Risk of chronic obstructive pulmonary disease in healthy individuals with high C-reactive protein levels by smoking status: a population-based cohort study in Korea

Figures & data

Figure 1 Flow chart of study design.

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; hsCRP, high-sensitivity C-reactive protein .

Table 1 Baseline characteristics of study participants by smoking status

Characteristic	Overall	Never	Former	Current	P-value
N	63,260	28,989	18,392	15,879
Age (years)	46.8 (6.3)	47.0 (6.6)	47.3 (6.6)	45.6 (5.3)	<0.001
C-reactive protein (mg/L)^a	0.5 (0.2–1.0)	0.4 (0.2–0.9)	0.5 (0.2–1.0)	0.6 (0.3–1.2)	<0.001
FEV1	3.3 (0.8)	2.9 (0.7)	3.6 (0.7)	3.6 (0.7)	<0.001
FVC	3.9 (0.9)	3.4 (0.8)	4.3 (0.7)	4.3 (0.7)	<0.001
FEV1/FVC	84.2 (6.6)	85.0 (6.3)	83.8 (6.6)	83.4 (6.7)	<0.001
COPD during follow-up	4,259 (6.7)	1,025 (3.5)	1,564 (8.5)	1,670 (10.5)	<0.001
Male	38,843 (61.4)	6,809 (23.5)	16,755 (91.1)	15,279 (96.2)	<0.001
Study center					<0.001
Seoul	50,962 (80.6)	23,299 (80.4)	14,948 (81.3)	12,715 (80.1)
Suwon	12,298 (19.4)	5,690 (19.6)	3,444 (18.7)	3,164 (19.9)
Body mass index (kg/m^2)	23.9 (2.9)	23.2 (3.0)	24.5 (2.7)	24.6 (2.8)	<0.001
Total cholesterol (mg/dL)	201.7 (34.7)	198.3 (34.2)	204.0 (34.8)	205.0 (35.1)	<0.001
HDL cholesterol (mg/dL)	55.6 (13.4)	59.0 (13.9)	53.8 (12.5)	51.4 (11.9)	<0.001
Triglycerides (mg/dL)^a	110.0 (77.0–162.0)	91.0 (66.0–130.0)	121.0 (86.0–173.0)	143.0 (101.0–204.0)	<0.001
Alcohol					<0.001
None	19,528 (30.9)	14,659 (50.6)	3,352 (18.2)	1,517 (9.6)
Moderate	34,949 (55.2)	13,128 (45.3)	11,758 (63.9)	10,063 (63.4)
Severe	8,783 (13.9)	1,202 (4.1)	3,282 (17.8)	4,299 (27.1)
Vigorous exercise (times/week)					<0.001
0	30,974 (49.0)	15,547 (53.6)	7,373 (40.1)	8,054 (50.7)
1–3	21,471 (33.9)	8,188 (28.2)	7,370 (40.1)	5,913 (37.2)
>3	10,815 (17.1)	5,254 (18.1)	3,649 (19.8)	1,912 (12.0)
Fasting glucose (mg/dL)	97.3 (18.2)	95.0 (15.6)	99.3 (18.6)	99.3 (21.4)	<0.001
Diabetes	3,795 (6.0)	1,206 (4.2)	1,378 (7.5)	1,211 (7.6)	<0.001
Systolic blood pressure (mmHg)	114.8 (14.6)	112.4 (15.2)	117.8 (14.1)	115.8 (13.4)	<0.001
Diastolic blood pressure (mmHg)	74.9 (10.4)	72.5 (10.4)	77.4 (10.0)	76.4 (9.9)	<0.001
Hypertension	13,915 (22.0)	5,089 (17.6)	5,247 (28.5)	3,579 (22.5)	<0.001

Notes: Values are expressed as mean (standard deviation) or number (%). ^aMedian (interquartile range).

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HDL, high-density lipoprotein.

Table 2 Hazard ratios for incident COPD by time-varying CRP levels

	Log (CRP) (90th vs 10th percentile)	1st Quintile (0.1–0.2 mg/L)	2nd Quintile (0.3 mg/L)	3rd Quintile (0.4–0.7 mg/L)	4th Quintile (0.8–1.3 mg/L)	5th Quintile (1.4–5 mg/L)
Overall
Incident rate^a	14.1	11.4	13.7	15.3	15.4	16.1
Model 1	1.31 (1.20, 1.43)	Reference (1)	0.94 (0.85, 1.04)	1.01 (0.92, 1.12)	1.17 (1.06, 1.28)	1.26 (1.15, 1.39)
Model 2	1.23 (1.12, 1.35)	Reference (1)	0.93 (0.85, 1.03)	0.99 (0.90, 1.09)	1.12 (1.02, 1.23)	1.19 (1.08, 1.31)
Model 3	1.14 (1.04, 1.25)	Reference (1)	0.94 (0.85, 1.04)	0.97 (0.88, 1.07)	1.06 (0.97, 1.16)	1.13 (1.02, 1.24)
Model 4	1.19 (1.08, 1.31)	Reference (1)	0.96 (0.87, 1.05)	1.00 (0.91, 1.10)	1.10 (1.00, 1.20)	1.17 (1.06, 1.29)
Never smoker
Incident rate^a	8.0	7.1	8.2	7.9	8.5	9.4
Model 1	1.08 (0.90, 1.30)	Reference (1)	1.04 (0.87, 1.25)	0.99 (0.82, 1.20)	1.05 (0.87, 1.26)	1.08 (0.88, 1.32)
Model 2	1.08 (0.90, 1.30)	Reference (1)	1.05 (0.88, 1.26)	1.00 (0.83, 1.22)	1.05 (0.87, 1.27)	1.08 (0.88, 1.33)
Model 3	1.02 (0.85, 1.23)	Reference (1)	1.06 (0.88, 1.27)	0.98 (0.81, 1.19)	1.00 (0.82, 1.20)	1.04 (0.85, 1.28)
Model 4	1.07 (0.89, 1.29)	Reference (1)	1.09 (0.91, 1.30)	1.03 (0.85, 1.25)	1.04 (0.86, 1.26)	1.10 (0.89, 1.35)
Former smoker
Incident rate^a	16.7	14.3	17	19.5	17.9	16.4
Model 1	1.29 (1.11, 1.49)	Reference (1)	0.94 (0.80, 1.10)	0.95 (0.81, 1.11)	1.17 (1.00, 1.35)	1.26 (1.07, 1.47)
Model 2	1.29 (1.11, 1.49)	Reference (1)	0.94 (0.81, 1.11)	0.95 (0.81, 1.11)	1.17 (1.01, 1.36)	1.26 (1.07, 1.47)
Model 3	1.20 (1.03, 1.39)	Reference (1)	0.96 (0.82, 1.12)	0.94 (0.80, 1.10)	1.11 (0.95, 1.29)	1.20 (1.02, 1.40)
Model 4	1.22 (1.05, 1.42)	Reference (1)	0.97 (0.82, 1.13)	0.96 (0.82, 1.12)	1.13 (0.97, 1.31)	1.22 (1.04, 1.43)
Current smoker
Incident rate^a	21.2	18.7	20.3	21.5	21.4	23.6
Model 1	1.26 (1.09, 1.46)	Reference (1)	0.84 (0.71, 1.00)	1.02 (0.87, 1.19)	1.10 (0.95, 1.28)	1.16 (1.00, 1.35)
Model 2	1.25 (1.08, 1.45)	Reference (1)	0.85 (0.72, 1.00)	1.02 (0.88, 1.20)	1.10 (0.95, 1.28)	1.15 (0.99, 1.34)
Model 3	1.15 (0.99, 1.33)	Reference (1)	0.84 (0.71, 1.00)	0.98 (0.84, 1.15)	1.03 (0.88, 1.19)	1.08 (0.92, 1.25)
Model 4	1.22 (1.05, 1.41)	Reference (1)	0.86 (0.73, 1.02)	1.02 (0.87, 1.19)	1.07 (0.92, 1.25)	1.14 (0.97, 1.33)

Notes: Hazard ratio derived from cox proportional hazard regression. Model 1: Age (continuous), sex (man or woman), study center (Seoul or Suwon), and body mass index (continuous). Model 2: Additionally adjusted for smoking (never, former, current), physical activity (0, 1 to 3, or >3 times/week), and alcohol consumption (none, moderate, high). Model 3: Additionally adjusted for baseline FEV₁ (continuous). Model 4: Model 2+ hypertension (yes or no), total and high-density lipoprotein cholesterol (continuous), triglycerides (continuous), and fasting glucose (continuous). ^aPer 1,000 person-years.

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second.

Figure 2 Hazard ratio for incident COPD by CRP levels at baseline. (A) represents overall hazard ratio and (B) represents hazard ratio by smoking status. Curves represent adjusted hazard ratios (solid lines) and their 95% confidence intervals (dashed lines) based on restricted cubic splines for CRP with knots at the 5th, 35th, 65th, and 95th percentiles of their sample distributions. The reference values (diamond dots) were set at the 10th percentile of the distributions (corresponding to 0.1 mg/L). Models were adjusted for age, sex, center, body mass index, smoking status, physical activity, alcohol consumption. Bars represent the frequency distribution of CRP.

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; HR, hazard ratio.

Figure 3 Associations between CRP (90th vs 10th percentile) and COPD by pre-specified subgroups. Models were adjusted for age, sex, center, smoking status, physical activity, alcohol consumption, and BMI.

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; HR, hazard ratio.

Table S1 Baseline characteristics of study participants by incident COPD status

Characteristic	No COPD during follow-up	COPD during follow-up	P-value
N	59,001	4,259
Age (years)	46.6 (6.2)	48.7 (7.8)	<0.001
C-reactive protein (mg/L)^a	0.5 (0.2–1.0)	0.6 (0.2–1.1)	<0.001
FEV1	3.3 (0.8)	3.3 (0.8)	0.45
FVC	3.9 (0.9)	4.1 (0.9)	<0.001
FEV1/FVC	84.5 (6.4)	80.2 (7.3)	<0.001
Male	35,339 (59.9)	3,504 (82.3)	<0.001
Study center			<0.001
Seoul	47,603 (80.7)	3,359 (78.9)
Suwon	11,398 (19.3)	900 (21.1)
Body mass index (kg/m^2)	23.9 (2.9)	24.0 (2.7)	0.16
Total cholesterol (mg/dL)	201.6 (34.8)	202.7 (34.3)	0.05
HDL cholesterol (mg/dL)	55.7 (13.5)	54.1 (12.6)	<0.001
Triglycerides (mg/dL)^a	110.0 (77.0–162.0)	120.0 (86.0–173.0)	<0.001
Smoking			<0.001
Never	27,964 (47.4)	1,025 (24.1)
Former	16,828 (28.5)	1,564 (36.7)
Current	14,209 (24.1)	1,670 (39.2)
Alcohol			<0.001
None	18,528 (31.4)	1,000 (23.5)
Moderate	32,460 (55.0)	2,489 (58.4)
Severe	8,013 (13.6)	770 (18.1)
Vigorous exercise (times/week)			0.005
0	29,105 (49.3)	1,869 (43.9)
1–3	19,895 (33.7)	1,576 (37.0)
>3	10,001 (17.0)	814 (19.1)
Fasting glucose (mg/dL)	97.3 (18.3)	97.3 (17.0)	0.86
Diabetes	3,523 (6.0)	272 (6.4)	0.27
Systolic blood pressure (mmHg)	114.6 (14.6)	117.1 (14.5)	<0.001
Diastolic blood pressure (mmHg)	74.8 (10.4)	76.5 (10.1)	<0.001
Hypertension	12,760 (21.6)	1,155 (27.1)	<0.001

Notes: Values are expressed as mean (standard deviation) or number (%). ^aMedian (interquartile range).

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HDL, high-density lipoprotein.