Two CHRN susceptibility variants for COPD are genetic determinants of emphysema and chest computed tomography manifestations in Chinese patients

Figures & data

Table 1 Distributions of the select characteristics and chest CT parameters with regard to degree of emphysema

Variables	Degree of emphysemaa			P-valueb
	Mild (n)	Moderate (n)	Severe (n)
Total no	68	86	190
Sex	M/F (66/2)	M/F (74/12)	M/F (131/59)	<0.001
Age (years)	65.10±7.67 (68)	68.24±8.93 (86)	71.97±10.30 (190)	<0.001
BMI	21.36±3.16 (68)	21.30±3.55 (86)	22.89±3.76 (190)	<0.001
Smoke	Y/N (64/4)	Y/N (81/5)	Y/N (141/49)	<0.001
Spirometry-diagnosed COPD	Y/N (58/10)	Y/N (70/16)	Y/N (113/77)	<0.001
Post-FEV1	1.65±0.75 (68)	1.50±0.78 (86)	1.42±0.71 (190)	0.091
Post-FVC	2.94±0.81 (68)	2.55±0.93 (86)	2.15±0.86 (190)	<0.001
Post-FEV1/FVC	0.54±0.15 (68)	0.57±0.16 (86)	0.65±0.14 (190)	<0.001
MLD	0.08±0.02 (68)	0.12±0.02 (86)	0.21±0.05 (188)	<0.001
LAA%	64.77±9.30 (68)	36.54±6.66 (86)	7.020±8.03 (189)	<0.001
EV	3,710.93±891.97 (68)	1,787.51±502.98 (86)	291.91±361.51 (154)	<0.001
EI	5.84±0.55 (68)	7.36±0.60 (86)	3.17±3.21 (189)	<0.001
AWT	1.42±0.45 (59)	1.28±0.50 (74)	1.20±0.48 (168)	0.009
AWT/AD	37.13±7.36 (57)	35.28±9.33 (69)	33.21±13.66 (162)	0.077
Grading of AWT	0/1/2 (7/48/2)	0/1/2 (18/48/3)	0/1/2 (65/87/10)	0.001

Notes:

a A small portion of data was missing for certain parameters.

b The one-way ANOVA test and χ² test were used to assess the P-value. Data presented as mean ± standard deviation unless otherwise specified.

Abbreviations: AD, airway dimension; ANOVA, analysis of variance; AWT, airway wall thickness; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EI, emphysema index; EV, emphysema volume; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; LAA%, low attenuation areas volume percentage; M/F, male/female; MLD, mean lung density; Y/N, yes/no.

Table 2 Distributions of CHRN variants and their associations with degree of emphysema

Variants	Degree of emphysema			P-valuea	OR (95% CI)b
	Mild n (%)	Moderate n (%)	Severe n (%)
Total subjects	68	86	190
rs76071148				0.199
TT	38 (55.9)	53 (61.6)	101 (53.2)		1.00 (Ref)
AT	23 (33.8)	29 (33.7)	81 (42.6)		0.66 (0.42–1.06)
AA	7 (10.3)	4 (4.7)	8 (4.2)		1.74 (0.68–4.47)
AT vs TT + AA					0.63 (0.40–0.99)
rs8040868				0.393
TT	30 (19.1)	36 (41.9)	74 (39.0)		1.00 (Ref)
CT	25 (36.8)	40 (46.5)	93 (48.9)		0.76 (0.47–1.22)
CC	13 (19.1)	10 (11.6)	23 (12.1)		1.14 (0.58–2.25)
rs56218866				0.312
TT	53 (77.9)	63 (73.3)	151 (79.5)		1.00 (Ref)
CT	14 (20.6)	21 (24.4)	39 (20.5)		1.13 (0.67–1.91)
CC	1 (1.5)	2 (2.3)	0 (0.0)		3.15 (0.37–26.8)
rs16969968/rs1051730				0.336
GG	65 (95.6)	77 (89.5)	177 (93.2)		1.00 (Ref)
AG	3 (4.4)	9 (10.5)	13 (6.8)		0.94 (0.41–2.14)

Notes:

a The two-sided χ² test between difference groups.

b Adjusted in a logistic regression model with age, sex, smoking status, and BMI as covariables.

Abbreviations: BMI, body mass index; CI, confidence interval; Ref, reference.

Table 3 Associations of CHRN variants with the chest CT quantitative parameters

CT parameters	P-value in total subjectsa				P-value in spirometry-diagnosed COPD individualsa				P-value in spirometry-diagnosed non-COPD individualsa
	rs76071148	rs8040868	rs56218866	rs16969968/rs1051730	rs76071148	rs8040868	rs56218866	rs16969968/rs1051730	rs76071148	rs8040868	rs56218866	rs16969968/rs1051730
MLD	0.584	0.101	0.368	0.283	0.985	0.699	0.878	0.901	0.431	0.028	0.371	0.111
LAA%	0.961	0.628	0.421	0.844	0.613	0.552	0.843	0.384	0.780	0.054	0.824	0.141
EV	0.921	0.749	0.458	0.827	0.527	0.593	0.810	0.441	0.705	0.074	0.753	0.174
EI	0.118	0.002	0.068	0.097	0.199	0.042	0.182	0.543	0.324	0.008	0.712	0.054
AWT	0.914	0.192	0.586	0.802	0.863	0.534	0.749	0.818	0.925	0.103	0.202	0.462
AWT/AD	0.178	0.105	0.968	0.874	0.698	0.915	0.960	0.912	0.036	0.004	0.346	0.805
AWT grade	0.379	0.068	0.547	0.486	0.757	0.916	0.509	0.388	0.046	0.002	0.395	0.741

Note:

a GLM was used to evaluate P-value for the correlations between CHRN variants and chest CT manifestations with age, sex, BMI, and smoking status as covariables.

Abbreviations: AD, airway dimension; AWT, airway wall thickness; BMI, body mass index; CT, computed tomography; EI, emphysema index; EV, emphysema volume; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; GLM, general linear model; LAA%, low attenuation areas volume percentage; M/F, male/female; MLD, mean lung density; Y/N, yes/no.

Figure 1 Effect of the CHRN variants on chest CT manifestations.

Notes: The effect of rs8040868 on EI in total samples (A), in spirometry-diagnosed COPD subjects (B) and in spirometry-diagnosed non-COPD subjects (C); (D) the effect of rs8040868 on MLD in spirometry-diagnosed non-COPD subjects; (E) the effect of rs8040868 on AWT/AD in spirometry-diagnosed non-COPD subjects; (F) the effect of rs76071148 on AWT/AD in spirometry diagnosed non-COPD subjects. Columns, mean; bars, SD; the one-way ANOVA test was used to assess the differences in above lung functional traits between different genotypes.
Abbreviations: ANOVA, analysis of variance; AWT/AD, airway wall thickness to airway dimensions; CT, computed tomography; COPD, chronic obstructive pulmonary disease; MLD, mean lung density; SD, standard deviation.

Table 4 Distributions of the select characteristics and chest CT parameters with regard to spirometry-diagnosed COPD status

Variables	Spirometry-diagnosed COPDa	Spirometry-diagnosed non-COPDa	P-valueb
Total no	241	103
Sex (n)	M/F (208/33)	M/F (63/40)	<0.001
Age (years)	70.01±9.41 (241)	68.81±10.84 (103)	0.283
BMI (kg/m^2)	21.66±3.40 (238)	23.43±3.96 (103)	<0.001
Smoke (n)	Y/N (210/31)	Y/N (76/27)	0.003
MLD (g/cm^3)	0.15±0.06 (240)	0.19±0.07 (102)	<0.001
EV (g/cm^3)	1,619.7±1,493.4 (240)	703.3±1,050.4 (103)	<0.001
LAA%	30.77±24.48 (240)	14.46±19.60 (103)	<0.001
EI	5.39±2.58 (240)	3.26±3.43 (103)	<0.001
AWT (mm)	1.22±0.51 (212)	1.37±0.42 (89)	0.012
AWT/AD	34.08±12.02 (200)	35.41±11.17 (88)	0.375
AWT grade	0/1/2 (66/124/5)	0/1/2 (24/59/5)	0.625
Post-FEV1 (L)	1.26±0.62 (241)	2.01±0.74 (103)	<0.001
Post-FVC (L)	2.34±0.91 (241)	2.57±0.95 (103)	0.038
Post-FEV1/FVC	0.54±0.11 (241)	0.79±0.06 (103)	<0.001

Notes:

a A small portion of data was missing for certain parameters.

b The Student’s t-test and χ² test were used to assess the P-value. Data presented as mean ± standard deviation unless otherwise specified.

Abbreviations: AD, airway dimension; AWT, airway wall thickness; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EI, emphysema index; EV, emphysema volume; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; LAA%, low attenuation areas volume percentage; M/F, male/female; MLD, mean lung density; Y/N, yes/no.

Table S1 Distributions of CHRN variants and their associations with degree of emphysema stratified by spirometry-diagnosed COPD status

Variants	Degree of emphysema			P-valuea	OR (95% CI)b
	Mild n (%)	Moderate n (%)	Severe n (%)
Spirometry-diagnosed COPD individuals	58	70	113
rs76071148				0.068
TT	32 (55.2)	42 (60.0)	64 (56.6)		1.00 (Ref)
AT	19 (32.7)	24 (34.3)	47 (41.6)		0.67 (0.39–1.16)
AA	7 (12.1)	4 (5.7)	2 (1.8)		2.53 (0.81–7.93)
AT vs TT + AA					0.61 (0.36–1.04)
rs8040868				0.031
TT	24 (41.4)	26 (37.1)	45 (39.8)		1.00 (Ref)
CT	21 (36.2)	37 (52.9)	60 (53.1)		0.76 (0.44–1.31)
CC	13 (22.4)	7 (10.0)	8 (7.1)		1.89 (0.82–4.35)
rs56218866				0.360
TT	45 (77.6)	48 (68.6)	87 (77.0)		1.00 (Ref)
CT	12 (20.7)	20 (28.6)	26 (23.0)		0.98 (0.54–1.77)
CC	1 (1.7)	2 (2.8)	0 (0.0)		2.74 (0.32–23.6)
rs16969968/rs1051730				0.678
GG	55 (94.8)	64 (91.4)	103 (91.1)		1.00 (Ref)
AG	3 (5.2)	6 (8.6)	10 (8.9)		0.69 (0.27–1.78)
Spirometry-diagnosed non-COPD individuals	10	16	77
rs76071148				0.439
TT	6 (60.0)	11 (68.8)	37 (48.0)		1.00 (Ref)
AT	4 (40.0)	5 (31.2)	34 (44.2)		0.55 (0.21–1.45)
AA	0 (0.0)	0 (0.0)	6 (7.8)		–
AT vs TT + AA					0.61 (0.23–1.60)
rs8040868				0.167
TT	6 (60.0)	10 (62.6)	29 (37.7)		1.00 (Ref)
CT	4 (40.0)	3 (18.7)	33 (42.8)		0.43 (0.15–1.23)
CC	0 (0.0)	3 (18.7)	15 (19.5)		0.36 (0.08–1.56)
CT + CC vs TT					0.41 (0.16–1.05)
rs56218866				0.520
TT	8 (80.0)	15 (93.7)	64 (83.1)		1.00 (Ref)
CT	2 (20.0)	1 (6.3)	13 (16.9)		0.93 (0.23–3.72)
CC	0 (0.0)	0 (0.0)	0 (0.0)		–
rs16969968/rs1051730				0.049
GG	10 (100.0)	13 (81.3)	74 (96.1)		1.00 (Ref)
AG	0 (0.0)	3 (18.7)	3 (3.9)		2.13 (0.37–12.3)

Notes:

a The two-sided χ² test between difference groups.

b Adjusted in a logistic regression model with age, sex, smoking status and BMI as covariables.

Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio; Ref, reference.