Introduction
Materials and methods
Study population
Risk factor assessment
NAFLD ascertainment
Genotyping
Statistical analyses
Observational analyses
Mendelian randomization
Results
Baseline characteristics and correlates of total bilirubin
Overall (N = 3824) Mean (SD) or median (IQR) or n (%) | Partial correlation r (95% CI)a | Percentage difference (95% CI) in total bilirubin levels per 1 SD higher or compared to reference category of correlateb | |
---|---|---|---|
Total bilirubin (µmol/l) | 7 (5–9) | – | – |
Sex | |||
Female | 2273 (59.4) | – | Ref |
Male | 1551 (40.6) | – | 28% (25, 31)*** |
Questionnaire | |||
Age at survey (years) | 47 (12) | − 0.02 (− 0.06, 0.01) | − 1% (− 2, 0) |
History of diabetes | |||
No | 3801 (99.4) | – | Ref |
Yes | 23 (0.6) | – | − 8% (− 22, 8) |
Smoking status | |||
Non-smokers | 1309 (34.2) | – | Ref |
Current and former smokers | 2515 (65.8) | – | − 12% (− 14, − 9)*** |
Alcohol consumption | |||
Non-consumers | 886 (23.2) | – | Ref |
Current consumers | 2938 (76.8) | – | 3% (0, 7)* |
Physical measurements | |||
BMI (kg/m2) | 24.4 (2.8) | − 0.11 (− 0.15, − 0.09)*** | − 5% (− 6, − 3)*** |
Waist circumference (cm) | 82.6 (9.5) | − 0.08 (− 0.11, − 0.05)*** | − 4% (− 5, − 2)*** |
SBP (mmHg) | 123 (18) | − 0.01 (− 0.04, 0.02) | − 1% (− 2, 1) |
DBP (mmHg) | 71 (9) | − 0.03 (− 0.06, 0.00) | − 1% (− 3, 0) |
Lipid, metabolic, inflammatory, liver, and renal markers | |||
Total cholesterol (mmol/l) | 5.44 (1.07) | − 0.09 (− 0.13, − 0.06)* | − 4% (− 5, − 3)* |
HDL-C (mmol/l) | 1.43 (0.39) | 0.10 (0.07, 0.13)*** | 5% (3, 6)*** |
Triglycerides (mmol/l) | 0.98 (0.75–1.31) | − 0.15 (− 0.18, − 0.12)*** | 6% (− 7, − 5)*** |
Glucose (mmol/l) | 4.60 (0.73) | − 0.05 (− 0.08, − 0.02)* | − 2% (− 3, − 1)* |
GGT (U/L) | 19 (14–27) | − 0.02 (− 0.05, 0.01) | − 1% (− 2, 0) |
ALT (U/L) | 18 (14–23) | 0.03 (0.00, 0.06)* | 1% (0, 3)* |
AST (U/L) | 23 (20–27) | 0.09 (0.06, 0.13)*** | 4% (3, 6)*** |
hsCRP (mg/l) | 0.90 (0.41–2.12) | − 0.24 (− 0.27, − 0.21)*** | − 9% (− 10, − 8)*** |
eGFR (ml/min/1.73 m2) | 90.8 (15.0) | − 0.01 (− 0.04, 0.02) | − 0% (− 2, 1) |
UAE (mg/24 h) | 8.14 (5.91–12.53) | − 0.01 (− 0.04, 0.03) | 1% (− 1, 2) |
Total bilirubin level (µmol/l) | Events/total | Model 1 | Model 2 | Model 3 | Model 4 | ||||
---|---|---|---|---|---|---|---|---|---|
OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | ||
Per 1 SD increase | 434/3824 | 0.72 (0.64 to 0.80) | < 0.001 | 0.78 (0.69 to 0.87) | < 0.001 | 0.77 (0.69 to 0.87) | < 0.001 | 0.82 (0.73 to 0.92) | 0.001 |
T1 (0.95–6) | 208/1627 | Ref. | Ref. | Ref. | Ref. | ||||
T2 (7, 8) | 116/1024 | 0.70 (0.55 to 0.90) | 0.006 | 0.85 (0.65 to 1.10) | 0.209 | 0.85 (0.66 to 1.11) | 0.232 | 0.92 (0.71 to 1.20) | 0.536 |
T3 (≥ 9) | 110/1173 | 0.51 (0.39 to 0.66) | < 0.001 | 0.62 (0.47 to 0.81) | < 0.001 | 0.61 (0.47 to 0.80) | < 0.001 | 0.69 (0.52 to 0.91) | 0.008 |
Total bilirubin levels and risk of incident NAFLD
Total bilirubin level (µmol/l) | Events/total | Model 1 | Model 2 | Model 3 | Model 4 | ||||
---|---|---|---|---|---|---|---|---|---|
OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | ||
Per 1 SD increase | 452/3570 | 0.79 (0.72 to 0.88) | < 0.001 | 0.83 (0.75 to 0.93) | 0.001 | 0.84 (0.75 to 0.93) | 0.001 | 0.87 (0.78 to 0.97) | 0.012 |
T1 (0.95–6) | 229/1476 | Ref. | Ref. | Ref. | Ref. | ||||
T2 (7, 8) | 107/967 | 0.67 (0.53 to 0.86) | 0.002 | 0.75 (0.58 to 0.97) | 0.026 | 0.77 (0.60 to 0.99) | 0.041 | 0.80 (0.62 to 1.04) | 0.094 |
T3 (≥ 9) | 116/1127 | 0.63 (0.49 to 0.81) | < 0.001 | 0.71 (0.55 to 0.92) | 0.009 | 0.73 (0.56 to 0.94) | 0.014 | 0.78 (0.61 to 1.02) | 0.066 |
Gender | Events/total | Model 1 | Model 2 | Model 3 | Model 4 | ||||
---|---|---|---|---|---|---|---|---|---|
OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | ||
NAFLD as measured by Fatty Liver Index | |||||||||
Males | 253/1551 | 0.71 (0.62 to 0.82) | < 0.001 | 0.80 (0.68 to 0.92) | 0.002 | 0.79 (0.68 to 0.92) | 0.002 | 0.81 (0.69 to 0.94) | 0.007 |
Females | 181/2273 | 0.71 (0.59 to 0.85) | < 0.001 | 0.75 (0.63 to 0.90) | 0.002 | 0.75 (0.63 to 0.90) | 0.002 | 0.83 (0.69 to 1.00) | 0.055 |
NAFLD as measured by Hepatic Steatosis Index | |||||||||
Males | 358/1591 | 0.84 (0.72 to 0.97) | 0.020 | 0.92 (0.80 to 1.08) | 0.308 | 0.94 (0.81 to 1.09) | 0.407 | 0.95 (0.81 to 1.11) | 0.527 |
Females | 91/1908 | 0.74 (0.64 to 0.86) | < 0.001 | 0.76 (0.65 to 0.88) | < 0.001 | 0.76 (0.65 to 0.88) | < 0.001 | 0.81 (0.69 to 0.94) | 0.006 |
Mendelian randomization findings
NAFLD outcome | Events/total | Unadjusted OR (95% CIs) | p value | Adjusteda OR (95% CIs) | p value |
---|---|---|---|---|---|
FLI | 187/1610 | 0.98 (0.69 to 1.38) | 0.900 | 0.99 (0.70 to 1.42) | 0.978 |
HSI | 190/1528 | 1.14 (0.81 to 1.59) | 0.451 | 1.10 (0.79 to 1.54) | 0.556 |