Table 1.
Significant associations from candidate gene studies and IFN-beta MS treatment response along with selected gene ontology (GO) annotations. Pperm, P-value permutation test; Pf, P-value exact Fisher's test.
| Gene symbol | Full gene name | dbSNP ID; P-value; OR, 95-CI | GO molecular function | GO biological processes |
|---|---|---|---|---|
| MXA promoter region (32), (33) | Myxovirus resistance protein |
rs464138 AA genotype, P < 0.0001, OR = 6.23 [2.77–14.03] rs2071430 G allele, P = 0.015, OR = 3.4 [1.1–11.4] rs17000900 GG genotype, P = 0.018, OR = 2.4 [1.1–5.4] |
– | – |
| ACE (41) | Angiotensin-converting enzyme |
I/D D allele, P = 0.022, OR = 2.43 [1.13–5.20] |
Carboxypeptidase activity Endopeptidase activity Metallopeptidase activity peptidyl-dipeptidase activity |
Regulation of vasoconstriction Regulation of blood pressure Neutrophil mediated immunity Antigen processing and presentation of peptide antigen via MHC class I Angiotensin maturation Mononuclear cell proliferation |
| CCR5, (6), (34), (35) | C-C motif chemokine receptor 5 |
rs333/
CCR5*d P = 0.01, OR = 3.2 [1.1–8.8] Another study, Pf = 0.036, OR = 1.9 In allelic combinations: CCR5*d+IFNAR1*G+IFNB1*T/T Pperm = 0.017, OR = 14.3 [1.7–119.4] CCR5*d+IFNAR1*G+IFNG*T Pperm = 0.035, OR = 2.8 [1.3–6.0] Comparative to GA: CCR5*d+IFNAR1*G+DRB1*15+TGFB1*T Pf = 0.00054, Pperm = 0.004, OR = 13.2 [3.1–55.4] CCR5*w/w+CTLA4*G Pperm = 0.017 |
Chemokine receptor activity Protein binding C-c chemokine receptor activity |
Cellular defense response MAPK cascade Dendritic cell chemotaxis Calcium ion transport Immune response Inflammatory response Chemotaxis |
| CD58 (42) | CD58 molecule |
rs12044852 CC genotype, P < 0.05 |
Receptor binding | Immune response Cellular response to interferon-gamma Leukocyte migration |
| PELI3 (38) | Pellino E3 ubiquitin protein ligase family member 3 |
rs2277302 P = 0.008, OR = 1.29 [1.07–1.56] |
Protein binding ubiquitin protein ligase activity | Toll signaling pathway Immune response |
| GABRR3 (38) | Gamma-aminobutyric acid type A receptor rho3 subunit (gene/pseudogene) |
rs832032 P = 0.006, OR = 1.31 [1.08–1.59] |
Gaba receptor activity signal transducer activity | Regulation of biological process Response to stimulus |
| IFNAR1 (6), (21), (32), (34) | Interferon alpha and beta receptor subunit 1 |
rs55884088 (GT)n repeat, P = 0.036 rs1012334 A allele, P = 0.030, OR = 0.9 [0.2–1.2] In allelic combinations rs1012335: CCR5*d+IFNAR1*G+IFNB1*T/T Pperm = 0.017, OR = 14.3 [1.7–119.4] CCR5*d+IFNAR1*G+IFNG*T Pperm = 0.035, OR = 2.8 [1.3–6.0] Comparative to GA: CCR5*d+IFNAR1*G+DRB1*15+TGFB1*T Pf = 0.00054, Pperm = 0.004, OR = 13.2 [3.1–55.4] |
Cytokine receptor activity protein binding signal transducer activity | Regulation of biological process Response to stimulus Type I interferon signaling pathway Defense response to virus TGFB1 (6), (34) |
| TGFB1 (6), (34) | Transforming growth factor beta 1 |
rs1800469 C allele, P = 0.042, OR = 9.2 [0.2–70.4] Comparative to GA: CCR5*d+IFNAR1*G+DRB1*15+TGFB1*T Pf = 0.00054, Pperm = 0.004, OR = 13.2 [3.1–55.4] |
Transforming growth factor beta receptor binding | MAPK cascade apoptotic process Biosynthetic process Mononuclear cell proliferation Nitrogen compound metabolic process Regulation of phosphate Regulation of transcription from RNA polymerase II promoter Response to endogenous stimulus Transmembrane receptor protein Serine/threonine kinase signaling pathway Positive regulation of regulatory T cell differentiation Leukocyte migration |
| USP18 (43) | Ubiquitin specific peptidase 18 |
rs2542109 AA genotype, P = 0.041, OR = 1.8 [1.0–3.1] |
Thiol-dependent ubiquitinyl hydrolase activity thiol-dependent ubiquitin-specific protease activity isg15-specific protease activity protein binding | Protein deubiquitination Ubiquitin-dependent protein catabolic process regulation of type I interferon mediated signaling Pathway regulation of inflammatory response |
| TRAILR-1 (44) | TRAIL receptor1 |
rs20576 CC genotype, validation cohort: P = 8.88 × 10−4, Pc = 0.048, OR = 0.30 [0.1–0.6] |
Cysteine-type peptidase activity Protein binding Signal transducer activity Tumor necrosis factor-activated receptor activity |
Apoptotic process Cell proliferation Cytokine-mediated signaling pathway Immune response Regulation of biological process Regulation of catalytic activity Response to biotic stimulus Response to stress Single-multicellular organism process Leukocyte migration |
| IFNG (34), (45) | Interferon gamma | polymorphic microsatellites in the first intron, (CA)12, P = 0.013, OR = 0.5 [0.3–0.9] (CA)13, P = 0.04, OR = 1.8 [1.0–3.1] (CA)14, P = 0.009, OR = NA (CA)15, P = 0.005, OR = 0 [0–0.6] In allelic combinations rs2430561: CCR5*d+IFNAR1*G+IFNG*T, Pperm = 0.035, OR = 2.8 [1.3–6.0] |
Cytokine activity | Immune response Cellular response to lipopolysaccharide Defense response to virus |
| IFNB1 (34) | Interferon beta 1 | In allelic combinations rs1051922: CCR5*d+IFNAR1*G+IFNB1*T/T Pperm = 0.017, Pf = 0.0028, OR = 14.3 [1.7–119.4] |
Interferon-alpha/beta receptor binding | JAK-STAT cascade biosynthetic process Cell differentiation Cell proliferation Cytokine-mediated signaling pathway Type I interferon signaling pathway Hemopoiesis Natural killer cell activation Protein phosphorylation Regulation of phosphate metabolic process Response to stress Single-multicellular organism process Defense response to virus Regulation of innate immune response |
| IRF5 (36) | Interferon regulatory factor 5 |
rs2004640 TT genotype, P = 0.0006, Preplication = 0.037 rs47281420 AA genotype, P = 0.0023 |
Sequence-specific dna binding transcription factor activity | Regulation of transcription from RNA polymerase II promoter Response to interferon-gamma Defense response to virus |
| IRF8 (19) | Interferon regulatory factor 8 |
rs17445836 AA genotype, P = 0.017, OR = 0.45 [0.2–0.9] |
Sequence-specific dna binding transcription factor activity | Regulation of transcription from RNA polymerase II promoter Cellular response to interferon-gamma Cellular response to lipopolysaccharide |
| CD46 (46) | CD46 molecule |
rs2724385 TT genotype, P = 0.006, OR = 3.5 [1.4–8.9] AT genotype, P = 0.007, OR = 0.40 [0.20–0.79] |
Endopeptidase activity complement binding virus receptor activity | Positive regulation of regulatory T cell differentiation Blood coagulation Cell-cell adhesion Complement activation signal transduction |
| GPC5 (30) | Glypican 5 |
rs10492503 AA genotype, P = 0.018, OR = 3.0 [1.3–6.6] rs1411751 GG genotype, P = 0.012, OR = 3.7 [1.5–9.4] |
Heparan sulfate proteoglycan binding | Glycosaminoglycan metabolic process Glycosaminoglycan catabolic process Glycosaminoglycan biosynthetic process Retinoid metabolic process |
| Il10 (39), (40) | Interleukin 10 | In allelic combinations, JAK2-IL10-CASP3 Pperm = 0.001 non-GCC haplotypes (rs1800896, rs1800871, rs1800872) P = 0.04 |
Protein binding cytokine activity | Positive regulation of endothelial cell proliferation Positive regulation of transcription, DNA-templated Negative regulation of B cell proliferation Negative regulation of cytokine secretion involved in immune response Response to molecule of bacterial origin Negative regulation of myeloid dendritic cell activation Cellular response to lipopolysaccharide |
| LMP7 (32) | Proteasome subunit beta 8 |
rs2071543 C allele, P = 0.002, OR = 6.4 [1.8–24.1] |
Threonine-type endopeptidase activity | Viral process Type I interferon signaling pathway Transmembrane transport MAPK cascade Protein polyubiquitination Protein deubiquitination |
| CTSS (32) | Cathepsin S |
rs1136774 C allele, P = 0.02, OR = 0.4 [0.2–0.8] |
Cysteine-type peptidase activity | Toll-like receptor signaling pathway Antigen processing and presentation Adaptive immune response Proteolysis Antigen processing and presentation of exogenous peptide antigen via MHC class II |
| HLA-DBR1, HLA-A, HLA-B (6), (47) | Histocompatibility complex |
HLA-DRB1*04 allele, P = 0.008OR = 1.94 [1.19–3.17] HLA-B*15 allele, P = 0.03OR = 0.29 [0.10–0.84] Comparative to GA: CCR5*d+IFNAR1*G+DRB1*15+TGFB1*T Pf = 0.00054, Pperm = 0.004, OR = 13.2 [3.1–55.4] |
Antigen binding, receptor binding | Antigen processing and presentation Type I interferon signaling pathway Regulation of immune response |