Causal Path of COPD Progression-Associated Genes in Different Biological Samples

Figures & data

Table 1. The summarized data indicating the primary, qualified, and differentially expressed probes in each biological sample.

Biological samples	GEO_ID	Platform	GOLD Stage (Number)	Samples	N. probes	N. differential probes
Lung tissue	GSE47460	GPL6480 GPL14550	Healthy=(N = 108) II=( N = 100) III=( N = 37) IV=( N = 83)	N = 328	N = 42,545	N = 1,942
Small Airway Epithelial cells (SAE)	GSE20257	GPL 570	Healthy=(N = 112) I=( N = 9) II=( N = 12) III=( N = 2)	N = 135	N = 54,675	N = 932
Blood samples	GSE54837	GPL570	I=( N = 88) II=( N = 70) III=( N = 55) IV=( N = 13)	N = 226	N = 54,675	N = 134
Macrophages	GSE13896	GPL6947	Healthy=( N = 54) I=( N = 8) II=( N = 3)	N = 65	N = 54,675	N = 1,074
Sputum	GSE22148	GPL570	II=( N = 71) III=( N = 59) IV=( N = 13)	N = 143	N = 54,675	N = 5,768

Figure 1. Statistical comparison of AUCs among different biological samples based on the identified genes (* indicated significant difference at the level of 0.05, ** indicated significant difference at the level of 0.01, ***indicated significant difference at the level of 0.001).

Table 2. Probes and corresponding 33 candidate genes by elastic-net penalized logistic regression model for the association between the genes with COPD progression.

	Gene symbol	Probe ID	Up/down upregulated	Tissue	Epithelium	Blood	Macrophage	Sputum
	CCR4	A_23_P72989	Up	100%	–	–	–	–
	ITK	A_23_P354151	Up	84%	–	–	–	–
Tissue	RPUSD2	A_23_P309850	Down	82%	–	–	–	–
	RAB11B	A_23_P67748	Down	78%	–	–	–	–
	OXNAD1	A_24_P927189	Up	68%	–	–	–	–
	GPR171	A_23_P253317	Up	62%	–	–	–	–
	BTBD19	1557049_at	Up	–	100%	–	–	–
	THSD4	222835_at	Down	–	96%	–	–	–
	PPP4R4	233002_at	Down	–	95%	–	–	–
	NRG1	206343_s_at	Up	–	90%	–	–	–
	DNM3	209839_at	Up	–	89%	–	–	–
Epithelium	ITGA6	201656_at	Down	–	84%	–	–	–
	CD109	226545_at	Down	–	77%	–	–	–
	UHRF1	225655_at	Down	–	76%	–	–	–
	CST6	206595_at	Down	–	75%	–	–	–
	EPHB2	209589_s_at	Up	–	70%	–	–	–
	CDKN2A	207039_at	Up	–	70%	–	–	–
	KIAA1199	212942_s_at	Up	–	67%	–	–	–
	RGS20	210138_at	Down	–	63%	–	–	–
	SH3RF2	243582_at	Down	–	62%	–	–	–
	MTHFSD	244734_at	Up	–	–	100%	–	–
	CLEC7A	1554406_a_at	Up	–	–	89%	–	–
Blood	VCAN	211571_s_at	Up	–	–	66%	–	–
	PTPN4	236935_at	Down	–	–	–	100%	–
	CCDC37	242615_at	Up	–	–	–	77%	–
	GABARAPL1	208869_s_at	Up	–	–	–	67%	–
Macrophage	ADAMTSL1	1552808_at	Down	–	–	–	64%	–
	ATOH8	1558706_a_at	Down	–	–	–	64%	–
	SSBP1	202591_s_at	Up	–	–	–	62%	–
	SRPX	204955_at	Up	–	–	–	61%	–
	CHRFAM7A/CHRNA7	210123_s_at	Up	–	–	–	–	100%
Sputum	HSPA4	208814_at	Down	–	–	–	–	63%
	CADM1	232767_at	Up	–	–	–	–	62%
	AUC (SD)			0.92 (0.035)	0.97 (0.039)	0.73 (0.051)	0.96 (0.052)	0.82 (0.064)
	Sensitivity (SD)			0.86 (0.073)	0.89 (0.138)	0.46 (0.079)	0.88 (0.222)	0.62 (0.122)
	Specificity (SD)			0.80 (0.097)	0.93 (0.057)	0.82 (0.023)	0.95 (0.064)	0.82 (0.044)

Figure 2. (A) Expression level of CCR4, ITK, RPUSD2, RAB11B, OXNAD1, and GPR171 in lung tissue. (B) Expression level of BTBD19, THSD4, PPP4R4, NRG1, DNM3, ITGA6, D109, UHRF1, CST6, EPHB2, CDKN2A, KIAA1199, RGS20, and SH3RF2 in SAE. (C) Expression level of MTHFSD, CLEC7A, and VCAN in Blood. (D) Expression level of PTPN4, CCDC37, GABARAPL1, ADAMTSL1, ATOH8, SSBP1, and SRPX in macrophages. (E) Expression level of CHRFAM7A/CHRNA7, HSPA4, and CADM1 in sputum.

Figure 3. Spearman’s rank correlation, co-expression, matrix between the selected genes in the COPD patients: heatmap for hierarchical clustering the 33 candidate genes based on their pattern of gene expression.

Figure 4. Co-expression network for the 33 selected genes from GeneMania. The size of the nodes indicates the co-expression degree between genes. The thickness of the edges indicates the weight of co-expression. The red-yellow color of the nodes/edges indicates the degree/weight, respectively.

Table 3. Confirmation of the association of 33 selected genes with COPD/or lung function by literature reviewing in PubMed databank.

Gene symbol	Probe ID	Number of studies	Associated diseases	References (PMIDs)
CCR4	A_23_P72989	4	idiopathic pulmonary fibrosis, lung cancer, lung metastasis in breast cancer	11590382, 16095529, 17168792, 23915095
ITK	A_23_P354151	7	idiopathic pulmonary fibrosis, sarcoidosis, allergic lung disease	16630934, 15323564, 12734350, 1646075, 26628680, 25512530, 24089408,
RPUSD2	A_23_P309850	0	–	–
RAB11B	A_23_P67748	0	–	–
OXNAD1	A_24_P927189	1	lung cancer	24040438
GPR171	A_23_P253317	1	lung cancer	26760963
BTBD19	1557049_at	0	–	–
THSD4	222835_at	8	COPD, airway diseases, asthma, pulmonary fibrosis	27564456, 24286382, 23932459, 23541324, 23409998, 22461431, 21965014, 20010834
PPP4R4	233002_at	1	COPD	28170284
NRG1	206343_s_at	23	lung cancer, COPD	31382039, 30988082, 30694715, 30568455, 30268483, 30069312, 29959202, and etc.
DNM3	209839_at	0	–	–
ITGA6	201656_at	4	Lung Fibrosis, idiopathic pulmonary fibrosis, lung cancer, prostate, head and neck cancers	31396340, 30936924, 28701000, 27143927
CD109	226545_at	5	Lung cancer, prostate and breast carcinoma, squamous epithelium, tumor cells	29113239, 28191885, 24667143, 17922683, 15116102
UHRF1	225655_at	8	Lung cancer, human ovarian cancer tissues, gastric and breast cancers, metastasis in hepatocellular carcinoma, renal cell carcinoma	30528265, 30008828, 29516630, 28849055, 27437769, 26695082, 21351083, 20517312
CST6	206595_at	1	lung cancer	24398667
EPHB2	209589_s_at	2	Allergic Rhinitis and Asthma, lung disease	28231727, 10037197
CDKN2A	207039_at	28	Lung cancer, COPD, head and neck cancer, malignant mesothelioma	30178167, 28487787, 27987577, and etc.
KIAA1199	212942_s_at	2	Non-small-cell lung cancer, cancer cells	30478628, 28901311
RGS20	210138_at	1	Lung cancer	29872324
SH3RF2	243582_at	0	–	–
MTHFSD	244734_at	0	–	–
CLEC7A	1554406_a_at	2	pulmonary fibrosis, lung inflammatory response	27852745, 27473664
VCAN	211571_s_at	7	Lung cancer, breast cancer, lung metastasis, asthma	27895126, 27581786, 27513329, 25044411, 21742797, 22392539, 23202429
PTPN4	236935_at	1	Non-small cell lung cancer (NSCLC)	26951513
CCDC37	242615_at	2		26200272, 22011669
GABARAPL1	208869_s_at	1	Non-small cell lung cancer (NSCLC)	26356813
ADAMTSL1	1552808_at	1	Lung cancer	29207642
ATOH8	1558706_a_at	0	–	–
SSBP1	202591_s_at	1	Lung cancer	28638454
SRPX	204955_at	0	–	–
CHRFAM7A/CHRNA7	210123_s_at	5	Non-small cell lung cancer (NSCLC), lung tumor, smoking-related lung cancers	25407004, 28283678, 28978081, 31096457, 30282908
HSPA4	208814_at	0	–	–
CADM1	232767_at	18	Lung cancer, lung tumor, lung epithelial cell apoptosis, lung fibroblasts, lung tumorigenesis	31069869, 23620770, 22429880, 22429880, and etc.

Figure 5. The path diagram: A diagram based on the connections between selected genes in the studied biological samples.

Table 4. Standardized direct, indirect, and total effects of selected genes in studied biological samples on COPD progression.

Predictor → outcome	Direct effect (p-value)	Indirect effect (p-value)	Total effect (p-value)
Tissue → progression of COPD	0.79 (0.019)	0.24 (0.041)	1.03 (0.001)
Epithelium → progression of COPD	−0.82 (<0.001)	−0.22 (0.028)	−1.04 (<0.001)
Blood → progression of COPD	0.70 (0.038)	0.14 (0.048)	0.84 (0.032)
Macrophage → progression of COPD	−0.77 (0.001)	−0.29 (0.001)	−1.08 (<0.001)
Sputum → progression of COPD	0.76 (0.009)	0.18 (0.032)	0.94 (0.021)

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.