Table 2.
Gene Expression Pathways Significantly Associated with Consortium Lung Phenotype (KNoRMA)
| Pathways with FDR <0.15 |
Genes |
Statistics |
|||||
|---|---|---|---|---|---|---|---|
| Identifier | Name | No. of Genes | P Value* | Q Value† | Increased Expression‡ | Genes in the Pathway that Significantly Contribute to Pathway Signal (Gene-Level P < 0.10, Ordered by P Value)§ | |
| KEGG pathways, n = 329 tested |
|
||||||
| 05160 | Hepatitis C virus | 104 |
0.0004 | 0.0476 | Detrimental | CDKN1A, SCARB1, ARAF, STAT1, BRAF, NRAS, PIAS1, IRF9, TICAM1, NFKB1, CLDN3, PIK3R5, TLR3, TP53, MAPK9, OAS3, MAVS | |
| 05168 | Herpes simplex virus infection | 158 |
0.0005 | 0.0476 | Detrimental | TLR2, PML, JUN, HLA-DRB1, HLA-DMB, STAT1, CD74, HLA-A, TAF4B, HLA-G, IRF9, TICAM1, HLA-F, NFKB1, FOS, EP300, TLR3, HLA-DRA, TP53, HLA-DMA, CCL5, TAP1, MAPK9, OAS3, HLA-B, HLA-E, MAVS, HCFC2, C3 | |
| 04640 | Hematopoietic cell lineage | 56 |
0.0016 | 0.0960 | Detrimental | IL1R1, HLA-DRB1, ITGAM, CD7, CSF1, HLA-DRA, TFRC | |
| 04115 | p53 signaling pathway | 64 |
0.0017 | 0.0960 | Detrimental | CDKN1A, CCNG2, BID, GADD45A, TP73, SERPINB5, GADD45B, BBC3, TP53, TNFRSF10B, EI24 | |
| 00592 | α-Linolenic acid metabolism | 13 |
0.0007 | 0.0981 | Protective | PLA2G4F, PLA2G6 | |
| 00591‖ | |||||||
| 05322 | Systemic lupus erythematosus | 62 |
0.0022 | 0.1042 | Detrimental | HLA-DRB1, HLA-DMB, HIST1H2BG, C2, HLA-DRA, HLA-DMA, HIST1H2AE, HIST2H2BE, HIST4H4, HIST1H4H, TROVE2, C3 | |
| 04514 | Cell adhesion molecules (CAMs) | 86 |
0.0026 | 0.1063 | Detrimental | PTPRC, HLA-DRB1, HLA-DMB, ITGAM, HLA-A, CD276, HLA-G, HLA-F, CLDN3, ICAM1, HLA-DRA, HLA-DMA, ITGB8, HLA-B, HLA-E, ITGB2 | |
| 04930 | Type 2 diabetes mellitus | 28 |
0.0040 | 0.1356 | Detrimental | PIK3R5, PRKCD, MAPK9 | |
| 05219 | Bladder cancer | 36 |
0.0045 | 0.1356 | Detrimental | ARAF, BRAF, NRAS, DAPK1, TP53 | |
| 05161 | Hepatitis B virus | 120 |
0.0047 | 0.1356 | Detrimental | TLR2, CDKN1A, CREB3L2, JUN, STAT1, NRAS, TICAM1, NFKB1, FOS, EP300, PIK3R5, TLR3, TP53, MAPK9, CCNA2, SMAD4, MAVS | |
| 05323 | Rheumatoid arthritis | 69 |
0.0055 | 0.1445 | Detrimental | JUN, HLA-DRB1, HLA-DMB, CCL3L1, ATP6V0A4, FOS, CSF1, ICAM1, FLT1, CCL3, HLA-DRA, HLA-DMA, CCL5, TNFSF13B, ITGB2 | |
| 04620 | Toll-like receptor signaling pathway | 80 |
0.0068 | 0.1485 | Detrimental | TLR2, JUN, STAT1, CCL3L1, TICAM1, NFKB1, FOS, PIK3R5, TLR3, CCL3, CCL5, MAPK9, CCL4 | |
| 00061 | Fatty acid biosynthesis | 10 |
0.0072 | 0.1485 | Detrimental | ACSL1, ACACA, ACACB | |
| 05164 | Influenza A virus | 145 |
0.0074 | 0.1485 | Detrimental | PML, JUN, HLA-DRB1, HLA-DMB, STAT1, IRF9, TICAM1, NFKB1, EP300, PIK3R5, ICAM1, TLR3, HLA-DRA, HLA-DMA, SLC25A6, CCL5, MAPK9, TNFRSF10B, OAS3, MAVS | |
| M00034 | Methionine salvage pathway | 10 |
0.0083 | 0.1485 | Detrimental | AMD1, MTAP | |
| 05203 | Viral carcinogenesis | 167 |
0.0086 | 0.1485 | Detrimental | JUN, PRKACB, HLA-A, CDKN2B, NRAS, HDAC9, HLA-G, HIST1H2BG, IRF9, HLA-F, NFKB1, EP300, PIK3R5, TP53, HIST2H2BE, CCNA2, HIST4H4, HIST1H4H, HLA-B, HLA-E, C3 | |
| M00676 | PI3K-Akt signaling | 13 |
0.0086 | 0.1485 | Detrimental | PIK3R5, FOXO3 | |
| | |||||||
| GO biological process pathways, n = 4,228 tested |
|
||||||
| 0051591 | Response to cAMP | 57 |
0.0002 | 0.1261 | Detrimental | JUN, IGFBP5, STAT1, EGR1, SREBF1, APEX1, BRAF, JUNB, FOS, DUSP1, AKAP6, COL1A1, SPARC, FOSL2, AKAP7 | |
| 0014074‖ | |||||||
| 0046683‖ | |||||||
| 0070665 | Positive regulation of leukocyte proliferation | 79 |
0.0003 | 0.1261 | Detrimental | IGFBP2, PTPRC, HHLA2, CDKN1A, HLA-DMB, CD74, HLA-A, CD276, BST1, TICAM1, CSF1, CCL5, HLA-E, TNFSF13B | |
| 0032946‖ | |||||||
| 0050671‖ | |||||||
| 0051155 | Positive regulation of striated muscle cell differentiation | 24 |
0.0003 | 0.1261 | Detrimental | EDN1, FOXP1, CD53, AKAP6 | |
| 0033631 | Cell–cell adhesion mediated by integrin | 11 |
0.0004 | 0.1493 | Detrimental | FERMT3, CCL5 | |
| | |||||||
| GO molecular function pathways, n = 779 tested |
|
||||||
| 0050431 | Transforming growth factor-β binding | 15 |
0.0003 | 0.1048 | Bidirectional | LTBP1¶, VASN¶, CD109¶, HYAL2, ENG, CD36, LTBP4 | |
| | |||||||
| MetaMiner cystic fibrosis–specific pathways (GeneGo)**, n = 36 tested |
|
||||||
| Cholesterol and sphingolipid transport/distribution to the intracellular membrane compartments (normal and CF) | 11 |
0.0058 | 0.0909 | Bidirectional | STARD4¶, NPC1¶, NPC2¶, RAB7A¶ | ||
| | |||||||
| CF-relevant custom pathways††, n = 74 tested |
|
||||||
| EHF transcription factor–negative correlation; PMID 25414352 | 18 |
0.0007 | 0.0237 | Detrimental | ACSL1, C10orf10, DMKN, ID2, H1F0 | ||
| Asthma-COPD (down); PMID 25611785 | 26 |
0.0023 | 0.0504 | Detrimental | CCDC81, PTGFR, FOLR1, STEAP2, DAPK1, LTF, CYP4X1 | ||
| Macrophage specific: M1 (classic) activation markers; PMID 25204199; and Macrophage activation: combined M1 and M2 markers‖; PMID 19635926 | 52 |
0.0038 | 0.0632 | Detrimental | TLR2, GBP3, IL1R1, GBP2, IL8, ICAM1, CCL3, CCL5, IL32, C3AR1, GBP5, CCL4, APOL3 | ||
| Hypoxia responses: HIF1 target hypoxia (up); PMID 19491311 | 188 |
0.0099 | 0.1219 | Detrimental | STARD4, KLHL24, IGFBP2, EDN1, NDRG1, CXCR4, BRAF, BCL2L11, GAPDH, PTGS2, FNDC3B, PSD3, ARL5B, GADD45B, FOXO3, ATF3, C1orf51, PLOD2 | ||
| Hypoxia responses: DC hypoxia (up); PMID 21148811 | 85 |
0.0117 | 0.1219 | Detrimental | TLR2, CHST15, LOC374443, PPIF, CD53, SYNJ2, GBP2, LGALS8, LCP2, CD109, CDCP1, SLC29A1, INSIG1, FCAR, ERRFI1 | ||
| Hypoxia responses: MCF7 hypoxia (up); PMID 16565084 | 163 |
0.0174 | 0.1355 | Detrimental | PLIN2, KLHL24, DSC2, SCARB1, JUN, HLA-DRB1, NDRG1, SOX9, CXCR4, IGFBP5, CCNG2, EGR1, ADM, DDR1, PLAUR, FLNB, FOS, CAV1, GADD45B, GJA1, ATF3, DUSP1, KLF7, ATXN1, EMR2 | ||
| Nasal scrape CF (down); PMID 16614352 | 29 |
0.0183 | 0.1355 | Detrimental | EPSTI1, CD74, PRKACB, HLA-G, HLA-F, RPS2 | ||
| |
|||||||
| CFTR interactome pathways (none), n = 11 tested |
|
||||||
| | |||||||
| HLA-specific pathways, n = 2 tested |
|||||||
| Class I and class II | 30 | 0.0853 | 0.0747 | Bidirectional | HLA-DRB1¶, HLA-DMB¶, HLA-H¶, HLA-A¶, HLA-G¶, HLA-F¶, HLA-DRA¶, HLA-DMA¶, TAP1¶, HLA-B¶, HLA-E¶, PSMB8¶ | ||
| Class I and class II | 30 | 0.0093 | 0.0080 | Detrimental | HLA-DRB1, HLA-DMB, HLA-H, HLA-A, HLA-G, HLA-F, HLA-DRA, HLA-DMA, TAP1, HLA-B, HLA-E, PSMB8 | ||
| Class II | 16 | 0.0968 | 0.0577 | Detrimental | HLA-DRB1, HLA-DMB, HLA-DRA, HLA-DMA | ||
Definition of abbreviations: CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; COPD = chronic obstructive pulmonary disease; DC = dendritic cell; EHF = ETS homologous factor; FDR = false discovery rate; GO = Gene Ontology Consortium; HIF1 = hypoxia-inducible factor 1; HLA = human leukocyte antigen; KEGG = Kyoto Encyclopedia of Genes and Genomes database; KNoRMA = Kulich Normal Residual Mortality Adjusted; PI3K = phosphoinositide 3-kinase; PMID = PubMed reference number.
Pathways limited to those with at least 10 but less than or equal to 200 genes.
SAFE (Significance Analysis of Function and Expression) analysis used 10,000 permutations to establish significance thresholds (18).
Benjamini-Hochberg FDR for pathway testing within each pathway set; Q values less than 0.15 were included.
Increased expression of genes in pathway are detrimental (associated with worse lung disease) or protective (associated with milder lung disease) or bidirectional (associated with either worse or milder lung disease).
See Table E5, tab A, for an inclusive list of genes for these pathways; see Table E3 for gene Online Mendelian Inheritance in Man catalogue numbers.
These pathways are statistically significant and carry robust overlap of genes with first-listed pathway; see Table E5, tab A, for an inclusive list of genes in pathways.
For bidirectional pathways, genes with increased expression associated with worse disease are noted.
MetaMiner CF-specific pathways represent a version of the Thomson Reuters (formerly GeneGo) MetaDiscovery suite that is enriched with content specific for cystic fibrosis.
CF-relevant custom pathways were developed (46) using human gene counterparts (Table E8).