF Controls | Other Allele | p | OR 3 (95% CI 4) |
---|---|---|---|---|---|---|---|
rs4896239 | 137,448,873 | C | 0.52 | 0.50 | T | 0.19 | 1.116 (0.942–1.31) |
rs17066096 | 137,452,908 | G | 0.29 | 0.27 | A | 0.26 | 1.132 (0.92–1.34) |
rs12194034 | 137,458,262 | A | 0.23 | 0.22 | T | 0.65 | 1.047 (0.86–1.274) |
rs1543509 | 137,465,656 | C | 0.15 | 0.14 | T | 0.92 | 1.012 (0.797–1.285) |
rs28366 | 137,466,087 | C | 0.24 | 0.23 | T | 0.52 | 1.066 (0.88–1.297) |
rs276466 | 137,466,614 | A | 0.78 | 0.78 | G | 0.99 | 1.001 (0.799–1.25) |
rs10484798 | 137,470,756 | A | 0.76 | 0.72 | G | 0.05 | 1.23 (1.0–1.508) |
rs13217897 | 137,471,327 | G | 0.83 | 0.79 | A | 0.02 | 1.291 (1.05–1.591) |
rs202573 | 137,473,672 | A | 0.33 | 0.28 | G | 0.007 | 1.273 (1.067–1.518) |
rs2064501 | 137,477,823 | T | 0.50 | 0.49 | C | 0.65 | 1.039 (0.879–1.226) |
rs11154914 | 137,480,411 | G | 0.19 | 0.16 | A | 0.06 | 1.23 (0.99–1.524) |
rs28385692 | 137,482,840 | C | 0.02 | 0.01 | T | 0.05 | 1.972 (0.983–3.954) |
rs13197049 | 137,491,211 | A | 0.83 | 0.80 | T | 0.03 | 1.260 (1.021–1.556) |
rs6570136 | 137,494,622 | A | 0.46 | 0.45 | G | 0.85 | 1.017 (0.847–1.222) |
rs7745487 | 137,496,672 | A | 0.18 | 0.15 | G | 0.10 | 1.201 (0.96–1.496) |
Conditioned to rs17066096 | Conditioned to rs28385692 | ||||
---|---|---|---|---|---|
SNP | Reference (minor) Allele | p | OR 1 (95% CI 2) | p | OR (95% CI) |
rs17066096 | G | NA | NA | 0.001042 | 1.098 (1.039–1.162) |
rs202573 | A | 0.2424 | 1.029 (0.981–1.079) | 0.3093 | 1.033 (0.9702–1.1) |
rs28385692 | C | 0.001146 | 1.098 (1.101–1.476) | NA | NA |
SNP | Proxy | Major Allele | Minor Allele (Frequency) 1 | Ensembl Consequence | SIFT | PolyPhen | RegulomeDB |
---|---|---|---|---|---|---|---|
rs10484798 | rs28362847 | G | A (0.21) | regulatory_region_variant | - | - | 5: TF binding or DNase peak |
rs10484798 | G | A (0.21) | intron_variant | - | - | 6: other | |
rs13197049 | rs13217897 | G | A (0.17) | intron_variant | - | - | 3a: TF binding + any motif + DNase peak |
rs17175239 | A | G (0.17) | intergenic_variant | - | - | 5: TF binding or DNase peak | |
rs1961618 | C | T (0.17) | intron_variant | - | - | 5: TF binding or DNase peak | |
rs12664889 | C | A (0.17) | intron_variant | - | - | 7: no data | |
rs13197049 | A | T (0.17) | intron variant | - | - | 7: no data | |
rs11154913 | A | G (0.17) | intron_variant | - | - | 5: TF binding or DNase peak | |
rs13193435 | C | A (0.17) | intron_variant | - | - | 5: TF binding or DNase peak | |
rs7749054 | T | G (0.17) | intergenic_variant | - | - | 6: other | |
rs13197049 | A | T (0.17) | intron_variant | - | - | 7: no data | |
rs7766677 | A | C (0.17) | intergenic_variant | - | - | 7: no data | |
rs13217897 | rs13217897 | G | A (0.17) | intron_variant | - | - | 3a: TF binding + any motif + DNase peak |
rs13193435 | C | A (0.17) | intron variant | - | - | 5: TF binding or DNase peak | |
rs1961618 | C | T (0.17) | intron_variant | - | - | 5: TF binding or DNase peak | |
rs17175239 | A | G (0.17) | intergenic_variant | - | - | 5: TF binding or DNase peak | |
rs7766677 | A | C (0.17) | intergenic_variant | - | - | 6: other | |
rs11154913 | A | G (0.17) | intron_variant | - | - | 7: no data | |
rs7749054 | T | G (0.17) | intergenic_variant | - | - | 7: no data | |
rs12664889 | C | A (0.17) | intron_variant | - | - | 7: no data | |
rs13197049 | A | T (0.17) | intron_variant | - | - | 7: no data | |
rs17066096 | rs17066063 | G | A (0.23) | TF_binding_site_variant | - | - | 3a: TF binding + any motif + DNase peak |
rs62420820 | G | A (0.23) | regulatory_region_variant | - | - | 3a: TF binding + any motif + DNase peak | |
rs72975618 | C | T (0.23) | TF_binding_site_variant | - | - | 4: TF binding + DNase peak | |
rs1322553 | A | G (0.23) | regulatory_region_variant | - | - | 5: TF binding or DNase peak | |
rs12214115 | G | T (0.23) | regulatory_region_variant | - | - | 5: TF binding or DNase peak | |
rs12214014 | C | T (0.23) | regulatory_region_variant | - | - | 5: TF binding or DNase peak | |
rs17066096 | A | G (0.23) | intergenic_variant | - | - | 6: other | |
rs202573 | rs202571 | T | C (0.31) | intron_variant | - | - | 7: no data |
rs202573 | G | A (0.31) | intron_variant | - | - | 7: no data | |
rs28385692 | rs28385692 | T | C (0.03) | missense_variant | Tolerated (0.11) | Benign (0.376) | 5: TF binding or DNase peak |
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Gómez-Fernández, P.; Lopez de Lapuente Portilla, A.; Astobiza, I.; Mena, J.; Urtasun, A.; Altmann, V.; Matesanz, F.; Otaegui, D.; Urcelay, E.; Antigüedad, A.; et al. 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. Cells 2020, 9, 175. https://doi.org/10.3390/cells9010175
Gómez-Fernández P, Lopez de Lapuente Portilla A, Astobiza I, Mena J, Urtasun A, Altmann V, Matesanz F, Otaegui D, Urcelay E, Antigüedad A, et al. 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. Cells. 2020; 9(1):175. https://doi.org/10.3390/cells9010175
Chicago/Turabian StyleGómez-Fernández, Paloma, Aitzkoa Lopez de Lapuente Portilla, Ianire Astobiza, Jorge Mena, Andoni Urtasun, Vivian Altmann, Fuencisla Matesanz, David Otaegui, Elena Urcelay, Alfredo Antigüedad, and et al. 2020. "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" Cells 9, no. 1: 175. https://doi.org/10.3390/cells9010175