Direct, indirect and total bilirubin and risk of incident coronary heart disease in the Dongfeng-Tongji cohort

Figures & data

Figure 1. The flow chart of study population in the present study.

Table 1. Baseline characteristics of participants across quintiles of direct bilirubin levels.^a

	Quintiles of direct bilirubin level (μmol/L)
Characteristics	Q1	Q2	Q3	Q4	Q5	p^b trend
n	2423	2480	2494	2439	2261
Total bilirubin	11.3 (8.1, 14.0)	10.2 (8.9, 11.9)	12.2 (10.7, 14.0)	15.2 (13.2, 17.2)	19.5 (17.0, 23.6)	–
Indirect bilirubin	9.6 (6.0, 12.0)	7.3 (6.0, 8.8)	8.6 (7.0, 10.2)	10.8 (8.7, 12.7)	13.5 (11.0, 17.2)	–
Direct bilirubin	2.1 (1.5, 2.3)	3.0 (2.8, 3.1)	3.7 (3.5, 3.9)	4.5 (4.3, 4.9)	6.0 (5.5, 7.0)	–
Age (year)	61.8 (7.8)	61.6 (7.7)	62.9 (7.9)	63.2 (7.8)	64.3 (7.6)	.005
Male, n (%)	772 (31.9)	770 (31.1)	1097 (44.0)	1285 (52.7)	1540 (68.1)	<.0001
Body mass index (kg/m^2)	24.3 (3.3)	23.9 (3.2)	24.0 (3.1)	24.0 (3.1)	24.0 (3.1)	.075
High school or above, n (%)	839 (34.6)	904 (36.5)	804 (32.2)	793 (32.5)	644 (28.5)	<.0001
Physical activity, n (%)	2145 (88.5)	2178 (87.8)	2227 (89.3)	2213 (90.7)	2063 (91.2)	.002
Current smokers, n (%)	356 (14.7)	382 (15.4)	472 (18.9)	552 (22.6)	582 (25.7)	.013
Current drinkers, n (%)	427 (17.6)	403 (16.3)	554 (22.2)	628 (25.8)	815 (36.1)	<.0001
Family history of CHD, n (%)	124 (5.1)	150 (6.1)	122 (4.9)	107 (4.4)	70 (3.1)	.030
Hypertension, n (%)	1157 (47.8)	1145 (46.2)	1141 (45.8)	1213 (49.7)	1201 (53.1)	.026
Diabetes, n (%)	360 (14.9)	364 (14.7)	397 (15.9)	391 (16.0)	374 (16.5)	.644
Hyperlipidemia, n (%)	1301 (53.7)	1366 (55.1)	1275 (51.1)	1131 (46.4)	929 (41.1)	<.0001
ALT (U/L)	19.0 (15.0, 24.0)	20.0 (15.0, 26.0)	20.0 (15.0, 26.0)	20.0 (15.0, 27.0)	21.0 (16.0, 28.0)	<.0001
AST (U/L)	22.0 (18.0, 26.0)	22.0 (19.0, 27.0)	23.0 (19.0, 27.0)	23.0 (19.0, 28.0)	24.0 (20.0, 29.0)	<.0001
ALP (U/L)	79.0 (68.0, 100.0)	88.0 (73.0, 107.0)	88.0 (74.0, 107.0)	88.0 (73.0, 104.0)	87.0 (72.0, 103.0)	<.0001

CHD: coronary heart disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase.

^a Data were means (SD), median (P₂₅, P₇₅) for continuous variables or numbers (%) for category variables, respectively.

^b p values were calculated after adjustment for age and sex except for itself.

Figure 2. Multivariable adjusted restricted cubic splines for the relationship between DBIL (a), IBIL (b), TBIL (c) levels and risk for CHD incidence in a Cox proportional hazard model. The model was adjusted for age, sex, body mass index, smoking, drinking, physical activity, education levels and family history of CHD, hypertension, hyperlipidemia, diabetes, ALT, AST and ALP. The solid lines and dashed lines indicates the adjusted hazard ratios (HR) and 95% confidence interval (CI), respectively. DBIL: direct bilirubin; IBIL: indirect bilirubin; TBIL: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; CHD: coronary heart disease.

Table 2. Hazard ratios (95% CI) for CHD incidence according to three types of serum bilirubin levels.

		Hazard ratios (95% CI)
Bilirubin types	Incidents/Participants	Unadjusted	Model 1^a	Model 2^b
Direct bilirubin (range; median, μmol/L)
Quartile 1 (0–2.6; 2.1 μmol/L)	198/2423	1.00 (Ref.)	1.00 (Ref.)	1.00 (ref.)
Quartile 2 (2.6–3.3; 3.0 μmol/L)	253/2480	1.23 (1.02, 1.48)	1.24 (1.03, 1.50)	1.21 (1.01, 1.47)
Quartile 3 (3.3–4.1; 3.7 μmol/L)	241/2494	1.18 (0.98, 1.43)	1.12 (0.92, 1.35)	1.09 (0.90, 1.32)
Quartile 4 (4.1–5.1; 4.5 μmol/L)	260/2439	1.34 (1.12, 1.61)	1.30 (1.08, 1.57)	1.26 (1.05, 1.53)
Quartile 5 (5.1–24.8; 6.0 μmol/L)	252/2261	1.44 (1.19, 1.73)	1.34 (1.10, 1.62)	1.30 (1.07, 1.58)
p for trend	–	.0001	.005	.013
Natural loge-transformed continuous  Direct bilirubin, per 1μmol/L	–	1.31 (1.16, 1.47)	1.26 (1.11, 1.42)	1.23 (1.09, 1.39)
Indirect bilirubin (range; median, μmol/L)
Quartile 1 (1.5–6.6; 5.3 μmol/L)	252/2440	1.00 (Ref.)	1.00 (Ref.)	1.00 (ref.)
Quartile 2 (6.6–8.5; 7.5 μmol/L)	243/2341	0.98 (0.82, 1.17)	0.93 (0.78, 1.11)	0.93 (0.78, 1.11)
Quartile 3 (8.5–10.5; 9.5 μmol/L)	231/2453	0.92 (0.77, 1.10)	0.88 (0.74, 1.06)	0.89 (0.74, 1.07)
Quartile 4 (10.5–13.1; 11.6 μmol/L)	232/2494	0.88 (0.73, 1.05)	0.82 (0.69, 0.98)	0.83 (0.69, 0.99)
Quartile 5 (13.1–50.8; 15.3 μmol/L)	246/2369	1.01 (0.84, 1.20)	0.94 (0.79, 1.13)	0.94 (0.79, 1.13)
p for quadratic trend	–	.065	.014	.021
Total bilirubin (range; median, μmol/L)
Quartile 1 (2.5–9.9; 8.2 μmol/L)	258/2412	1.00 (ref.)	1.00 (ref.)	1.00 (ref.)
Quartile 2 (9.9–12.0; 11 μmol/L)	239/2534	0.90 (0.75, 1.07)	0.89 (0.74, 1.06)	0.89 (0.74, 1.06)
Quartile 3 (12.0–14.1; 13.0 μmol/L)	196/2315	0.82 (0.68, 0.99)	0.76 (0.63, 0.91)	0.76 (0.63, 0.92)
Quartile 4 (14.1–17.5; 15.7 μmol/L)	238/2422	0.93 (0.78, 1.11)	0.89 (0.75, 1.07)	0.90 (0.75, 1.07)
Quartile 5 (17.5–59.7; 20.0 μmol/L)	273/2414	1.08 (0.91, 1.28)	1.01 (0.85, 1.20)	1.01 (0.84 1.20)
p for quadratic trend	–	.013	.026	.040

CHD: coronary heart disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase.

^a Adjusted for age, sex, body mass index, education levels, smoking, drinking, physical activity, history of CHD, hypertension, hyperlipidemia and diabetes.

^b Adjusted for model 1 plus liver enzymes including ALT, AST and ALP.

Table 3 Associations of CHD incidence with serum direct bilirubin levels stratified by baseline characteristics^a.

Stratified covariates	Q1	Q2	Q3	Q4	Q5	p trend	p for interaction
Age							.896
<65						.042
Incidents / participants	84/1453	118/1667	104/1354	120/1562	119/1562
HR (95% CI)	1.00 (ref.)	1.28 (0.96, 1.70)	1.36 (1.01, 1.83)	1.36 (1.02, 1.82)	1.37 (1.02, 1.84)
≥ 65						.054
Incidents / participants	116/897	142/939	127/889	140/869	134/905
HR (95% CI)	1.00 (ref.)	1.08 (0.85, 1.39)	1.12 (0.87, 1.45)	1.32 (1.03, 1.70)	1.25 (0.97, 1.62)
Sex							.941
Male						.245
Incidents / participants	110/1067	140/1181	127/1035	132/1106	125/1075
HR (95% CI)	1.00 (ref.)	1.02 (0.79, 1.32)	1.18 (0.91, 1.53)	1.17 (0.91, 1.51)	1.13 (0.87, 1.47)
Female						.017
Incidents / participants	87/1283	124/1476	117/1156	120/1428	122/1290
HR (95% CI)	1.00 (ref.)	1.26 (0.95, 1.66)	1.40 (1.06, 1.86)	1.25 (0.94, 1.65)	1.48 (1.12, 1.96)
Smoking status							.316
Non-current smokers						.005
Incidents / participants	150/2057	174/1885	174/1757	212/1972	212/2082
HR (95% CI)	1.00 (ref.)	1.30 (1.04, 1.62)	1.22 (0.98, 1.53)	1.41 (1.14, 1.75)	1.39 (1.12, 1.73)
Current smokers						.956
Incidents / participants	62/469	51/444	58/514	51/453	60/464
HR (95% CI)	1.00 (ref.)	0.82 (0.56, 1.19)	0.85 (0.59, 1.22)	0.89 (0.61, 1.31)	0.93 (0.64, 1.34)
Drinking status							.905
Non-current drinkers						.002
Incidents / participants	140/1771	173/1833	197/1932	213/1894	201/1840
HR (95% CI)	1.00 (ref.)	1.26 (1.01, 1.58)	1.21 (0.97, 1.51)	1.42 (1.14, 1.76)	1.42 (1.13, 1.77)
Current drinkers						.872
Incidents / participants	47/554	62/569	49/584	57/544	65/576
HR (95% CI)	1.00 (ref.)	1.06 (0.72, 1.57)	0.89 (0.60, 1.33)	1.05 (0.70, 1.55)	1.03 (0.70, 1.52)
Hypertension							.894
No						.045
Incidents / participants	75/1262	73/1205	82/1164	96 / 1303	115 / 1306
HR (95% CI)	1.00 (ref.)	0.94 (0.68, 1.30)	1.03 (0.75, 1.42)	1.11 (0.98, 1.51)	1.26 (1.03, 1.71)
Yes						.129
Incidents / participants	122/1157	170/1156	165/1254	151 / 1091	155 / 1199
HR (95% CI)	1.00 (ref.)	1.38 (1.09, 1.75)	1.19 (0.94, 1.51)	1.32 (1.03, 1.69)	1.30 (1.01, 1.66)
Hyperlipidemia							.004
No						.005
Incidents / participants	54/1120	74/1052	100/1153	119 / 1285	140 / 1485
HR (95% CI)	1.00 (ref.)	1.33 (0.94, 1.90)	1.23 (0.88, 1.73)	1.46 (1.05, 2.03)	1.59 (1.15, 2.20)
Yes						.379
Incidents / participants	143/1299	169/1309	147/1265	128 / 1109	130 / 1020
HR (95% CI)	1.00 (ref.)	1.16 (0.93, 1.46)	1.08 (0.85, 1.36)	1.13 (0.88, 1.44)	1.15 (0.90, 1.48)
Diabetes							.843
No						.019
Incidents / participants	149/2051	185/2128	197/2097	202 / 2048	189 / 1887
HR (95% CI)	1.00 (ref.)	1.18 (0.95, 1.47)	1.16 (0.94, 1.44)	1.28 (1.03, 1.60)	1.31 (1.05, 1.64)
Yes						.263
Incidents / participants	47/360	76/413	38/348	58 / 391	63 / 374
HR (95% CI)	1.00 (ref.)	1.34 (0.92, 1.94)	0.95 (0.61, 1.47)	1.25 (0.84, 1.86)	1.34 (0.90, 1.99)

CHD: coronary heart disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase.

^a Adjusted covariates for age, sex, body mass index, education levels, smoking, drinking, physical activity, history of CHD, hypertension, hyperlipidemia, diabetes, liver enzymes including ALT, AST, and ALP except for the stratified covariate itself.