The Study of the Influence of IL5RA Variants on Chronic Obstructive Pulmonary Disease

Figures & data

Table 1. Characteristics of COPD patients and controls.

Variables	Cases (N = 498)	Controls (N = 498)	p value
Age, year	70.89 ± 10.19	65.86 ± 5.56	< 0.001^a
≤68	187(37.55%)	372(74.70%)	< 0.001^b
>68	311(62.45%)	126(25.30%)
Sex			0.690^b
Male	328(65.86%)	322(64.66%)
Female	170(34.14%)	176(35.34%)
Smoking
Current	106(21.3%)	221(44.4%)
Former	134(26.9%)	0
Never	258(51.8%)	277(55.6%)
Smoking pack year	33.44 ± 15.56
Drinking			0.800^b
Yes	251(50.40%)	255(51.20%)
No	247(49.60%)	243(48.80%)
BMI (kg/m^2)	23.1 ± 3.12	25.2 ± 3.21	< 0.001^a
≥24	438(87.95%)	152(30.52%)
<24	47(9.44%)	152(30.52%)
missing	13(2.61%)	194(38.96%)
The history of exacerbation (yes/no/unavailable), n	171/310/17
COPD with cough (yes/no/unavailable), n	475/12/11
COPD with expectoration (yes/no/unavailable), n	437/50/11
COPD with wheezing (yes/no/unavailable), n	153/334/11
COPD with dyspnea (yes/no/unavailable), n	65/422/11
COPD with chest distress (yes/no/unavailable), n	146/341/11
History of asthma (yes/no/unavailable), n	142/336/20
FVC (L)	2.18 ± 0.69
FEV1 (L)	1.35 ± 0.45
FEV1/FVC	62.21 ± 7.41
Gold Group, n (%)
A	73(14.7%)
B	172(34.5%)
C	200(40.2%)
D	53(10.6%)

COPD: Chronic obstructive pulmonary disease; BMI: body mass index; FVC: forced vital capacity; FEV1: forced the first second of expiratory volume.

^a p value were calculated from an independent sample t-test.

^b p value were calculated from a two-sided χ² test.

p < 0.05 indicates statistical significance.

Table 2. Basic information of SNPs in IL5RA gene.

SNP	Chromosome position	Function	Allele (A/B)	MAF		HWE p	HaploReg v4.2
				Case	Control
rs3804795	3: 3088961	Intron Variant	C/T	0.761	0.772	0.899	Promoter histone marks, Enhancer histone marks, DNAse, Motifs changed, NHGRI/EBI GWAS hits, GRASP QTL hits
rs2290610	3: 3098273	Missense Variant	C/T	0.543	0.577	0.233	Enhancer histone marks, Motifs changed, GRASP QTL hits
rs13097407	3: 3102835	Intron Variant	G/A	0.968	0.928	0.999	Promoter histone marks, Enhancer histone marks, Proteins bound, Motifs changed
rs334782	3: 3106774	Intron Variant	C/T	0.776	0.784	0.691	Enhancer histone marks, Motifs changed
rs3856850	3: 3109662	Intron Variant	G/A	0.542	0.590	0.064	Promoter histone marks, Enhancer histone marks, DNAse, Proteins bound, Motifs changed

NP: single nucleotide polymorphism; A: minor; B: major; MAF: minor allele frequency; HWE: Hardy-Weinberg equilibrium.

Figure 1. Association of five SNPs in IL5RA with COPD risk. A: Significant overall analysis results. B: SNP-SNP interaction dendrogram of MDR analysis. C: Fruchterman-reingold of MDR analysis (The closer to red the stronger the synergy, the closer to blue the more redundancy.).

Table 3. Associations between SNPs in IL5RA and chronic obstructive pulmonary disease (COPD).

SNP	Model	Genotype	Without adjusted			With adjusted
			OR (95% CI)	p^1	p (FDR)	OR (95% CI)	p^2	p (FDR)
rs3804795	Allele	T				1.00
		C				1.06 (0.86–1.31)	0.596	0.721
	Recessive	TT-CT	1.00			1.00
		CC	1.25 (0.73–2.16)	0.414	0.414	1.45 (0.82–2.56)	0.197	0.197
rs2290610	Allele	T				1.00
		C				1.15 (0.96–1.37)	0.136	0.219
	Recessive	TT-CT	1.00			1.00
		CC	1.41 (1.03–1.94)	0.034*	0.051	1.39 (0.99–1.94)	0.053	0.079
rs13097407	Allele	A				1.00
		G				0.43 (0.28–0.65)	<0.001**	<0.001**
	Dominant	AA	1.00			1.00
		AG-GG	0.39 (0.25–0.61)	<0.001**	<0.001**	0.40 (0.25–0.64)	<0.001**	<0.001**
rs334782	Allele	T				1.00
		C				1.05 (0.85–1.30)	0.705	0.705
	Log-additive	/	1.05 (0.85–1.30)	0.661	0.397	1.12 (0.90–1.41)	0.312	0.234
rs3856850	Allele	A				1.000
		G				1.22 (1.02–1.45)	0.034*	0.075
	Recessive	AA-AG	1.00			1.00
		GG	1.73 (1.25–2.39)	<0.001**	0.003	1.71 (1.22–2.41)	0.002**	0.006

SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval; FDR: false discovery rate.

p value were calculated by logistic regression analysis. p¹ was without adjustment. p² was adjusted by age, sex, smoking, and drinking status.

Bold text and *p < 0.05 or **p < 0.01 represent statistical significance.

Table 4. Relationship between rs13097407 in IL5RA and COPD under stratification analyses.

Age			>68					≤68
SNP	Model	Genotype	Case	Control	OR (95% CI)	p	p (FDR)	Case	Control	OR (95% CI)	p	p (FDR)
rs13097407	Allele	A	602	237	1.00			362	687	1.00
		G	20	15	0.52 (0.26–1.04)	0.084	0.308	12	57	0.40 (0.21–0.75)	0.003**	0.018
	Dominant	AA	292	111	1.00			176	317	1.00
		AG-GG	19	15	0.44 (0.20–0.96)	0.038*	0.115	11	55	0.35 (0.17–0.70)	0.003**	0.009
Sex			Male					Female
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs13097407	Allele	A	630	598	1.00			334	326	1.00
		G	26	46	0.54 (0.33–0.88)	0.015*	0.061	6	26	0.23 (0.09–0.55)	<0.001**	0.002
	Dominant	AA	304	277	1.00			164	151	1.00
		AG-GG	24	45	0.49 (0.28–0.84)	0.010*	0.030	6	25	0.23 (0.09–0.59)	0.002**	0.007
Smoking			Smoking					Nonsmoking
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs13097407	Allele	A	371	396	1.00			548	518	1.00
		G	20	36	0.54 (0.31–0.95)	0.038*	0.155	12	36	0.32 (0.16–0.61)	<0.001**	0.002
	Dominant	AA	200	186	1.00			268	242	1.00
		AG-GG	18	35	0.41 (0.22–0.79)	0.008**	0.023	12	35	0.31 (0.15–0.63)	0.001**	0.004
Drinking			Drinking					Non-drinking
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs13097407	Allele	A	487	476	1.00			477	448	1.00
		G	15	34	0.43 (0.23–0.80)	0.008**	0.032	17	38	0.42 (0.23–0.76)	0.003**	0.015
	Dominant	AA	237	223	1.00			231	205	1.00
		AG-GG	14	32	0.41 (0.21–0.82)	0.012*	0.036	16	38	0.39 (0.21–0.74)	0.004**	0.012

SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval; FDR: false discovery rate.

p value were calculated by logistic regression analysis with adjustment for age, sex, smoking, and drinking status.

Bold text and *p < 0.05 or **p < 0.01 represent statistical significance.

Table 5. Relationship between rs3856850 in IL5RA and COPD under stratification analyses.

Age			> 68					≤ 68
SNP	Model	Genotype	Case	Control	OR (95% CI)	p	p (FDR)	Case	Control	OR (95% CI)	p	p (FDR)
rs3856850	Allele	A	336	152	1.00			204	436	1.00
		G	286	100	1.29 (0.96–1.74)	0.089	0.224	170	308	1.18 (0.92–1.52)	0.196	0.326
	Recessive	AA-AG	238	109	1.00			146	316	1.00
		GG	73	17	1.93 (1.06–3.53)	0.032*	0.097	41	56	1.61 (1.01–2.56)	0.045*	0.136
Sex			Male					Female
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs3856850	Allele	A	351	376	1.00			189	212	1.00
		G	305	286	1.22 (0.98–1.52)	0.076	0.191	151	140	1.21 (0.89–1.64)	0.217	0.361
	Recessive	AA-AG	249	273	1.00			135	152	1.00
		GG	79	49	1.64 (1.08–2.50)	0.022*	0.065	35	24	1.78 (0.99–3.18)	0.053	0.159
Smoking			Smoking					Nonsmoking
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs3856850	Allele	A	242	251	1.00			298	337	1.00
		G	194	191	1.05 (0.81–1.38)	0.702	0.877	262	217	1.36 (1.08–1.73)	0.010*	0.026
	Recessive	AA-AG	165	180	1.00			219	245	1.00
		GG	53	41	1.33 (0.80–2.21)	0.274	0.411	61	32	2.26 (1.39–3.69)	0.001**	0.003
Drinking			Drinking					Non-drinking
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs3856850	Allele	A	277	310	1.00			263	278	1.00
		G	225	200	1.26 (0.98–1.62)	0.071	0.177	231	208	1.17 (0.91–1.51)	0.212	0.531
	Recessive	AA-AG	196	221	1.00			188	204	1.00
		GG	55	34	1.98 (1.20–3.27)	0.008**	0.023	59	39	1.53 (0.96–2.43)	0.075	0.226

SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval; FDR: false discovery rate.

pvalue were calculated by logistic regression analysis with adjustment for age, sex, smoking, and drinking status.

Bold text and *p < 0.05 or **p < 0.01 represent statistical significance.

Table 6. Relationship between rs2290610 in IL5RA and COPD under stratification analyses.

Age			>68					≤68
SNP	Model	Genotype	Case	Control	OR (95% CI)	p	p (FDR)	Case	Control	OR (95% CI)	p	p (FDR)
rs2290610	Allele	T	337	147	1.00			204	424	1.00
		C	285	105	1.18 (0.88–1.59)	0.263	0.439	170	314	1.13 (0.88–1.45)	0.356	0.356
	Recessive	TT-CT	241	105	1.00			148	308	1.00
		CC	70	21	1.40 (0.80–2.47)	0.240	0.240	39	61	1.36 (0.86–2.17)	0.193	0.290
Sex			Male					Female
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs2290610	Allele	T	353	360	1.00			188	211	1.00
		C	303	280	1.10 (0.89–1.37)	0.378	0.629	152	139	1.23 (0.91–1.66)	0.184	0.461
	Recessive	TT-CT	252	263	1.00			137	150	1.00
		CC	76	57	1.34 (0.89–2.02)	0.159	0.239	33	25	1.46 (0.82–2.61)	0.199	0.199
Smoking			Smoking					Nonsmoking
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs2290610	Allele	T	243	243	1.00			298	328	1.00
		C	193	197	0.98 (0.75–1.28)	0.880	0.880	262	222	1.30 (1.02–1.65)	0.031*	0.052
	Recessive	TT-CT	171	176	1.00			218	237	1.00
		CC	47	44	1.11 (0.66–1.84)	0.698	0.523	62	38	1.85 (1.16–2.96)	0.010*	0.015
Drinking			Drinking					Non-drinking
SNP	Model	Genotype	Case	Control	OR (95% CI)	p		Case	Control	OR (95% CI)	p
rs2290610	Allele	T	273	293	1.00			268	278	1.00
		C	229	215	1.14 (0.89–1.47)	0.292	0.364	226	204	1.149 (0.89–1.48)	0.281	0.469
	Recessive	TT-CT	197	213	1.00			192	200	1.00
		CC	54	41	1.50 (0.93–2.41)	0.099	0.149	55	41	1.28 (0.80–2.05)	0.297	0.297

SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval; FDR: false discovery rate.

pvalue were calculated by logistic regression analysis with adjustment for age, sex, smoking, and drinking status.

Bold text and *p < 0.05 represent statistical significance.

Table 7. SNP–SNP interaction in IL5RA models analyzed by the MDR method.

Model	Training Bal. Acc.	Testing Bal. Acc.	CVC	OR (95% CI)	p
rs3856850	0.5435	0.5090	6/10	1.73 (1.25–2.39)	0.0009
rs3804795,rs3856850	0.5593	0.5161	5/10	1.96 (1.45–2.67)	<0.0001
rs13097407,rs334782,rs3856850	0.5775	0.5090	5/10	1.82 (1.41–2.36)	<0.0001
rs3804795,rs2290610,rs334782,rs3856850	0.5975	0.5151	6/10	2.15 (1.67–2.78)	<0.0001
rs3804795,rs2290610,rs13097407,rs334782,rs3856850	0.6199	0.5592	10/10	2.61 (2.02–3.36)	<0.0001

MDR, multifactor dimensionality reduction; Bal. Acc., balanced accuracy; CVC, cross-validation consistency; OR, odds ratio; 95% CI, 95% confidence interval.

p values were calculated using χ² tests.

Figure 2. Biological function of IL5RA and its related proteins. A: Interaction diagram of IL5RA and its related proteins. B: KEGG enrichment of IL5RA and its related proteins. C: IL5RA and its related proteins are involved in the JAK/STAT signaling pathway.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.