Background
Methods
Study participants
Data collection and measures
Genotyping
Statistical analyses
Results
Socio-economic factors, lifestyle habits, clinical factors and comorbidities by PNPLA3 rs738409 and TM6SF2 rs58542926
PNPLA3 rs738409 | TM6SF2 rs58542926 | |||||
---|---|---|---|---|---|---|
CC | CG | GG | CC | CT | TT | |
N (%) | 2238 (59.6 %) | 1347 (35.8 %) | 173 (4.6 %) | 3471 (80.6 %) | 580 (13.5 %) | 28 (0.7 %) |
Annual number of outpatient visitsa | 7.5 (2.5) | 7.5 (3.5) | 7.5 (2.6) | 4.9 (2.2) | 7.3 (2.6) | 7.9 (2.5)* |
Hospitalization during the last year, % | 14.1 | 14.2 | 19.7* | 7.4 | 13.7 | 14.6 |
Annual number of inpatient days among subjects with hospitalization during the last year, daysa | 9.7 (2.6) | 9.7 (2.3) | 10.6 (2.5)* | 6.9 (1.2) | 9.6 (2.5) | 11.1 (2.5)** |
Age, years | 49.91 (16.28) | 49.40 (16.58) | 50.00 (15.83) | 49.3 (16.2) | 48.7 (16.5) | 47.4 (16.1) |
Female, % | 50.7 | 50.6 | 56.7* | 50.1 | 54.7 | 74.1 |
School education (<10 years), % | 39.1 | 37.7 | 39.1 | 38.4 | 40.3 | 33.3* |
Equivalent household income, €a | 852 (1.7) | 833 (1.8) | 879 (1.7) | 852 (1.7) | 807 (1.8) | 929 (1.6) |
Alcohol intake, g/da | 7.3 (3.5) | 7.5 (3.4) | 5.9 (2.5)** | 7.5 (3.5) | 6.9 (3.5) | 5.1 (3.9) |
Regular smoking, % | 29.7 | 32.3 | 28.3 | 30.4 | 31.3 | 25.9 |
Body mass index, kg/m2 | 27.3 (4.8) | 27.1 (4.8) | 26.9 (4.8) | 27.3 (4.5) | 27.3 (4.8) | 26.2 (4.3) |
Obesity, % | 26.8 | 24.1 | 22.0 | 25.3 | 28.1 | 14.8 |
Waist circumference, cm | 90.0 (14.0) | 88.4 (13.8)** | 87.3 (13.3)** | 89.2 (13.9) | 89.2 (14.2) | 84.4 (13.1) |
Systolic blood pressure, mmHg | 135.6 (20.7) | 135.6 (20.7) | 136.2 (20.8) | 132.4 (18.5) | 136.0 (21.2) | 134.6 (20.8) |
Hypertension, % | 51.9 | 52.8 | 52.6 | 37.0 | 52.9 | 49.1 |
Ferritin, μg/la | 68.4 (2.7) | 68.6 (2.6) | 61.56 (2.58) | 68.2 (2.6) | 68.5 (2.7) | 66.6 (3.0) |
Hepatic steatosis, % | 27.4 | 31.9** | 39.9** | 28.4 | 36.3** | 44.4* |
Increased ALT (>75th percentile), % | 17.9 | 22.7** | 28.3** | 19.4 | 24.2* | 29.6 |
GFR, ml.min.1.73 m2 | 79.5 (15.1) | 80.0 (15.1) | 79.8 (15.1) | 79.5 (15.1) | 80.9 (14.8) | 78.8 (11.1) |
High-density lipoprotein cholesterol, | 1.45 (0.45) | 1.46 (0.43) | 1.49 (0.43) | 1.45 (0.44) | 1.48 (0.43) | 1.50 (0.39) |
Low-density cholesterol, mmol/l | 3.59 (1.18) | 3.54 (1.13) | 3.54 (1.25) | 3.59 (1.25) | 3.50 (1.10)* | 2.75 (1.27)** |
Total cholesterol, | 5.80 (1.28) | 5.72 (1.19) | 5.76 (1.32) | 5.79 (1.25) | 5.69 (1.22)** | 4.82 (1.43)** |
Dyslipidemia (TC/HDL-C ratio ≥ 5), % | 27.8 | 25.8 | 24.3 | 27.6 | 24.0 | 14.8 |
triglycerides | 1.91 (1.57) | 1.80 (1.36) | 1.78 (1.31) | 1.89 (1.46) | 1.74 (1.62)** | 1.34 (1.53)** |
Serum glucose | 5.70 (1.87) | 5.62 (1.67) | 5.53 (1.76) | 5.66 (1.81) | 5.70 (1.81) | 5.45 (1.00) |
HbA1c, % | 5.45 (0.97) | 5.42 (0.88) | 5.34 (0.84) | 5.44 (0.92) | 5.42 (0.99) | 5.38 (0.49) |
Diabetes, % | 8.0 | 7.6 | 6.9 | 7.7 | 8.6 | 7.4 |
Upper gastrointestinal disease (ulcer, hernia, reflux), % | 1.6 | 2.1 | 1.7 | 1.7 | 2.1 | 3.7 |
Myocardial infarction, % | 3.4 | 3.3 | 3.5 | 3.3 | 3.4 | 3.9 |
Angina pectoris, % | 5.0 | 3.4* | 1.7* | 3.9 | 5.8* | 7.4 |
Congestive heart failure, % | 12.51 | 10.62 | 14.45 | 22.2 | 12.0 | 11.1 |
Arthritis | 7.2 | 7.3 | 11.6* | 7.4 | 7.7 | 11.1 |
Osteoporosis | 4.7 | 4.3 | 4.1 | 4.5 | 4.9 | 0 |
Chronic obstructive pulmonary disease, % | 6.1 | 5.0 | 4.6 | 5.6 | 5.4 | 14.8 |
Multiple sclerosis or Parkinson’s disease, % | 0.5 | 0.2 | 0 | 0.4 | 0.2 | 0 |
Stroke or TIA, % | 2.3 | 1.6 | 1.7 | 2.1 | 1.7 | 0 |
Peripheral vascular disease, % | 1.4 | 1.0 | 0.6 | 1.4 | 0 | 0 |
Degenerative disc disease, % | 37.2 | 35.0 | 38.2 | 36.6 | 35.4 | 40.7 |
Anxiety, % | 23.5 | 22.9 | 22.0 | 23.2 | 23.0 | 33.3 |
Depression, % | 12.4 | 12.8 | 17.9* | 12.6 | 13.9 | 14.8 |
Functional Comorbidity Indexa | 1.6 (1.7) | 1.6 (1.6) | 1.7 (1.7) | 1.6 (1.6) | 1.6 (1.6) | 1.7 (1.6) |
Regression analyses of PNPLA3 rs738409and TM6SF2 rs58542926 with outpatient services utilization and hospitalization
Reference: PNPLA3 rs738409 CC | Effect on annual outpatient visits, % Bootstrap (95 %-CI)a | Hospitalization, OR Bootstrap (95 %-CI) | Effect on annual inpatient days, % Bootstrap (95 %-CI)a |
---|---|---|---|
Model 1 (age, sex, school education, income, alcohol intake, smoking status, GFR) | |||
CG | −3.17 (−9.00, +4.08) | 1.01 (0.83, 1.21) | −9.00 (−25.12, +7.10) |
GG | +2.93 (−12.9, +21.7) | 1.51 (1.02, 2.15)* | +7.38 (−22.45, +42.87) |
Model 2: model 1 + Functional Comorbidity Index | |||
CG | −2.43 (−8.5, +3.5) | 1.03 (0.89, 1.23) | −10.31 (−23.1, +10.44) |
GG | +1.81 (−11.62, +18.29) | 1.51 (1.01, 2.28)* | +7.49 (−21.24, +48.61) |
Model 3: Model 2 + hepatic steatosis | |||
CG | −2.64 (−8.89, +2.65) | 1.03 (0.83, 1.23) | −11.30 (−26.33, +8.15) |
GG | +1.98 (−9.49, +19.92) | 1.54 (1.03, 2.17)* | +7.51 (−23.45, +59.25) |
Model 4: Model 2 + ALT | |||
CG | −2.33 (−8.82, +4.83) | 1.04 (0.85, 1.26) | −9.90 (−23.65, +3.81) |
GG | +2.84 (−9.20, +21.91) | 1.56 (1.02, 2.27)* | +8.80 (−22.86, 50.62) |
Model 5: Model 2 + ferritin | |||
CG | −2.41 (−7.74, +5.52) | 1.02 (0.85, 1.20) | −11.3 (−25.02, +7.89) |
GG | +1.57 (−12.67, +25.28) | 1.49 (1.01, 2.35)* | +7.42 (−67.07, +49.20) |
Model 6: Model 1 + metabolic syndrome | |||
CG | −2.45 (−8.97, +4.41) | 1.03 (0.84, 1.31) | −9.73 (−24.1, +10.60) |
GG | +4.13 (−9.85, +24.94) | 1.53 (1.02, 2.28)* | +6.23 (−24.49, +40.60) |
Model 7: Model 1 + waist circumference | |||
CG | −2.48 (−9.04, +4.56) | 1.02 (0.84, 1.23) | −9.34 (−25.14, +7.67) |
GG | +4.18 (−9.17, +20.31) | 1.51 (1.02, 2.26)* | +7.29 (−22.41, +50.45) |
Model 8: Model 1 + BMI | |||
CG | −2.74 (−8.65, +4.67) | 1.02 (0.85, 1.22) | −9.44 (−23.11, +8.88) |
GG | +3.31 (−14.11, +20.54) | 1.51 (0.99, 2.23)* | +6.75 (−28.51, +43.60) |
Model 9: Model 1 + triglycerides | |||
PNPLA3 | |||
CG | −2.70 (−8.43, +5.48) | 1.02 (0.87, 1.31) | −7.83 (−23.36, +10.71) |
GG | +3.16 (−11.65, +23.22) | 1.51 (1.01, 2.21)* | +7.02 (+22.9, +58.96) |
Model 10: Model 1 + HDL cholesterol | |||
CG | −2.83 (−9.55, +3.89) | 1.005 (0.83, 1.25) | −9.52 (−23.12, +7.25) |
GG | +3.24 (−7.22, +23.89) | 1.52 (1.02, 2.22)* | +7.97 (−27.34, +44.13) |
Model 11: Model 1 + systolic blood pressure | |||
CG | −2.69 (−8.49, +3.44) | 1.02 (0.85, 1.24) | −9.03 (+26.12, +10.44) |
GG | +3.44 (−14.57, +19.68) | 1.52 (1.03, 2.32)* | +7.02 (−22.73, +43.84) |
Model 12: Model 1 + serum glucose | |||
CG | −2.92 (−9.10, +4.59) | 1.02 (0.83, 1.22) | −9.59 (−24.54, +12.97) |
GG | +3.30 (+11.4, +23.1) | 1.49 (1.02, 2.24)* | +6.06 (−24.05, 43.55) |
Model 13: Model 1 + hbA1c | |||
CG | −3.32 (−9.67, +4.24) | 1.02 (0.83, 1.22) | −9.20 (−23.78, +7.61) |
GG | +4.44 (−11.01, +26.81) | 1.52 (0.96, 2.05)* | +7.79 (−21.70, +41.90) |
Reference: TM6SF2 rs58542926 CC | Effect on annual outpatient visits, % Bootstrap (95 %-CI),a | Hospitalization, OR Bootstrap (95 %-CI) | Effect on annual inpatient days, % Bootstrap (95 %-CI),a |
---|---|---|---|
Model 1 (age, sex, school education, income, alcohol intake, smoking status, eGFR) | |||
CT | +53.04 (+18.33, +115.29)* | 1.93 (0.67, 5.03) | +85.33 (+18.94, +188.78)* |
TT | +67.56 (+28.28, +134.59)* | 1.81 (0.59, 5.08) | +123.74 (+33.14, +275.97)* |
Model 2: model 1 + Functional Comorbidity Index | |||
CT | +57.82 (+23.62, +113.43)* | 1.96 (0.68, 5.56) | +94.01 (37.83, 173.1)* |
TT | +69.79 (+31.60, 145.43)* | 1.82 (0.72, 5.75) | +133.49 (51.86, 259.0)* |
Model 3: Model 2 + hepatic steatosis | |||
CT | +56.54 (+15.03, +110.21)* | 1.93 (0.78, 5.44) | +93.36 (+35.99, +174.93)* |
TT | +69.28 (+24.58, +130.01)* | 1.80 (0.68, 5.10) | +132.83 (+51.83, +257.1)* |
Model 4: Model 2 + ALT | |||
CT | +56.51 (+19.96, +112.33)* | 1.91 (0.65, 4.98) | +91.50 (+40.32, +161.36)* |
TT | +69.65 (+31.38, 136.92)* | 1.79 (0.63, 5.04) | +131.08 (+53.60, 247.63)* |
Model 5: Model 2 + ferritin | |||
CT | +55.75 (+21.37, +106.99)* | 1.83 (0.63, 5.38) | +94.00 (+37.65, +173.43)* |
TT | +69.09 (+31.92, +134.08)* | 1.73 (0.56, 4.98) | +133.47 (+52.00, +259.61)* |
Model 6: Model 1 + metabolic syndrome | |||
CT | +45.21 (+7.26, +107.45)** | 1.81 (0.65, 5.34) | +74.58 (+13.38, +168.79)** |
TT | +60.48 (+14.54, 124.9)* | 1.73 (0.68, 5.63) | +114.92 (+30.05, +255.17)* |
Model 7: Model 1 + waist circumference | |||
CT | +49.27 (7.63, +95.57)* | 1.92 (0.80, 5.12) | +90.50 (+32.88, +73.10)* |
TT | +63.27 (+23.38, +138.34)* | 1.79 (0.70, 4.71) | +131.9 (+47.56, 264.6)* |
Model 8: Model 1 + BMI | |||
CT | +50.28 (+12.46, 106.67)* | 1.92 (0.58, 5.49) | +92.70 (+27.32, 191.65)* |
TT | +64.73 (+23.39, +119.28)* | 1.80 (0.55, 5.21) | +133.3 (+41.87, 283.35)* |
Model 9: Model 1 + triglycerides | |||
CT | +50.08 (+15.38, +195.16)* | 1.89 (0.68, 5.61) | +83.47 (+16.35, +189.29)* |
TT | +65.92 (+23.72, +120.61)* | 1.79 (0.62, 5.14) | +119.17 (+29.87, 269.89)* |
Model 10: Model 1 + HDL cholesterol | |||
CT | +50.69 (+15.98, +238.0)* | 1.89 (0.69, 5.14) | +77.12 (+11.73, +180.78)** |
TT | +66.26 (+26.23, +158.59)* | 1.75 (0.64, 5.04) | +116.1 (+27.42, +266.50)* |
Model 11: Model 1 + systolic blood pressure | |||
CT | +53.16 (+22.27, +141.1)* | 1.93 (0.60, 5.09) | +84.63 (+18.88, +186.75)* |
TT | +66.64 (+30.17, 167.93)* | 1.77 (0.51, 4.73) | +124.11 (+33.36, +276.62)* |
Model 12: Model 1 + serum glucose | |||
CT | +50.51 (+13.57, +105.38)* | 1.91 (0.64, 5.50) | +82.57 (+17.68, 183.2)* |
TT | +63.36 (+21.72, 116.9)* | 1.81 (0.58, 5.47) | +121.82 (+32.44, 271.50)* |
Model 13: Model 1 + hbA1c | |||
CT | +53.38 (+21.00, +109.69)* | 1.94 (0.82, 5.74) | +85.09 (+18.75, +188.49)* |
TT | +67.02 (+29.44, 23.17)* | 1.82 (0.72, 5.52) | +122.18 (+32.83, 275.01)* |
Incremental predictive power of PNPLA3 rs738409and TM6SF2 rs58542926
Statistical evaluation criteria | Annual outpatient visits | Hospitalization | Annual inpatient days |
---|---|---|---|
Median (Nagelkerke R2) | |||
Model 2 | 22.62 | 1.61 | 0.0175 |
Model 2 + PNPLA3 rs738409 | 22.96 | 1.74 | 0.0138 |
Model 2 + TM6SF2 rs58542926 | 20.33 | 1.56 | 0.0218 |
Model 2 + PNPLA3 rs738409 + TM6SF2 rs58542926 | 22.73 | 1.99 | 0.0268 |
Median (root mean squared error) | – | ||
Model 2 | 8.70 | 8.111 | |
Model 2 + PNPLA3 rs738409 | 8.78 | 7.121 | |
Model 2 + TM6SF2 rs58542926 | 8.69 | 7.422 | |
Model 2 + PNPLA3 rs738409 + TM6SF2 rs58542926 | 8.68 | 7.174 | |
Median (absolute prediction error) | – | ||
Model 2 | 5.89 | 3.605 | |
Model 2 + PNPLA3 rs738409 | 5.97 | 3.548 | |
Model 2 + TM6SF2 rs58542926 | 6.01 | 3.565 | |
Model 2 + PNPLA3 rs738409 + TM6SF2 rs58542926 | 6.07 | 3.594 | |
Area under ROC curve (p-value for comparison to model 2) | – | – | |
Model 2 | 0.605 | ||
Model 2 + PNPLA3 rs738409 | 0.605 (0.846) | ||
Model 2 + TM6SF2 rs58542926 | 0.606 (0.868) | ||
Model 2 + PNPLA3 rs738409 + TM6SF2 rs58542926 | 0.606 (0.965) |