Table 2.
Gene Expression Pathways Significantly Associated with Consortium Lung Phenotype
|
Pathway |
Genes |
Statistics |
||||||
|---|---|---|---|---|---|---|---|---|
| ID | Name | Number | ↑a | ↓b | Trendc | p Valued | q Valuee | Genes with Gene-Level p Value < 0.05 (Ordered by p Value)f |
| GO Cellular Component Pathways | ||||||||
| 0001673 | male germ cell nucleus | 14 | 0 | 14 | down | 0.0001 | 0.0164 | TNP1; REC8; TCFL5 |
| 0012507 | ER to Golgi transport vesicle membrane | 25 | 23 | 2 | up | 0.0003 | 0.0481 | HLA-E; MCFD2; TMED7; HLA-F |
| 0043073 | germ cell nucleus | 17 | 1 | 16 | down | 0.0004 | 0.0442 | TNP1; REC8; TCFL5 |
| 0042470;0048770 | melanosome; pigment granule | 78 | 52 | 26 | up | 0.0007 | 0.0582 | SLC3A2; TPP1; CTSD; ANXA2; STOM; HSPA5; BSG |
| 0030134 | ER to Golgi transport vesicle | 29 | 25 | 4 | up | 0.0011 | 0.0737 | HLA-E; MCFD2; TMED7; HLA-F |
| 0030176 | integral to endoplasmic reticulum membrane | 85 | 64 | 21 | up | 0.0024 | 0.1181 | TTC35; HLA-E; EDEM1; TAP1; SELS; HLA-F; HSPA5; MMGT1 |
| 0031301 | integral to organelle membrane | 171 | 113 | 58 | up | 0.0026 | 0.1181 | TTC35; HLA-E; EDEM1; TAP1; SELS; ST6GALNAC6; HLA-F; A4GALT; ARMCX3; P2RX7; LARGE; HSPA5; MMGT1 |
| 0000421 | autophagic vacuole membrane | 13 | 11 | 2 | up | 0.0028 | 0.1181 | WIPI1; ATG9A |
| 0031227 | intrinsic to endoplasmic reticulum membrane | 95 | 70 | 25 | up | 0.0031 | 0.1181 | TTC35; HLA-E; EDEM1; TAP1; SELS; HLA-F; HSPA5; MMGT1 |
| 0031300 | intrinsic to organelle membrane | 184 | 121 | 63 | up | 0.0036 | 0.1231 | TTC35; HLA-E; EDEM1; TAP1; SELS; ST6GALNAC6; HLA-F; A4GALT; ARMCX3; P2RX7; LARGE; HSPA5; MMGT1 |
| 0030658 | transport vesicle membrane | 49 | 33 | 16 | up | 0.0039 | 0.1231 | HLA-E; MCFD2; TMED7; HLA-F; NCALD |
| GO Biological Process Pathways | ||||||||
| 0006518 | peptide metabolic process | 64 | 46 | 18 | up | 0.0001 | 0.0837 | GSTK1; DNPEP; PSEN2; TPP1 |
| 0072384 | organelle transport along microtubule | 24 | 21 | 3 | up | 0.0001 | 0.0837 | PRKCZ; COPG |
| 0006925 | inflammatory cell apoptotic process | 10 | 10 | 0 | up | 0.0003 | 0.1107 | none |
| 0006944 | cellular membrane fusion | 61 | 42 | 19 | up | 0.0003 | 0.1107 | CD9; PLDN; ANXA2; BET1 |
| 0007030 | golgi organization | 38 | 28 | 10 | up | 0.0003 | 0.1107 | GCC2; BHLHA15; GOLGB1; PLK3; COG1; TMED2 |
| 0043603 | cellular amide metabolic process | 101 | 65 | 36 | up | 0.0003 | 0.1107 | GSTK1; DNPEP; PSEN2; TPP1; PRKCD |
| 0034067 | protein localization to Golgi apparatus | 14 | 13 | 1 | up | 0.0004 | 0.1166 | GOLGA4; GCC2; ATG9A |
| 0045684 | positive regulation of epidermis development | 11 | 10 | 1 | up | 0.0004 | 0.1166 | none |
| GO Molecular Function Pathways | ||||||||
| 0050839 | cell adhesion molecule binding | 33 | 15 | 18 | two sided | 0.0004 | 0.1181 | P2RX4; MLLT4; CD1D;gCTNNA1; PVRL1g |
| 0042287 | MHC protein binding | 15 | 9 | 6 | two sided | 0.0006 | 0.1191 | TAP1; LAG3; MARCH8 |
| MSigDB Pathways | ||||||||
| ATAAGCT.MIR.21 | 81 | 45 | 36 | two sided | 0.0001 | 0.0387 | BAHD1; BTBD3;gC5orf41; STK40; UBR3; NF2;gSSFA2; JAG1; PPARA; PELI1; RHOB; CREBL2 | |
| V.HMGIY_Q6 | 158 | 70 | 88 | two sided | 0.0006 | 0.1499 | ZNF675;gLMO4; TNFSF11;gPLAGL2; POLD3;gSLC7A1; UBE2E2;gTAZ; UBR3; MRC2;gTNFSF4; IKZF2g | |
| MetaMiner Cystic Fibrosis Specific Pathwaysh | ||||||||
| cholesterol and sphingolipids transport/recycling to plasma membrane in lung (normal and CF) | 14 | 9 | 5 | two sided | 0.0036 | 0.0597 | ABCG1g | |
| normal wtCFTR traffic/sorting endosome formation | 14 | 11 | 3 | up | 0.0052 | 0.0621 | none | |
| F508-CFTR traffic/ER-to-Golgi in CF; Normal wtCFTR traffic/ER-to-Golgi | 22 | 20 | 2 | up | 0.0075 | 0.0621 | COPG; COPZ2 | |
| mucin expression in CF via TLRs, EGFR signaling pathways | 48 | 34 | 14 | up | 0.0116 | 0.0770 | JUN; PRKCD | |
| PFAM Pathways | ||||||||
| 00035 | double-stranded RNA binding motif | 17 | 2 | 15 | down | 0.0001 | 0.0135 | STRBP; STAU2 |
| 07716 | basic region leucine zipper | 11 | 7 | 4 | two sided | 0.0002 | 0.0276 | DDIT3; CREBL2; CEBPB |
| 03953 | tubulin C-terminal domain | 15 | 2 | 13 | down | 0.0009 | 0.0804 | TUBB2B |
| CF Relevant Custom Pathways | ||||||||
| ER stress response | 169 | 127 | 42 | up | 0.0005 | 0.0106 | DNAJB9; EDEM1; CISD2; TANK; DDIT3; SERP1; FDPS; LONP1; NANS; SSR4; JUN; GADD45A; LY9; PGM3; HSPA5; ARF4; IER3IP1; BTG2; CEBPB; CNIH; MANF; PDIA6 | |
| XBP1 target genes | 13 | 10 | 3 | two sided | 0.0079 | 0.1165 | DNAJB9; EDEM1; SERP1; PDIA6 | |
| HLA-Specific Pathways | ||||||||
| class I | 3 | 3 | 0 | up | 0.0221 | 0.0261 | HLA-E; HLA-F | |
| class II | 8 | 7 | 1 | up | 0.0868 | 0.0580 | none | |
| class I and class II | 11 | 10 | 1 | up | 0.0299 | 0.0261 | HLA-E; HLA-F | |
Pathways limited to those with ≥10 but ≤200 genes. SAFE analysis utilized 10,000 permutations to establish significance thresholds. CF Relevant Custom Pathways developed primarily as described for mice46 using human gene counterparts (Table S8).
Number of genes in pathway with increased expression.
Number of genes in pathway with decreased expression.
Up (increased) or down (decreased) differential expression of genes in the pathways associated with milder lung disease. Two-sided indicates pathways that contained both increased and decreased differentially expressed genes that contributed significantly to the signal.
Determined by 10,000 permutations in the SAFE package.22
Benjamini-Hochberg false-discovery for pathways testing within each pathway set; q values < 0.15 were included.
See Table S6 (tab A) for the inclusive list of genes for these pathways; “none” indicates that no individual genes within the pathway had a p value less than 0.05; see Table S5 for gene MIM numbers.
For the two-sided “Trend,” these genes have a “down” trend.
MetaMiner CF Specific Pathways represent a version of Thomson Reuters’ (formerly GeneGo) MetaDiscovery suite that is enriched with content specific for cystic fibrosis.