. 2018 Jan 1;197(1):79–93. doi: 10.1164/rccm.201701-0134OC

Table 4.

Gene Expression Pathways Significantly Associated with Risk Alleles for Significant Cystic Fibrosis Genome-Wide Association Study Loci

Chr	SNP rs Number	Pathway Identifier		Genes (n)	Statistics		Minor Allele	Risk Allele	Association with Risk Allele^‡	Genes with Gene-Level P Value <0.10 (Ordered by P Value)^§
Chr	SNP rs Number	Set	Name	Genes (n)	P Value^*	Q Value^†	Minor Allele	Risk Allele	Association with Risk Allele^‡	Genes with Gene-Level P Value <0.10 (Ordered by P Value)^§
11	rs10742326	CF-relevant custom pathways	COPD signature; PMID 23471465	66	0.0001	0.0035	A	G	Decreased expression	MUC4, ATP10B, SAA2, TMPRSS11D, SLC26A2, SLC26A4, SLC5A8, SAA1, SAA4, IRAK3, C15orf48, SLCO1B3, SERPINB7, EPB41L2, TPRXL, TRIM31, CCDC81, MTNR1A
11	rs10742326	CF-relevant custom pathways	Asthma nitric oxide gene cluster 3; PMID 25338189	48	0.0002	0.0046	A	G	Decreased expression	DUOXA1, FER1L5, WDR90, C16orf93, STK36, ARHGAP33, CEP164, HGS, PDXDC2P, KIAA0895L, TMEM234, MAP4K4, FAM193B, FBXO31, LINC00479, SPPL2B, RAD9A, MYO15B
11	rs10742326	CF-relevant custom pathways	CF MI Lasso; PMID 22466613	21	0.0005	0.0087	A	G	Decreased expression	PROM1, SLC9A3, CD44, CTSB
11	rs10742326	CF-relevant custom pathways	COPD up; PMID 23471465	49	0.0011	0.0153	A	G	Decreased expression	MUC4, ATP10B, SAA2, TMPRSS11D, SLC26A2, SLC26A4, SLC5A8, SAA1, SAA4, IRAK3, C15orf48, SLCO1B3, TPRXL, TRIM31, MTNR1A
11	rs10742326	MetaMiner cystic fibrosis–specific pathways (GeneGo)	CFTR-dependent regulation of ion channels in airway epithelium (normal and CF)	33	0.0040	0.0605	A	G	Decreased expression	ITPR3, ABCC9, WBP1, PRSS8, SLC9A3R1, GNA11, NEDD4, KCNN4, SCNN1A
11	rs10742326	CFTR interactome pathways	Core increased dCF over WT; Table E6, 52 genes	50	0.0337	0.0993	A	G	Increased expression	PSMD3, PSMD4, UBXN1, PSMD8, PSMD11, PSMA2, LMAN2, UBAC2
6	rs116003090	HLA specific	HLA class II	16	0.0626	0.0527	C	C	Bidirectional	HLA-DQB1, HLA-DRB1^‖, HLA-DRB4^‖, HLA-DQA2^‖, HLA-DQA1^‖, HLA-DRB5, HLA-DOB^‖, HLA-DQB2
6	rs116003090	CFTR interactome pathways	HDAC7 dCF; Table E13, 450 genes	410	0.0202	0.0343	C	C	Increased expression	RDX, APOL2, HSPH1, PPP2R2A, PPP2CA, DNAJA1, SLC25A22, SAMHD1, EZR, YWHAH, SPTLC2, HSPA8, ICAM1, LMNA, PHGDH, KRT7, YWHAE, DCTN2, GART, SFXN3, PPL, LGALS3BP, CDH1, TUBB6, PSMA4, ACTN4, TMEM40, RUVBL1, CAST, UBXN1, TPM4, TIMM50, HSPD1, KLHL22, PSMA6, LAMB3, ITGA3, TAPBP, VDAC2, ERAP1, TF, RAB18, PDXK, ILVBL, SFN, PSMA1, MARS, NCAPG2, AHSA1, YME1L1, CALR
			loT6hr dCF; Table E8, 618 genes^¶
			SAHA dCF; Table E11, 681 genes^¶
6	rs116003090	CFTR interactome pathways	loT24hr dCF; Table E9, 199 genes	175	0.0226	0.0343	C	C	Increased expression	APOL2, HSPH1, PPP2CA, DNAJA1, YWHAH, HSPA8, KRT7, YWHAE, LMO7, LGALS3BP, TUBB6, ZW10, PSMA4, ACTN4, RUVBL1, TPM4, TIMM50, HSPD1, LAMB3, ERAP1, SFN, MARS
6	rs116003090	CFTR interactome pathways	loT24hr rev dCF; Table E10, 199 genes^¶	175	0.0226	0.0343	C	C	Increased expression
6	rs116003090	CFTR interactome pathways	Core dCF specific; Table E5, 208 genes	193	0.0344	0.0404	C	C	Increased expression	TMEM165, SAMHD1, CBR1, SEC24C, C9orf167, ICAM1, DCTN2, SFXN3, CDH1, MX1, ISG15, ZW10, PSMA4, TMEM40, CAST, UBXN1, MX2, MOV10, LAMB3, ITGA3, RFC2, PPA1, VDAC2, PDXK, AHSA1, YME1L1
5	rs57221529	MetaMiner cystic fibrosis–specific pathways (GeneGo)	Cholesterol and sphingolipids transport/distribution to the intracellular membrane compartments (normal and CF)	11	0.0002	0.0032	G	A^**	Increased expression	RAB9A, SCP2
5	rs57221529	HLA specific	HLA class II	16	0.0320	0.0268	G	A^**	Increased expression	HLA-DMA, HLA-DRA, HLA-DMB, HLA-DOA, HLA-DRB1, HLA-DPB1, HLA-DPA1
5	rs57221529	HLA specific	HLA class I and class II	30	0.0957	0.0554	G	A^**	Increased expression	HLA-DMA, HLA-DRA, HLA-DMB, HLA-DOA, HLA-DRB1, HLA-DPB1, HLA-DPA1
X	rs5952223	KEGG: M00154	Cytochrome c oxidase	17	0.0007	0.0957	T	C	Decreased expression	COX7A2L, COX6C, COX5B

Definition of abbreviations: CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; COPD = chronic obstructive pulmonary disease; dCF = Phe508del; HDAC7 = histone deacetylase 7; KEGG = Kyoto Encyclopedia of Genes and Genomes database; MI = meconium ileus; PMID = PubMed reference number; SAHA = suberoylanilide hydroxamic acid; WT = wild type.

Pathways were limited to those with at least 10 but less than or equal to 200 genes. CF-relevant custom pathways were developed (46) using human gene counterparts (Table E8).

Significance Analysis of Function and Expression analysis used 10,000 permutations to establish significance thresholds (18).

^{^†}

Benjamini-Hochberg false discovery rate for pathway testing within each pathway set; Q values less than 0.15 were included.

^{^‡}

Risk alleles may be associated with increased expression, decreased expression, or bidirectional expression of genes in pathway.

^{^§}

See Table E5, tab G, for an inclusive list of genes for these pathways; see Table E3 for gene Online Mendelian Inheritance in Man catalogue numbers.

^{^‖}

For bidirectional pathways, genes with increased expression associated with CF genome-wide association study loci risk alleles are noted.

^{^¶}

These pathways are statistically significant and carry robust overlap of genes with first-listed pathway; see Table E5, tab G, for a complete list of pathway genes.

^**

For this study cohort, risk allele differs from that reported in broader CF genome-wide association studies (5).