Baseline characteristics
In total, 30,430 participants were screened. Among the data exclusions, there were 286 because of a previous history of stroke, 315 because of an unclear stroke history, 372 because of loss to follow-up with unknown vital status, and 1646 because of incomplete information on the NEUT, the LYM and platelet counts, hypertension, diabetes, dyslipidaemia, smoking, alcohol consumption, physical activity, BMI, self-rated health, cancer, genitourinary disease or chest disease. A total of 27,811 participants who were free of stroke at baseline were included in this study. After a mean follow-up time of 11.5 (standard deviation = 2.3) years with 320,859 person-years, 503 stroke deaths (227 ischaemic, 172 haemorrhagic and 104 unclassified) were recorded (Fig. 1).
The baseline characteristics of the participants are presented in Table 1. Compared to the population in the 1st NLR quartile (≤ 1.39), the population in the highest NLR (≥ 2.24) included more men, were older, had more hypertensive, current smoking and drinker, diabetes; had less physical activity, dyslipidemia, genitourinary disease and cancer, and had poorer self-rated health.
Table 1
Baseline characteristics by the NLR quartiles of participants in the GBCS (n = 27811)
Characteristic
|
Quartile of NLR
|
P
|
the 1st
(≤ 1.39)
|
the 2nd
(1.40-1.752)
|
the 3rd
(1.76–2.23)
|
the 4th
(≥ 2.24)
|
Number, n
|
7032
|
6992
|
6762
|
7025
|
|
Age (years)
|
60.8 ± 6.7
|
61.5 ± 6.9
|
62.2 ± 7.1
|
63.5 ± 7.4
|
< 0.001
|
Sex, male (%)
|
1336 (19%)
|
1670 (23.9%)
|
1941 (28.7%)
|
2684 (38.2%)
|
< 0.001
|
Hypertension, n (%)
|
1726 (24.5%)
|
1891 (27%)
|
2017 (29.8%)
|
2182 (31.1%)
|
< 0.001
|
Diabetes, n (% )
|
782 (11.1%)
|
853 (12.2%)
|
925 (13.7%)
|
1069(15.2%)
|
< 0.001
|
Dyslipidemia, n (%)
|
5983 (85.1%)
|
5821 (83.3%)
|
5613 (83%)
|
5607 (79.8%)
|
< 0.001
|
Smoking, n (%)
|
|
|
|
|
< 0.001
|
never
|
6090 (86.6%)
|
5875 (84%)
|
5385 (79.6%)
|
5175 (73.7%)
|
|
ever
|
476 (6.8%)
|
541 (7.8%)
|
623 (9.2%)
|
882 (12.5%)
|
|
current
|
466 (6.6%)
|
576 (8.2%)
|
754 (11.2%)
|
968 (13.8%)
|
|
Alcohol drinking, n (%)
|
|
|
|
|
< 0.001
|
never
|
5056 (71.9%)
|
4969 (71.1%)
|
4700 (69.5%)
|
4816 (68.6%)
|
|
ever
|
132 (1.9%)
|
141 (2%)
|
156 (2.3%)
|
212 (3%)
|
|
current
|
1844 (26.2%)
|
1882 (26.9%)
|
1906 (28.2%)
|
1997 (28.4%)
|
|
Body mass index, kg/㎡
|
|
|
|
|
< 0.001
|
< 18.5
|
280 (4%)
|
275 (3.9%)
|
281 (4.2%)
|
410 (5.8%)
|
|
18.5–23.9
|
3598 (51.1%)
|
3441 (49.2%)
|
3347 (49.5%)
|
3652 (50.7%)
|
|
24–27.9
|
2480 (35.3%)
|
2549 (36.5%)
|
2436 (36%)
|
2392 (34.1%)
|
|
≥ 28
|
674 (9.6%)
|
727 (10.4%)
|
698 (10.3%)
|
661 (9.4%)
|
|
Physical activity, n (%)
|
|
|
|
|
< 0.001
|
inactive
|
610 (8.7%)
|
564 (8.1%)
|
525 (7.8%)
|
556 (7.9%)
|
|
moderate
|
2712 (38.5%)
|
2806 (40.1%)
|
2797 (41.3%)
|
3031 (43.2%)
|
|
active
|
3710 (52.8%)
|
3622 (51.8%)
|
3440 (50.9%)
|
3438 (48.9%)
|
|
Self-rated health, n (% )
|
5880 (83.6%)
|
5847 (83.6%)
|
5539 (81.9%)
|
5711 (81.3%)
|
< 0.001
|
(good/very good)
|
Cancer, n (% )
|
152 (2.2%)
|
141 (2%)
|
120 (1.8%)
|
126 (1.8%)
|
0.28
|
GD, n (% )
|
1995 (28.4%)
|
1906 (27.3%)
|
1732 (25.6%)
|
1772 (25.2%)
|
< 0.001
|
Chest disease, n (% )
|
1092 (15.5%)
|
1004 (14.4%)
|
1009 (14.9%)
|
1108 (15.8%)
|
0.09
|
NEUT, *10^9/L
|
2.8 ± 0.78
|
3.5 ± 0.80
|
4.0 ± 0.93
|
5.0 ± 1.68
|
< 0.001
|
Lym, *10^9/L
|
2.5 ± 0.64
|
2.2 ± 0.50
|
2.0 ± 0.47
|
1.7 ± 0.44
|
< 0.001
|
Platelet, *10^9/L
|
221.4 ± 61
|
226.5 ± 56.7
|
228.4 ± 56
|
233.1 ± 66.1
|
< 0.001
|
hsCRP, mg/L
|
2.9 ± 2.5
|
3.2 ± 2.6
|
3.7 ± 2.8
|
4.2 ± 3.2
|
< 0.001
|
Hypertension: systolic blood pressure, ≥ 140 mmHg, diastolic blood pressure, ≤ 90 mmHg, medication or diagnoseis; diabetes: fasting blood glucose ≥ 7, medication or diagnosis; dyslipidemia: total cholesterol ≥ 5.2 mmol/L, triglyceride ≥ 1.7 mmol/L, low density lipoprotein ≥ 3.4 mmol/L, high density lipoprotein < 1.0 mmol/L, medication or diagnosis; hsCRP: high-sensitivity C-reactive protein; NLR: neutrophil to lymphocyte ratio; NEUT: neutrophil; Lym: lymphocyte; GD: Genitourinary disease (including nephropathy, prostatic disease, and gynecologic diseases); chest disease: including COPD, chronic bronchitis, emphysema, asthma, tuberculosis, and pneumonia. |
TheNEUT and the LYM in relation to the risk of fatal stroke occurrence
Prior to the NLR analysis, we observed that those in the highest NEUT quartile had a significant association with an increased risk for fatal stroke (aHR = 1.45, 95% CI 1.10–1.89, P = 0.008) and fatal ischaemic stroke (aHR = 1.65, 95% CI 1.10–2.47, P = 0.02), while no significant association was obtained between the LYM and the risk of fatal stroke after adjustments for a series of factors (Table 2).
Table 2
Association between the neutrophil and the lymphocyte counts and the risk of fatal stroke in the GBCS, 2003–2017 (n = 27811)
P value trend
|
Quartiles of NEUT (*10^9/L)
|
P value trend
|
Quartiles of LYM (*10^9/L)
|
P value trend
|
the 1st
(< 3.0)
|
the 2nd (3.0-3.6)
|
the 3rd (3.7–4.4)
|
the 4th
(> 4.5)
|
the 1s
t(< 1.8)
|
the 2nd (1.8–2.1)
|
the 3rd (2.2–2.5)
|
the 4th
(> 2.5)
|
Stroke
|
Person years
|
79448
|
83038
|
77517
|
80857
|
|
|
86199
|
93678
|
73358
|
67624
|
|
per 10^5 person-years
|
109.5
|
116.8
|
152.2
|
248.6
|
|
|
178.7
|
156.9
|
140.4
|
146.4
|
|
No. of deaths
|
87
|
97
|
118
|
201
|
|
|
154
|
147
|
103
|
99
|
|
Model 1 (HR; 95% CI)
|
Ref.
|
1.06
(0.79–1.41)
|
1.38 (1.05–1.82)a
|
2.25 (1.75–2.90)c
|
< 0.001
|
Ref.
|
0.88 (0.70–1.10)
|
0.78
(0.61-1.00)
|
0.82 (0.64–1.06)
|
0.07
|
P value
|
|
0.70
|
0.02
|
< 0.001
|
|
|
|
0.26
|
0.05
|
0.13
|
|
Model 2 (HR; 95% CI)
|
Ref.
|
0.87
(0.65–1.17)
|
1.06 (0.80–1.41)
|
1.45 (1.10–1.89)b
|
0.001
|
|
Ref.
|
1.01 (0.80–1.27)
|
0.92
(0.71–1.19)
|
0.95
(0.73–1.24)
|
0.56
|
P value
|
|
0.36
|
0.68
|
0.008
|
|
|
.
|
0.92
|
0.51
|
0.71
|
|
Ischaemic stroke
|
Person years
|
79045
|
82625
|
76875
|
80068
|
|
|
85536
|
93017
|
72896
|
67163
|
|
per 10^5 person-years
|
46.8
|
54.5
|
61.1
|
122.4
|
|
|
86.5
|
77.4
|
52.1
|
64.0
|
|
No. of deaths
|
37
|
45
|
47
|
98
|
|
|
74
|
72
|
38
|
43
|
|
Model 1 (HR; 95% CI)
|
Ref.
|
1.16
(0.75–1.78)
|
1.29 (0.84–1.99)
|
2.59 (1.78–3.79)c
|
< 0.001
|
Ref.
|
0.90
(0.65–1.24)
|
0.60
(0.41–0.89)a
|
0.75
(0.51–1.09)
|
0.03
|
P value
|
|
0.52
|
0.24
|
< 0.001
|
|
|
|
0.51
|
0.01
|
0.13
|
|
Model 2 (HR; 95% CI)
|
Ref.
|
0.95
(0.61–1.48)
|
1.00 (0.64–1.55)
|
1.65 (1.10–2.47)a
|
0.004
|
|
Ref.
|
1.05
(0.75–1.45)
|
0.71
(0.48–1.07)
|
0.89
(0.60–1.32)
|
0.24
|
P value
|
|
0.83
|
0.99
|
0.02
|
|
|
|
0.80
|
0.10
|
0.56
|
|
Haemorrhagic stroke
|
Person years
|
79017
|
82461
|
76779
|
79663
|
|
|
85280
|
92716
|
72823
|
67083
|
|
per 10^5 person-years
|
50.6
|
37.6
|
48.2
|
82.8
|
|
|
64.5
|
43.1
|
57.7
|
52.2
|
|
No. of deaths
|
40
|
31
|
37
|
66
|
|
|
55
|
40
|
42
|
35
|
|
Model 1 (HR; 95% CI)
|
Ref.
|
0.74
(0.46–1.18)
|
0.94 (0.60–1.47)
|
1.61 (1.09–2.39)a
|
0.004
|
|
Ref.
|
0.67
(0.45–1.01)
|
0.89
(0.60–1.33)
|
0.81
(0.53–1.24)
|
0.55
|
P value
|
|
0.20
|
0.79
|
0.02
|
|
|
|
0.05
|
0.57
|
0.34
|
|
Model 2 (HR; 95% CI)
|
Ref.
|
0.63
(0.39–1.02)
|
0.77 (0.49–1.22)
|
1.14 (0.74–1.75)
|
0.26
|
|
Ref.
|
0.77
(0.51–1.16)
|
1.03
(0.68–1.57)
|
0.94
(0.60–1.46)
|
0.94
|
P value
|
|
0.06
|
0.27
|
0.56
|
|
|
|
0.21
|
0.88
|
0.77
|
|
Ref: reference; CP < 0.001, bP < 0.01, aP < 0.05; model 1: a crude hazard ratio model without adjustment for confounders; model 2: a multivariate model adjusted for sex, age, education, occupation, diabetes, hypertension, dyslipidaemia, smoking, alcohol consumption, physical activity, body mass index, self-rated health, cancer, genitourinary disease (including nephropathy, prostatic disease, and gynaecologic diseases), chest disease (including chronic obstructive pulmonary disease, chronic bronchitis, emphysema, asthma, tuberculosis, and pneumonia) and platelet count. |
The NLR in relation to the risk of fatal stroke occurrence
In a restricted cubic splines model, there is an increased trend of the relationship between the NLR and the risk of fatal stroke occurrence, and the cutoff value of NLR level was of 1.19 after adjustments were made in a multivariable adjustment analysis (Fig. 2). Both Table 3 and Fig. 3 shows the NLRs in relation to the risk of fatal stroke occurrence. After adjustment for a series of factors, the NLRs were associated an increased risk of fatal stroke and fatal ischaemic stroke (all P for trend < 0.001); the participants in the 4th NLR quartile (≥ 2.24) had an increased risk of fatal stroke (adjusted HR (aHR) = 1.76, 95% CI 1.33–2.32, P < 0.001) and fatal ischaemic stroke (aHR = 2.15, 95% CI 1.41–3.28, P < 0.001), respectively. Similar results were observed for fatal stroke (men: aHR = 1.96, 95% CI 1.24–3.08, P = 0.004; women: aHR = 1.57, 95% CI 1.10–2.25, P = 0.01) and fatal ischaemic stroke (men: aHR = 2.23, 95% CI 1.17–4.27, P = 0.02; women: aHR = 2.01, 95% CI 1.15–3.53, P = 0.02). Table 4 shows higher NLR in relation to an increased risk of fatal stroke (aHR = 1.89, 95% CI 1.26–2.82, P = 0.002), fatal ischaemic stroke (aHR = 3.34, 95% CI 1.73–6.45, P < 0.001); and an increasing trend was obtained for fatal stroke (P < 0.001) and fatal ischaemic stroke (P < 0.001) after further CRP adjustment.
Table 3
Association between the NLRs and the risk of fatal stroke occurrence in the GBCS (n = 27811)
|
Quartiles of NLR
|
|
the 1st
(≤ 1.39)
|
the 2nd
(1.40-1.752)
|
the 3rd
(1.76–2.23)
|
the 4th
(≥ 2.24)
|
Stroke
|
overall
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.33 (0.98–1.80), P = 0.07
|
2.08 (1.57–2.77), P < 0.001
|
2.78 (2.12–3.65), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.19 (0.87–1.62), P = 0.27
|
1.61 (1.21–2.15), P = 0.001
|
1.76 (1.33–2.32), P < 0.001
|
P for trend
|
< 0.001
|
men
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.04 (0.61–1.78), P = 0.89
|
1.80 (1.11–2.91), P = 0.02
|
2.37 (1.51–3.71), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.07 (0.62–1.83), P = 0.82
|
1.71 (1.05–2.76), P = 0.03
|
1.96 (1.24–3.08), P = 0.004
|
P for trend
|
< 0.001
|
women
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.41 (0.97–2.05), P = 0.07
|
1.99 (1.40–2.85), P < 0.001
|
2.36 (1.66–3.36), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.26 (0.87–1.84), P = 0.23
|
1.58 (1.10–2.26), P = 0.01
|
1.57 (1.10–2.25), P = 0.01
|
P for trend
|
0.007
|
Ischemic stroke
|
overall
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.50 (0.94–2.40), P = 0.09
|
1.86 (1.18–2.93), P = 0.008
|
3.59 (2.38–5.42), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.34 (0.84–2.14), P = 0.22
|
1.40 (0.88–2.20), P = 0.15
|
2.15 (1.41–3.28), P < 0.001
|
P for trend
|
< 0.001
|
men
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.05 (0.48–2.29), P = 0.90
|
1.73 (0.86–3.47), P = 0.13
|
2.73 (1.43–5.20), P = 0.002
|
Model 2 (HR, 95% CI)
|
1.00
|
1.06 (0.49–2.31), P = 0.89
|
1.59 (0.79–3.21), P = 0.19
|
2.23 (1.17–4.27), P = 0.02
|
P for trend
|
0.002
|
women
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.70 (0.94–3.06), P = 0.08
|
1.56 (0.85–2.87), P = 0.16
|
3.11 (1.79–5.39), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.52 (0.84–2.74), P = 0.16
|
1.21 (0.66–2.25), P = 0.54
|
2.01 (1.15–3.53), P = 0.02
|
P for trend
|
0.029
|
Hemorrhagic stroke
|
overall
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
0.99 (0.60–1.64), P = 0.98
|
1.84 (0.19–2.86), P = 0.007
|
1.88 (0.22–2.92), P = 0.005
|
Model 2 (HR, 95% CI)
|
1.00
|
0.93 (0.56–1.53), P = 0.76
|
1.51 (0.97–2.36), P = 0.07
|
1.32 (0.85–2.07), P = 0.22
|
P for trend
|
0.071
|
men
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.03 (0.36–2.97), P = 0.95
|
2.05 (0.82–5.18), P = 0.13
|
2.65 (1.11–6.36), P = 0.03
|
Model 2 (HR, 95% CI)
|
1.00
|
1.12 (0.39–3.24), P = 0.84
|
1.99 (0.79–5.04), P = 0.15
|
2.27 (0.94–5.46), P = 0.07
|
P for trend
|
0.022
|
women
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
0.97 (0.55–1.72), P = 0.93
|
1.73 (1.04–2.88), P = 0.03
|
1.36 (0.79–2.36), P = 0.27
|
Model 2 (HR, 95% CI)
|
1.00
|
0.91 (0.51–1.60), P = 0.73
|
1.43 (0.86–2.38), P = 0.17
|
0.97 (0.55–1.70), P = 0.91
|
P for trend
|
0.66
|
NLR: neutrophil to lymphocyte ratio; model 1: a crude hazard ratio model without adjustments; model 2: a multivariate model adjusted for age, sex, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, physical activity, body mass index, self-rated health, cancer, genitourinary disease (nephropathy, prostatic disease, and gynecologic diseases) and chest disease (COPD, chronic bronchitis, emphysema, asthma, tuberculosis, and pneumonia) and platelet count. |
Table 4
Association between the NLRs and the risk of fatal stroke occurrence among participants without CVD at baseline and further CRP adjustment (n = 10606)
|
Quartiles of NLR
|
|
the 1st
(≤ 1.39)
|
the 2nd
(1.40-1.752)
|
the 3rd
(1.76–2.23)
|
the 4th
(≥ 2.24)
|
Stroke
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.31 (0.84–2.05), P = 0.23
|
2.07 (1.37–3.11), P = 0.001
|
2.60 (1.75–3.85), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.23 (0.79–1.92), P = 0.37
|
1.71 (1.13–2.58), P = 0.01
|
1.89 (1.26–2.82), P = 0.002
|
P for trend
|
< 0.001
|
Ischemic stroke
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.84 (0.89–3.79), P = 0.10
|
2.37 (1.18–4.74), P = 0.02
|
4.57 (2.40–8.70), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.73 (0.84–3.58), P = 0.14
|
1.98 (0.98–3.97), P = 0.06
|
3.34 (1.73–6.45), P < 0.001
|
P for trend
|
< 0.001
|
Hemorrhagic stroke
|
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
0.71 (0.34–1.46), P = 0.35
|
1.54 (0.85–2.81), P = 0.16
|
1.18 (0.63–2.21), P = 0.60
|
Model 2 (HR, 95% CI)
|
1.00
|
0.67 (0.32–1.38), P = 0.28
|
1.30 (0.71–2.39), P = 0.39
|
0.89 (0.46–1.70), P = 0.71
|
P for trend
|
0.79
|
NLR: neutrophil to lymphocyte ratio; CRP: high-sensitivity C-reactive protein; CVD: including coronary heart disease, angina, myocardial infarction and peripheral vascular disease; model 1: a crude hazard ratio model without adjustments; model 2: a multivariate model adjusted for age, sex, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, physical activity, body mass index, self-rated health, cancer, and genitourinary disease (nephropathy, prostatic disease, and gynecologic diseases), chest disease (COPD, chronic bronchitis, emphysema, asthma, and tuberculosis, pneumonia), platelet count and CRP. |
Table 5 shows the NLRs in relation to the risk of fatal stroke occurrence with another model. Compared with those in NLR ≤ 1.75, the participants in NLRs > 1.75 had an increased risk of fatal stroke (aHR = 1.57, 95% CI 1.20–2.06, P = 0.001) and fatal ischaemic stroke (aHR = 1.91, 95% CI 1.27–2.88, P = 0.002); Similar results for fatal stroke (aHR = 1.11 95% CI 1.06–1.17, P < 0.001) and fatal ischaemic stroke (aHR = 1.15 95% CI 1.09–1.21, P < 0.001) were observed in a model conducting NLR as a continuous variable.
Table 5
Association between the NLR categories or continuous and the risk of fatal stroke among the participants without CVD at baseline and further CRP adjustment (n = 10606)
|
NLR categories
|
NLR continuous
|
|
≤ 1.75
|
> 1.75
|
Stroke
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
2.01 (1.54–2.62), P < 0.001
|
1.16 (1.11–1.20), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.57 (1.20–2.06), P = 0.001
|
1.11 (1.06–1.17), P < 0.001
|
Ischemic stroke
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
2.42 (1.62–3.62), P < 0.001
|
1.18 (1.13–1.23), P < 0.001
|
Model 2 (HR, 95% CI)
|
1.00
|
1.91 (1.27–2.88), P = 0.002
|
1.15 (1.09–1.21), P < 0.001
|
Hemorrhagic stroke
|
|
|
|
Model 1 (HR, 95% CI)
|
1.00
|
1.60 (1.02–2.51), P = 0.04
|
1.09 (0.95–1.27), P = 0.23
|
Model 2 (HR, 95% CI)
|
1.00
|
1.33 (0.84–2.10), P = 0.23
|
1.02 (0.81–1.30), P = 0.85
|
NLR: neutrophil to lymphocyte ratio; CRP: high-sensitivity C-reactive protein; CVD: including coronary heart disease, angina, myocardial infarction and peripheral vascular disease; model 1: a crude hazard ratio model without adjustments; model 2: a multivariate model adjusted for age, sex, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, physical activity, body mass index, self-rated health, cancer, and genitourinary disease (nephropathy, prostatic disease, and gynecologic diseases), chest disease (COPD, chronic bronchitis, emphysema, asthma, tuberculosis, and pneumonia), platelet and CRP. |