Background
Materials and methods
Data source
Study population
Vitamin D status
Biomarkers of systemic inflammatory response
Biomarkers | Equation | |
---|---|---|
CRP based | CRP | Measured value, mg/L |
mGPS | 0: CRP ≤ 10 mg/L and albumin ≥ 35 g/L 1: CRP > 10 mg/L and albumin ≥ 35 g/L 2: CRP > 10 mg/L and albumin < 35 g/L | |
HS_mGPS | 0: CRP ≤ 3 mg/L and albumin ≥ 35 g/L 1: CRP > 3 mg/L and albumin ≥ 35 g/L 2: CRP > 3 mg/L and albumin < 35 g/L | |
Blood cell count based | NLR | Neutrophil count/lymphocyte count |
PLR | Platelet count/neutrophil count | |
LMR | Lymphocyte count/monocyte count | |
SII | Platelet count × neutrophil count/lymphocyte count | |
PNI | Serum albumin (g/L) + 0.005 × 1000 × lymphocyte count (109/L) | |
NPS | 0: Neutrophils ≤ 7.5 × 109/L and platelets ≤ 400 × 109/L 1: Neutrophils > 7.5 × 109/L or platelets > 400 × 109/L 2: Neutrophils > 7.5 × 109/L and platelets > 400 × 109/L |
Mortality
Covariates
Statistical analyses
General remarks
Disadvantageous levels of biomarkers of systemic inflammatory response and their association with mortality
Association of vitamin D status and biomarkers of systemic inflammatory response
Association of vitamin D status and mortality
Mediation analysis
Results
Description of the study population
Variables | Ntotal (%) a | Median (IQR) |
---|---|---|
Sex | ||
Male | 186,755 (46.9) | NA |
Female | 210,982 (53.1) | NA |
Age (years) | 397,737 (100.0) | 58 (50; 63) |
BMI (kg/m2) | 396,196 (100.0) | 26.7 (24.1; 29.9) |
Smoking | ||
Never | 217,643 (54.8) | NA |
Former | 137,932 (34.8) | NA |
Current | 41,560 (10.4) | NA |
Alcohol consumptionb | ||
Abstainer | 123,409 (31.0) | NA |
Low | 159,230 (40.0) | NA |
Medium | 67,419 (17.0) | NA |
High | 47,679 (12.0) | NA |
Hypertension | 107,411 (27.0) | NA |
Diabetes | 19,953 (5.1) | NA |
CHD | 18,739 (4.7) | NA |
History of any cancerc | 29,710 (7.5) | NA |
25(OH)D levels (nmol/L) | 397,737 (100.0) | 46.8 (32.3; 62.4) |
Vitamin D statusd | ||
Vitamin D deficiency | 83,929 (21.1) | NA |
Vitamin D insufficiency | 136,692 (34.4) | NA |
Vitamin D sufficiency | 177,116 (44.5) | NA |
CRP based biomarkers of SIR | ||
CRP | 397,737 (100.0) | 1.3 (0.7; 2.8) |
mGPS | ||
0 | 381,157 (95.8) | NA |
1 | 16,496 (4.2) | NA |
2 | 84 (< 0.1) | NA |
HS_mGPS | ||
0 | 307,861 (77.4) | NA |
1 | 89,728 (22.6) | NA |
2 | 148 (< 0.1) | NA |
Blood cell based biomarkers of SIR | ||
NLR | 397,737 (100.0) | 2.1 (1.7; 2.8) |
PLR | 397,737 (100.0) | 132.3 (105.4; 166.5) |
LMR | 397,737 (100.0) | 4.2 (3.2; 5.3) |
SII | 397,737 (100.0) | 529.0 (392.2; 716.8) |
PNI | 397,737 (100.0) | 54.7 (52.2; 57.4) |
NPS | ||
0 | 382,192 (96.1) | NA |
1 | 14,811 (3.7) | NA |
2 | 734 (0.2) | NA |
Disadvantageous levels of biomarkers of systemic inflammatory response and their association with mortality
Mortality | Biomarkers of systemic inflammatory response, HR (95% CI), N = 397,737 | ||||||||
---|---|---|---|---|---|---|---|---|---|
CRP > 2.75 mg/L | mGPS ≥ 1 | HS_mGPS ≥ 1 | NLR > 2.78 | PLR > 237 | LMR < 2.56 | SII > 717 | PNI < 50 | NPS ≥ 1 | |
All-cause mortality (Ndeaths = 29,548) | |||||||||
Adjusted for age and sex | 1.76 (1.72, 1.80) | 2.18 (2.10, 2.27) | 1.77 (1.73, 1.82) | 1.48 (1.45, 1.52) | 1.54 (1.48, 1.61) | 1.54 (1.49, 1.58) | 1.48 (1.45, 1.52) | 1.52 (1.47, 1.56) | 2.24 (2.14, 2.34) |
Plus BMI and waist circumference | 1.57 (1.54, 1.61) | 1.91 (1.83, 1.99) | 1.59 (1.55, 1.64) | 1.47 (1.43, 1.51) | 1.62 (1.55, 1.69) | 1.52 (1.48, 1.57) | 1.47 (1.43, 1.50) | 1.51 (1.46, 1.55) | 2.10 (2.01, 2.19) |
Plus vitamin D status | 1.56 (1.52, 1.60) | 1.89 (1.81, 1.97) | 1.58 (1.54, 1.62) | 1.46 (1.42, 1.49) | 1.61 (1.54, 1.68) | 1.53 (1.48, 1.57) | 1.45 (1.41, 1.48) | 1.50 (1.46, 1.55) | 2.04 (1.95, 2.13) |
CVD mortality (Ndeaths = 6,091) | |||||||||
Adjusted for age and sex | 2.00 (1.90, 2.11) | 2.28 (2.09, 2.5) | 2.04 (1.93, 2.15) | 1.68 (1.60, 1.77) | 1.37 (1.24, 1.52) | 1.68 (1.58, 1.78) | 1.64 (1.55, 1.72) | 1.51 (1.41, 1.62) | 2.56 (2.34, 2.80) |
Plus BMI and waist circumference | 1.61 (1.53, 1.70) | 1.79 (1.64, 1.96) | 1.64 (1.55, 1.73) | 1.67 (1.58, 1.75) | 1.51 (1.36, 1.67) | 1.66 (1.56, 1.77) | 1.61 (1.53, 1.70) | 1.50 (1.40, 1.60) | 2.32 (2.12, 2.54) |
Plus vitamin D status | 1.60 (1.51, 1.69) | 1.77 (1.62, 1.94) | 1.62 (1.54, 1.71) | 1.65 (1.57, 1.74) | 1.50 (1.35, 1.66) | 1.66 (1.56, 1.77) | 1.59 (1.51, 1.68) | 1.50 (1.40, 1.60) | 2.24 (2.05, 2.46) |
Cancer mortality (Ndeaths = 14,895) | |||||||||
Adjusted for age and sex | 1.62 (1.57, 1.67) | 1.89 (1.78, 2.01) | 1.62 (1.57, 1.68) | 1.30 (1.26, 1.35) | 1.51 (1.42, 1.61) | 1.38 (1.32, 1.45) | 1.34 (1.29, 1.39) | 1.38 (1.32, 1.45) | 1.77 (1.66, 1.9) |
Plus BMI and waist circumference | 1.52 (1.47, 1.58) | 1.75 (1.65, 1.86) | 1.53 (1.47, 1.58) | 1.30 (1.26, 1.35) | 1.56 (1.47, 1.66) | 1.38 (1.32, 1.44) | 1.33 (1.29, 1.38) | 1.39 (1.32, 1.45) | 1.70 (1.59, 1.82) |
Plus vitamin D status | 1.52 (1.46, 1.57) | 1.74 (1.64, 1.85) | 1.52 (1.46, 1.57) | 1.29 (1.25, 1.34) | 1.56 (1.46, 1.66) | 1.38 (1.32, 1.44) | 1.32 (1.28, 1.37) | 1.38 (1.32, 1.45) | 1.67 (1.57, 1.79) |
Respiratory mortality (Ndeaths = 2,086) | |||||||||
Adjusted for age and sex | 2.73 (2.51, 2.98) | 3.73 (3.30, 4.22) | 2.75 (2.52, 2.99) | 2.02 (1.85, 2.20) | 2.15 (1.87, 2.48) | 2.03 (1.83, 2.25) | 2.25 (2.06, 2.45) | 1.82 (1.63, 2.03) | 4.75 (4.21, 5.37) |
Plus BMI and waist circumference | 2.63 (2.40, 2.88) | 3.25 (2.87, 3.67) | 2.61 (2.39, 2.86) | 1.96 (1.79, 2.14) | 2.16 (1.87, 2.49) | 1.97 (1.78, 2.19) | 2.19 (2.01, 2.39) | 1.76 (1.57, 1.96) | 4.35 (3.85, 4.92) |
Plus vitamin D status | 2.59 (2.37, 2.84) | 3.19 (2.82, 3.62) | 2.56 (2.34, 2.80) | 1.93 (1.77, 2.10) | 2.13 (1.85, 2.46) | 1.98 (1.78, 2.19) | 2.14 (1.96, 2.33) | 1.76 (1.58, 1.96) | 4.13 (3.65, 4.67) |
Association of vitamin D status and biomarkers of systemic inflammatory response
Biomarkers of systemic inflammatory response | Vitamin D Deficiency | Vitamin D Insufficiency | Vitamin D Sufficiency | |
---|---|---|---|---|
OR (95% CI), FDR | OR (95% CI), FDR | OR (95% CI), FDR | ||
Ntotal = 83,929 | Ntotal = 136,692 | Ntotal = 177,116 | ||
CRP based | CRP, Ncase >2.75 mg/L (%) | 25,271 (30.1) | 35,106 (25.7) | 38,982 (22.0) |
Model 1a | 1.65 (1.62, 1.69), < .001 | 1.27 (1.25, 1.29), < .001 | Ref | |
Model 2b | 1.60 (1.56, 1.63), < .001 | 1.27 (1.24, 1.29), < .001 | Ref | |
Model 3c | 1.37 (1.34, 1.40), < .001 | 1.18 (1.16, 1.20), < .001 | Ref | |
Model 4d | 1.01 (0.99, 1.04), 0.271 | 0.97 (0.96, 0.99), 0.007 | Ref | |
Model 5e | 0.96 (0.94, 0.99), 0.005 | 0.96 (0.94, 0.98), < .001 | Ref | |
mGPS, Ncase ≥1 (%) | 4659 (5.6) | 5598 (4.1) | 6323 (3.6) | |
Model 1a | 1.65 (1.59, 1.73), < .001 | 1.17 (1.13, 1.22), < .001 | Ref | |
Model 2b | 1.55 (1.48, 1.62), < .001 | 1.15 (1.11, 1.20), < .001 | Ref | |
Model 3c | 1.28 (1.22, 1.34), < .001 | 1.06 (1.02, 1.10), 0.008 | Ref | |
Model 4d | 0.97 (0.93, 1.02), 0.233 | 0.90 (0.87, 0.94), < .001 | Ref | |
Model 5e | 0.92 (0.88, 0.97), 0.002 | 0.89 (0.86, 0.93), < .001 | Ref | |
HS_mGPS, Ncase ≥1 (%) | 23,179 (27.6) | 31,694 (23.2) | 35,003 (19.8) | |
Model 1a | 1.68 (1.64, 1.71), < .001 | 1.27 (1.25, 1.29), < .001 | Ref | |
Model 2b | 1.62 (1.58, 1.65), < .001 | 1.26 (1.24, 1.29), < .001 | Ref | |
Model 3c | 1.38 (1.35, 1.42), < .001 | 1.18 (1.16, 1.20), < .001 | Ref | |
Model 4d | 1.03 (1.00, 1.05), 0.059 | 0.97 (0.95, 0.99), 0.006 | Ref | |
Model 5e | 0.97 (0.95, 1.00), 0.050 | 0.96 (0.94, 0.98), < .001 | Ref | |
Blood cell based | NPS, Ncase ≥1 (%) | 4506 (5.4) | 5187 (3.8) | 5852 (3.3) |
Model 1a | 1.67 (1.60, 1.75), < .001 | 1.16 (1.11, 1.20), < .001 | Ref | |
Model 2b | 1.54 (1.47, 1.61), < .001 | 1.13 (1.09, 1.17), < .001 | Ref | |
Model 3c | 1.23 (1.17, 1.29), < .001 | 1.04 (1.00, 1.08), 0.097 | Ref | |
Model 4d | 1.14 (1.09, 1.20), < .001 | 0.99 (0.96, 1.04), 0.817 | Ref | |
Model 5e | 1.13 (1.07, 1.18), < .001 | 1.01 (0.97, 1.06), 0.534 | Ref | |
NLR, Ncase >2.78 (%) | 22,111 (26.3) | 33,797 (24.7) | 43,264 (24.4) | |
Model 1a | 1.17 (1.15, 1.20), < .001 | 1.03 (1.01, 1.05), 0.001 | Ref | |
Model 2b | 1.13 (1.11, 1.16), < .001 | 1.02 (1.00, 1.04), 0.030 | Ref | |
Model 3c | 1.08 (1.06, 1.10), < .001 | 1.00 (0.98, 1.01), 0.770 | Ref | |
Model 4d | 1.09 (1.07, 1.12), < .001 | 1.01 (0.99, 1.03), 0.291 | Ref | |
Model 5e | 1.11 (1.08, 1.13), < .001 | 1.03 (1.01, 1.05), 0.003 | Ref | |
PLR, Ncase >237 (%) | 4418 (5.3) | 6598 (4.8) | 9009 (5.1) | |
Model 1a | 1.07 (1.02, 1.11), 0.003 | 0.96 (0.93, 0.99), 0.013 | Ref | |
Model 2b | 1.04 (1.00, 1.08), 0.074 | 0.95 (0.92, 0.98), 0.002 | Ref | |
Model 3c | 1.02 (0.98, 1.07), 0.406 | 0.93 (0.90, 0.96), < .001 | Ref | |
Model 4d | 1.13 (1.08, 1.18), < .001 | 1.00 (0.96, 1.03), 0.880 | Ref | |
Model 5e | 1.17 (1.12, 1.22), < .001 | 1.04 (1.00, 1.07), 0.060 | Ref | |
LMR, Ncase <2.56 (%) | 8409 (10.0) | 13,680 (10.0) | 18,326 (10.4) | |
Model 1a | 1.08 (1.04, 1.11), < .001 | 1.00 (0.97, 1.02), 0.880 | Ref | |
Model 2b | 1.05 (1.02, 1.08), 0.003 | 0.99 (0.97, 1.02), 0.500 | Ref | |
Model 3c | 1.04 (1.01, 1.07), 0.027 | 0.98 (0.96, 1.01), 0.195 | Ref | |
Model 4d | 1.05 (1.02, 1.09), 0.003 | 0.99 (0.97, 1.02), 0.664 | Ref | |
Model 5e | 1.06 (1.03, 1.10), 0.001 | 1.01 (0.99, 1.04), 0.443 | Ref | |
SII, Ncase >717 mg/L (%) | 23,213 (27.7) | 33,921 (24.8) | 42,207 (23.8) | |
Model 1a | 1.28 (1.26, 1.31), < .001 | 1.07 (1.05, 1.09), < .001 | Ref | |
Model 2b | 1.25 (1.22, 1.27), < .001 | 1.06 (1.04, 1.08), < .001 | Ref | |
Model 3c | 1.17 (1.15, 1.20), < .001 | 1.04 (1.02, 1.06), < .001 | Ref | |
Model 4d | 1.17 (1.14, 1.20), < .001 | 1.04 (1.02, 1.06), < .001 | Ref | |
Model 5e | 1.18 (1.15, 1.20), < .001 | 1.05 (1.04, 1.07), < .001 | Ref | |
PNI, Ncase <50 (%) | 8320 (9.9) | 13,047 (9.5) | 17,550 (9.9) | |
Model 1a | 1.14 (1.10, 1.17), < .001 | 1.01 (0.99, 1.04), 0.391 | Ref | |
Model 2b | 1.09 (1.06, 1.12), < .001 | 0.99 (0.97, 1.02), 0.716 | Ref | |
Model 3c | 1.07 (1.04, 1.10), < .001 | 0.98 (0.96, 1.01), 0.186 | Ref | |
Model 4d | 1.07 (1.04, 1.11), < .001 | 0.99 (0.97, 1.02), 0.534 | Ref | |
Model 5e | 1.10 (1.06, 1.14), < .001 | 1.02 (0.99, 1.04), 0.218 | Ref |
Association of vitamin D status and mortality
Outcome: Mortality | Covariates adjusted for | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Model 4 a | Model 4 + CRP | Model 4 + mGPS | Model 4 + HS_mGPS | Model 4 + NLR | Model 4 + PLR | Model 4 + LMR | Model 4 + SII | Model 4 + PNI | Model 4 + NPS | |
Exposure: Vitamin D deficiency (n = 83,929) versus sufficient vitamin D status (n = 177,116), HR (95%CI) | ||||||||||
All-cause (Ndeaths = 19,545) | 1.35 (1.30, 1.39) | 1.35 (1.30, 1.39) | 1.35 (1.30, 1.39) | 1.34 (1.30, 1.39) | 1.34 (1.29, 1.39) | 1.34 (1.30, 1.39) | 1.35 (1.30, 1.39) | 1.33 (1.29, 1.38) | 1.35 (1.30, 1.39) | 1.34 (1.30, 1.39) |
CVD (Ndeaths = 4002) | 1.40 (1.30, 1.51) | 1.40 (1.30, 1.51) | 1.41 (1.30, 1.51) | 1.40 (1.30, 1.51) | 1.39 (1.29, 1.50) | 1.40 (1.30, 1.51) | 1.40 (1.30, 1.51) | 1.39 (1.29, 1.49) | 1.40 (1.30, 1.51) | 1.40 (1.30, 1.51) |
Cancer (Ndeaths = 9833) | 1.20 (1.14, 1.26) | 1.20 (1.14, 1.25) | 1.20 (1.14, 1.26) | 1.19 (1.14, 1.25) | 1.19 (1.13, 1.25) | 1.19 (1.14, 1.25) | 1.20 (1.14, 1.25) | 1.19 (1.13, 1.25) | 1.19 (1.14, 1.25) | 1.19 (1.14, 1.25) |
Respiratory (Ndeaths = 1374) | 1.66 (1.47, 1.89) | 1.66 (1.46, 1.88) | 1.66 (1.47, 1.89) | 1.65 (1.45, 1.87) | 1.65 (1.45, 1.87) | 1.66 (1.46, 1.88) | 1.67 (1.47, 1.89) | 1.63 (1.43, 1.85) | 1.66 (1.47, 1.89) | 1.65 (1.45, 1.87) |
Exposure: Vitamin D insufficiency (n = 136,692) versus sufficient vitamin D status (n = 177,116), HR (95%CI) | ||||||||||
All-cause (Ndeaths = 21,812) | 1.09 (1.06, 1.12) | 1.09 (1.06, 1.13) | 1.10 (1.07, 1.13) | 1.09 (1.06, 1.13) | 1.09 (1.06, 1.12) | 1.09 (1.06, 1.13) | 1.09 (1.06, 1.12) | 1.09 (1.06, 1.12) | 1.09 (1.06, 1.13) | 1.09 (1.06, 1.13) |
CVD (Ndeaths = 4385) | 1.12 (1.05, 1.19) | 1.12 (1.05, 1.19) | 1.12 (1.06, 1.20) | 1.12 (1.05, 1.19) | 1.12 (1.05, 1.19) | 1.12 (1.05, 1.19) | 1.12 (1.05, 1.19) | 1.12 (1.05, 1.19) | 1.12 (1.05, 1.19) | 1.12 (1.06, 1.20) |
Cancer (Ndeaths = 11,414) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.10) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) | 1.05 (1.01, 1.09) |
Respiratory (Ndeaths = 1425) | 1.27 (1.14, 1.41) | 1.27 (1.14, 1.41) | 1.27 (1.14, 1.42) | 1.27 (1.14, 1.41) | 1.27 (1.14, 1.41) | 1.27 (1.14, 1.42) | 1.27 (1.14, 1.41) | 1.26 (1.13, 1.41) | 1.27 (1.14, 1.42) | 1.28 (1.14, 1.42) |
HR (95% CI) per 5 nmol/L increase of 25(OH)D levels in subjects with vitamin D deficiency (25(OH)D < 30 nmol/L) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Covariates adjusted for | ||||||||||
Mortality | Model 4a | Model 4 + CRP | Model 4 + mGPS | Model 4 + HS_mGPS | Model 4 + NLR | Model 4 + PLR | Model 4 + LMR | Model 4 + SII | Model 4 + PNI | Model 4 + NPS |
All-cause (Ndeaths = 7736) | 0.87 (0.85, 0.89) | 0.87 (0.86, 0.89) | 0.87 (0.85, 0.89) | 0.87 (0.86, 0.89) | 0.87 (0.86, 0.90) | 0.88 (0.86, 0.90) | 0.88 (0.86, 0.90) | 0.88 (0.86, 0.90) | 0.87 (0.85, 0.89) | 0.87 (0.86, 0.90) |
CVD (Ndeaths = 1706) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.91) | 0.86 (0.82, 0.90) | 0.86 (0.82, 0.90) |
Cancer (Ndeaths = 3481) | 0.91 (0.88, 0.94) | 0.91 (0.88, 0.94) | 0.91 (0.88, 0.94) | 0.91 (0.88, 0.95) | 0.91 (0.88, 0.94) | 0.91 (0.88, 0.95) | 0.91 (0.88, 0.94) | 0.91 (0.88, 0.95) | 0.91 (0.88, 0.94) | 0.91 (0.88, 0.94) |
Respiratory (Ndeaths = 661) | 0.79 (0.73, 0.86) | 0.79 (0.74, 0.86) | 0.79 (0.73, 0.86) | 0.79 (0.73, 0.86) | 0.80 (0.74, 0.86) | 0.80 (0.74, 0.86) | 0.80 (0.74, 0.86) | 0.80 (0.74, 0.87) | 0.79 (0.73, 0.86) | 0.80 (0.74, 0.86) |