Table 3.
Pathway |
Genes (n) | Corrected P Value* | Genes with Gene-Level P Value <0.10 (Ordered by P Value) | |
---|---|---|---|---|
Identifier | Name | |||
Analyses included all available pathways† |
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KEGG pathways, n = 338 tested |
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00510 | N-glycan biosynthesis | 48 | 0.019 | ALG12, MAN1C1, MGAT5B, MGAT4C, MGAT4A, TUSC3, ALG14, MAN1A1, MAN2A1, GANAB, DPM3, ALG6 |
05168 | Herpes simplex virus infection | 173 | 0.030 | HLA-DQA1, HLA-DQB1, HLA-DRB1, PVRL2, PVRL1, PER2, CCL2, TLR2, SRSF2, TYK2, CCL5, POLR2A, IFNA6, TP53, C3, IFNA13, IFNA1, EIF2AK2, LTA, TNF, IFNA2, IFNA5, MCRS1, TBPL1, IFNA14, TLR3, IFNA8, TAF5, HLA-B, IFNA17, PPP1CC, HLA-DOB, TAP1, TAP2, MAPK9, HCFC2, ALYREF, TBPL2 |
00601 | Glycosphingolipid biosynthesis lacto and neolacto series | 24 | 0.030 | ST3GAL6, B3GALT5, FUT3, FUT5, FUT6, FUT2, B3GALT2, GCNT2, ST3GAL3, FUT4 |
05310 | Asthma | 23 | 0.102 | HLA-DQA1, HLA-DQB1, HLA-DRB1, FCER1A, IL13, IL4, TNF, CCL11, HLA-DOB, PRG2 |
04650 | Natural killer cell–mediated cytotoxicity | 123 | 0.120 | FCGR3B, ICAM1, PRKCB, KRAS, VAV2, VAV3, IFNA6, VAV1, PIK3R2, TNFSF10, IFNA13, IFNA1, NCR3, TNF, RAC2, IFNA2, IFNA5, HCST, TYROBP, PRF1, IFNA14, LCP2, IFNA8, MAPK3, HLA-B, IFNA17, PIK3R3, ULBP3, FCGR3A, RAET1L, RAF1 |
| ||||
GO cellular component pathways, n = 516 tested |
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0044448 | Cell cortex part | 114 | 0.057 | EXOC3, CAPZA2, GYS2, TCHP, CAPZB, PCLO, EXOC4, CORO1A, MYH2, SPTAN1, EXOC7, TRPV4, SPTBN4, EXOC3L2, SPTBN2, SPTA1, CDH1, LLGL1, ANK1, GYPC, PRKCZ, CALD1 |
0009898 | Cytoplasmic side of plasma membrane | 152 | 0.114 | FRK, TNK2, GNA12, ACP1, KRAS, TYK2, LDLRAP1, PTK6, LYN, GNAO1, NPHS2, GNG5, GNG7, RASA1, GNA14, CABP1, HTRA2, TEC, SRMS, SPTA1, PTPN7, CDH1, ALOX15, GNAI3 |
0098562‡ | ||||
GO biological pathways, n = 4,670 tested |
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0032770 | Positive regulation of monooxygenase activity | 25 | 0.024 | AGTR2, APOE, KRAS, TNF, CALM1, POR, TERF2 |
0051000‡ | ||||
2000027 | Regulation of organ morphogenesis | 165 | 0.029 | AGTR2, MET, POU5F1, FOXP2, HNF1B, CNTF, SFRP2, SIX4, SMAD4, SNAI2, SOX17, MSX1, IFT88, MMP20, HGF, DMRT3, CTHRC1, SFRP1, FGFR2, CAV3, XBP1, SIX1, EDNRA, GPC3, TNF, WNT9B, ZNRF3, CDH1, EDN1, FGF1, POR, TBX5 |
0042311 | Vasodilation | 67 | 0.058 | AGTR2, APOE, MRVI1, NPR1, SMTNL1, ADCYAP1, CFTR, NPPB, UTS2B, ADORA1, MKKS, P2RY2, HMOX1, BDKRB2, NOS1 |
0035150‡ | ||||
0050880‡ | ||||
0003018‡ | ||||
0001711 | Endodermal cell fate commitment | 16 | 0.098 | POU5F1, HNF1B, SOX17, CDC73, EOMES |
0042659‡ | ||||
0031960 | Response to corticosteroid | 140 | 0.139 | AGTR2, TRH, S100B, KRAS, AQP1, CCL2, ALPL, ADCYAP1, GHRHR, SCGB1A1, STAR, BMP6, CASP9, SPARC, TNF, CALM1, ALDH3A1, GBA, TPH2, EDN1, SSTR3, ACADS, SLC18A2 |
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GO molecular function pathways, n = 910 tested |
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0044548 | S100 protein binding | 10 | 0.123 | S100B, AHNAK, S100A1, ATP2A2, FGF1 |
0032794 | GTPase-activating protein binding | 11 | 0.144 | PLCD1, TSC1, GNAO1, FMNL3, CDH1, GNAI3 |
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CF-relevant custom pathways, n = 72 tested |
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Goblet cell relevant | 37 | 0.001 | MUC4, TFF2, CFTR, FUT6, GALNT12, SCGB1A1, ERN2, B4GALNT2, ST6GALNAC1, XBP1, MUC1, GCNT3, FUT4 | |
Ciliary trafficking | 157 | 0.006 | RAB8B, TBC1D7, PTCH1, EFHC1, ARFGEF2, IFT88, TTC26, IFT74, KIF19, RAB4A, RP1, VMA21, GLI3, IFT122, TRAF3IP1, TRPV1, COPG2, DNAH2, MKKS, OFD1, HSPB11, ODF2, IFT81, SSTR3, PACS1, ARHGEF1, KLC3, PCM1, GLI2, SCLT1 | |
Mucin Calu3 | 12 | 0.024 | MUC4, MUC20, MUC1 | |
MCF7 hypoxia (down) | 162 | 0.054 | OSTM1, ADAT1, CORO1A, SNRNP40, GAS2L1, SPAG1, POLR3K, RAB35, EEF1E1, GPATCH2, CALM1, ADORA1, KPNA1, PPIF, GDPD3, SLCO3A1, GYG1, PIK3R3, ARHGDIA | |
HIF1si (up)/MCF7 hypoxia (down)‡ | ||||
Asthma-COPD (up) | 36 | 0.059 | CEP72, FAM110C, CD44, TMEM200A, S100A16, CSTA, GCNT3, IGF2BP3, CEACAM5, CDC42EP5 | |
EHF positive correlation | 154 | 0.092 | MUC20, SLC44A4, SH3YL1, RAB25, LCN2, LIMA1, FUT3, STAP2, CTNND1, CEACAM6, FUT6, PTK6, CHMP4C, SH2D3A, SPAG1, PIGR, ST6GALNAC1, S100A14, MYH14, RIPK4, FUT2, SPINT2, CDH1, C10orf99, YAP1, CEACAM5, CGN, CDC42EP5, SLC44A3 | |
COPD (up) | 50 | 0.099 | MUC4, CFB, NR4A1, LCN2, ARNTL2, FUT3, IRAK3, MTNR1A, GCNT3, IGF2BP3, CEACAM5 | |
Airway epithelium T-helper type 2 | 92 | 0.115 | CEP72, SCGB2A1, TFF3, FAM110C, CD44, TMEM200A, S100A16, CSTA, GCNT3, ITLN1, IGF2BP3, ALOX15, CEACAM5, CDC42EP5, SLC18A2, SLC22A16 | |
CFTR interactome pathways§, n = 11 tested |
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loT1hr dCF; Table E7, 484 genes | 466 | 0.055 | LMNA, PRDX1, AHNAK, LIMA1, CAPZB, PDCD6, MCM6, CFTR, ACLY, STAU1, CLPTM1, PPP6R1, SDHA, MYH2, RDX, XRCC5, STRBP, SPTAN1, TPM1, TUBB6, ACSL4, TP53, RBBP4, C3, POLR2E, CNN2, UBR4, MYH13, MOV10, PPP1R12A, RPLP0, MMS19, YTHDF3, SAE1, CSTA, MYH14, SNX27 | |
loT6hr dCF; Table E8, 618 genes | 592 | 0.059 | LMNB2, ICAM1, LMNA, PRDX1, AHNAK, LIMA1, CAPZB, PDCD6, MCM6, THADA, STAU1, CLPTM1, EXOC4, PPP6R1, SDHA, MYH2, RDX, XRCC5, STRBP, SPTAN1, TPM1, TUBB6, ACSL4, TP53, RBBP4, C3, POLR2E, SLC35E1, UBR4, SLC27A3, MYH13, MOV10, PPP1R12A, RPLP0, DARS, MMS19, NUP155, SAE1, MSN, MYH14, SNX27 | |
Core CFTR interactome; Table E1, 638 genes | 620 | 0.088 | CAPZA2, LMNB2, HSPA1B, BLMH, HSPA1A, ICAM1, LMNA, PRDX1, AHNAK, LIMA1, CAPZB, MCM6, THADA, RGPD2, COG6, CFTR, ACLY, STAU1, SORCS1, CLPTM1, EXOC4, SDHA, MYH2, RDX, XRCC5, STRBP, SPTAN1, TPM1, TUBB6, EXOC7, ACSL4, TP53, RBBP4, C3, POLR2E, CNN2, YTHDF2, UBR4, MYH13, MOV10, PPP1R12A, RPLP0, DARS, MMS19, YTHDF3, SAE1, RAC2, CSTA, MSN, MYH14, SNX27 | |
SAHA dCF‡; Table E11, 681 genes | ||||
MetaMiner cystic fibrosis–specific pathways (GeneGo)‖, n = 36 tested |
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Cytokine production by Th17 cells in CF | 41 | 0.090 | ICAM1, CFTR, RELB, IL12RB1, CXCL1, IL8, RORC, CXCL6 | |
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HLA-specific pathways, n = 2 tested |
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Class I and class II | 18 | 0.095 | HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-B, HLA-DOB, PSMB8, PSMB9, TAP1, TAP2 | |
Class II | 8 | 0.146 | HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DOB | |
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Analyses confined to pathways significant for differential expression in nasal scrape samples¶, n = 37 tested |
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KEGG pathways |
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05168 | Herpes simplex virus infection | 173 | 0.008 | HLA-DQA1, HLA-DQB1, HLA-DRB1, PVRL2, PVRL1, PER2, CCL2, TLR2, SRSF2, TYK2, CCL5, POLR2A, IFNA6, TP53, C3, IFNA13, IFNA1, EIF2AK2, LTA, TNF, IFNA2, IFNA5, MCRS1, TBPL1, IFNA14, TLR3, IFNA8, TAF5, HLA-B, IFNA17, PPP1CC, HLA-DOB, TAP1, TAP2, MAPK9, HCFC2, ALYREF, TBPL2 |
05164 | Influenza A virus | 165 | 0.080 | HSPA1B, HLA-DQA1, HLA-DQB1, HLA-DRB1, HSPA1A, HSPA1L, PABPN1L, ICAM1, PRKCB, CCL2, TYK2, CCL5, IFNA6, PIK3R2, TNFSF10, IFNA13, IFNA1, CASP9, EIF2AK2, TNF, IFNA2, IFNA5, IFNA14, TLR3, KPNA1, IFNA8, MAPK3, IFNA17, DDX39B, PIK3R3, HLA-DOB, MAPK9, RAF1 |
Definition of abbreviations: CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; COPD = chronic obstructive pulmonary disease; dCF = Phe508del; EHF = ETS homologous factor; GO = Gene Ontology Consortium; GTPase = GTP (guanosine triphosphate) enzyme; HIF1si = HIF-1α siRNA; HLA = human leukocyte antigen; KEGG = Kyoto Encyclopedia of Genes and Genomes database; KNoRMA = Kulich Normal Residual Mortality Adjusted; SAHA = suberoylanilide hydroxamic acid.
Default parameters with 1,000 simulations were used, and pathways were limited to those that contained at least 10 but less than or equal to 200 genes. GeneSetScan uses mapping of genotyped single-nucleotide polymorphisms to 50 kb upstream and downstream of protein-coding genes based on ENSEMBL version 82 annotation and maps genes to annotated pathways and gene sets. CF relevant custom pathways were developed (46) using human gene counterparts (Table E8). See Table E3 for gene Online Mendelian Inheritance in Man catalogue numbers.
Multiple comparison corrected P values.
Gene level P values were calculated using family-wise error rate (all single-nucleotide polymorphisms, genes, and pathways tested) as provided by GeneSetScan. Pathways are listed if corrected P value is less than 0.15.
These pathways are statistically significant and carry robust overlap of genes with first-listed pathway; see Table E5, tab F, for complete listing of pathway genes.
For gene sets containing more than 200 genes, genes with P < 0.05 are listed; see Table E5, tab F, for complete list of pathway genes.
MetaMiner CF-specific pathways represent a version of the Thomson Reuters (formerly GeneGo) MetaDiscovery suite that is enriched with content specific for CF.
Pathways listed in Table 2 were evaluated for association with genotype.