Plasma cytokine levels and risks of abdominal aortic aneurysms: A population-based prospective cohort study

Figures & data

Figure 1. Plasma IL6, IFN-γ, IL10, IL17A, and CRP levels in patients with and without AAA. Data were presented as mean ± SEM; Student's t test, P < 0.05 was considered statistical significant.

Figure 2. Spearman's correlations of logarithmized plasma IL10 levels with logarithmized plasma IL6, IFN-γ, IL17A, and CRP in controls (A) and AAA patients (B).

Table I. Dichotomous and continuous variables between AAA patients and controls and their associations with plasma medians of IL6, IFN-γ, IL10, IL17A, and CRP levels.

	AAA versus Non-AAA^a	IL6	IFN-γ	IL10	IL17A	CRP
Dichotomous variables	(OR [95% CI])	(25th; 50th; 75th percentiles) (No versus Yes)^b	(25th; 50th; 75th percentiles) (No versus Yes)^b	(25th; 50th; 75th percentiles) (No versus Yes)^b	(25th; 50th; 75th percentiles) (No versus Yes) ^b	25th; 50th; 75th percentiles) (No versus Yes)^b
Current smoking	3.44 [2.31; 5.13]***	0.00; 1.35; 4.277	6.35; 6.88; 46.8	0.00; 11.0; 62.0	0.00; 0.00; 0.00	1.1; 2.3; 4.9
		0.00; 1.42; 3.49*	5.52; 13.96; 40.32	0.00; 0.00; 0.00	0.00; 0.00; 10.1	1.7; 3.8; 7.7***
Diabetes mellitus	0.70 [0.44; 1.11]	0.00; 1.42; 4.52	6.22; 17.1; 47.1	0.00; 10.7; 69.7	0.00; 0.00; 11.1	1.4; 2.7;5.6
		0.00; 1.03; 3.37	5.92; 14.6; 44.6	0.04; 14.0; 104.8	0.00; 0.00; 10.5	0.9; 2.6; 6.1
Hypertension	1.52 [1.10; 2.10]***	0.00; 1.32; 3.75	6.44; 17.2; 43.2	0.00; 12.1; 86.0	0.00; 0.00; 11.1	1.4; 2.6; 5.2
		0.00; 1.40; 4.88	6.22; 16.1; 56.6	6.22; 16.17; 56.6	0.00; 0.00; 10.46	1.4;2.7;6.2
Use of ACE inhibitor	1.35 [0.92; 1.98]	0.00; 1.15; 4.26	5.99; 17.4; 46.8	0.00; 10.9; 84.60	0.00; 0.00; 13.9	1.4; 2.6;5.3
		0.00; 1.64; 4.83	6.61; 15.0; 55.2	0.00; 9.16; 60.8	0.00; 0.00; 8.90	1.3; 2.7; 6.5
Use of β-blocker	1.49 [1.02; 2.17]**	0.00; 1.10; 3.75	5.87; 16.4; 44.2	0.00; 10.7; 71.8	0.00; 0.00; 9.95	1.4; 2.6; 5.5
		0.00; 1.85; 5.86*	7.10; 19.2; 62.0	0.00; 11.6; 74.7	0.00; 0.00; 10.5	1.3; 2.7; 6.0
Use of statin	2.15 [1.54; 2.99]***	0.00; 1.19; 3.96	6.80; 18.2; 51.6	0.00; 11.0; 87.8	0.00; 0.00; 13.9	1.5; 2.9; 6.5
		0.00; 1.47; 4.86	5.45; 15.0; 42.0*	5.45; 15.0; 42.1	0.00; 0.00; 9.83	1.1;2.4; 5.0***
Use of steroids	1.53 [0.78; 3.03]	0.00; 1.23; 4.58	6.00; 15.9; 47.1	0.00; 11.5; 76.2	.0.00; 0.00; 10.4	1.3; 2.4; 5.3
		0.00; 1.58; 4.01	7.34; 21.2; 44.6	0.00; 8.18; 44.1	0.00; 0.00; 14.0	2.1; 5.1; 8.6***
Use of NSAIDs	9.07 [1.22; 67.50]***	0.00; 1.33; 4.60	6.08; 17.1; 48.4	0.00; 17.8; 76.2	0.00; 0.00; 9.78	1.3; 2.6; 5.6
		0.00; 1.02; 2.28	4.07; 10.3; 25.5	0.00; 8.47; 46.0	0.00; 2.63; 27.7	1.0; 2.6; 9.3
Continuous variables	Non-AAA versus AAA ^b	IL6	IFN-γ	IL10	IL17A	CRP
	(25th; 50th; 75th percentiles)	(Rho) ^c	(Rho) ^c	(Rho) ^c	(Rho) ^c	(Rho) ^c
Systolic blood pressure (mmHg)	137; 146; 159	-0.025	-0.042	-0.103***	-0.073	-0.006
	142; 155; 169***
Diastolic blood pressure (mmHg)	74; 80; 87	-0.001	-0.037	-0.067*	-0.017	0.098**
	79; 87; 95***
Age (years)	67.2; 69.3; 71.9	0.011	-0.033	-0.048	-0.036	-0.024
	67.6; 69.9; 72.4**
Body mass index	24.4; 25.9; 27.6	-0.018	-0.012	-0.012	0.001	0.137***
	24.9; 27.2; 29.4***

^a Chi-square test.

^b Mann–Whitney U test.

^c Spearman's correlation test.

*P < 0.10 (considered as confounding factor); ** P < 0.05; *** P < 0.01

Table II. Univariate and multivariate logistic regression analyses of logarithmization-transformed plasma medians of IL6, IFN-γ, IL10, IL17A, and CRP levels as independent risk factors of human aneurismal disease.

Dependent variables	AAA status	Percentiles 25 / 50 / 75	OR	Adjusted OR ^a
Ln [IL6]	Non-AAA	0.00 / 1.52 / 4.92	0.88 (0.78; 1.04) P = 0.141	0.91 (0.76; 1.08) P = 0.272
	AAA	0.00 / 1.37 / 3.93
Ln [IFN-γ]	Non-AAA	5.79 / 21.24 / 87.23	0.91 (0.82; 0.99) P = 0.044	0.98 (0.87; 1.10) P = 0.743
	AAA	6.54 / 16.07 / 40.46
Ln [IL10]	Non-AAA	0.00 / 13.46 / 113.1	0.91 (0.85; 0.98) P = 0.011	0.96 (0.88; 1.05) P = 0.372
	AAA	0.00 / 9.74 / 55.47
Ln [IL17A]	Non-AAA	0.00 / 0.00 / 26.99	0.98 (0.90; 1.06) P = 0.585	1.012 (0.92; 1.12) P = 0.735
	AAA	0.00 / 0.00 / 9.75
Ln [CRP]	Non-AAA	0.80 / 1.70 / 3.95	1.54 (1.31; 1.82) P < 0.001	1.41 (1.17; 1.70) P < 0.001
	AAA	1.58 / 3.00 / 6.30

^aAdjusted for smoking, diabetes, hypertension, use of β-blocker, statins, NSAIDs, systolic blood pressure, diastolic blood pressure, age, and body mass index.

Table III. Comparison and risk assessment of five cytokines in controls versus cases of small and large AAA.

	Mean	SD	P ^a	P ^b	Adjusted OR ^c (95% CI)	P ^c	Adjusted OR ^d (95% CI)	P ^d
Ln [IL6]
Control	1.155	1.320
Small AAA	1.002	1.076	0.142		0.79 (0.96–1.13)	0.651
Large AAA	1.165	1.062	0.553	0.711	1.06 (0.78–1.44)	0.751	1.03 (0.82–1.30)	0.796
Ln [IFN-g]
Control	3.284	1.885
Small AAA	2.976	1.688	0.050		0.99 (0.86–1.13)	0.847
Large AAA	2.999	1.894	0.265	0.933	0.92 (0.79–1.07)	0.339	1.00 (0.85–1.18)	0.972
Ln [IL10]
Control	2.893	2.453
Small AAA	2.405	2.26	0.016		0.98 (0.89–1.07)	0.606
Large AAA	2.394	2.453	0.036	0.976	0.91 (0.73–1.13)	0.281	1.01 (0.90–1.14)	0.862
Ln [IL17A]
Control	1.443	2.218
Small AAA	1.364	1.843	0.649		1.03 (0.92–1.15)	0.635
Large AAA	1.459	2.233	0.657	0.754	1.01 (0.84–1.20)	0.953	0.97 (0.84–1.12)	0.681
Ln [CRP]
Control	0.624	1.213
Small AAA	1.121	1.064	< 0.001		1.25 (1.01–1.55)	0.046
Large AAA	1.363	1.181	< 0.001	0.127	1.47 (1.00–1.77)	0.049	1.19 (0.93–1.53)	0.168

^a Univariate Student's t test comparison between control and small AAA, and control and large AAA.

^b Univariate Student's t test comparison between small AAA and large AAA.

^c Multivariate logistic regression analysis between control and small AAA, and control and large AAA, adjusted for smoking, diabetes, hypertension, use of β-blocker, statins, NSAIDs, systolic blood pressure, diastolic blood pressure, age, body mass index, and lowest measured ABI.

^d Multivariate logistic regression analysis between small AAA and large AAA adjusted for above-mentioned variables.

Table IV. Univariate and multivariate Pearson's correlation analyses of the five cytokines’ potential associations with maximal aortic diameter in healthy and aneurysmal cases.

n = 676	Maximal aortic diameter
Pearson's correlation analysis	Univariate (r)	P value	Multivariate (r)	P value ^a
Ln [IL6]	–0.048	0.224	–0.043	0.306
Ln [IFN-γ]	–0.055	0.162	–0.008	0.842
Ln [IL10]	–0.075	0.051	–0.028	0.481
Ln [IL17A]	–0.026	0.506	–0.011	0.792
Ln [CRP]	0.202	< 0.001	0.165	< 0.001

^a Adjusted for smoking, diabetes, hypertension, use of β-blocker, statins, NSAIDs, systolic blood pressure, diastolic blood pressure, age, and body mass index.

Table V. Univariate and multivariate Pearson's correlation analysis to determine the associations between the five cytokines and AAA size and AAA expansion rate.

	Maximal cross-sectional AAA area (n = 476)				Maximal annual growth rate (mm/year) (n = 386)
	Univariate (r)	P value	Multivariate (r)	P value ^a	Univariate (r)	P value	Multivariate (r)	P value ^b
Ln [IL6]	–0.051	0.361	–0.052	0.314	–0.034	0.220	–0.017	0.787
Ln [IFN-γ]	0.116	0.044	0.133	0.009	0.022	0.704	0.041	0.500
Ln [IL10]	0.057	0.436	–0.058	0.255	0.126	0.028	0.108	0.036
Ln [IL17A]	0.092	0.086	0.101	0.044	0.025	0.667	0.097	0.108
Ln [CRP]	0.078	0.087	0.097	0.036	0.121	0.024	0.062	0.279

^a Adjusted for smoking, diabetes, hypertension, use of β-blocker, statins, NSAIDs, systolic blood pressure, diastolic blood pressure, age, body mass index, lowest measured ABI, and initial AAA size.

^b Only in the analysis of independent risk factors for the growth rate.

Table VI. Univariate and multivariate Cox's proportional regression analysis to determine the associations of cytokines above the median in cases with screening-detected AAA and mid-term mortality.

	HR	95% CI for HR		P value	Adjusted HR ^a	95% CI for adjusted HR ^a		Adjusted P value ^a
		Lower	Upper			Upper	Lower
IL6 > median ^b	0.89	0.58	1.35	0.569	0.92	0.59	1.44	0.714
IFN-γ > median ^b	0.89	0.59	1.36	0.590	0.83	0.53	2.20	0.172
IL10 > median ^b	1.14	0.75	1.72	0.544	0.91	0.59	1.41	0.667
IL17A > median ^b	1.13	0.75	1.71	0.552	1.23	0.79	1.90	0.362
CRP > median ^b	1.91	1.25	2.93	0.003	2.20	1.38	3.51	< 0.001

^aAdjusted for smoking, diabetes, hypertension, use of β-blocker, statins, NSAIDs, systolic blood pressure, diastolic blood pressure, age, body mass index, lowest measured ABI, and initial AAA size.

^bMedians: IL6 = 1.35 pg/mL, IFN-γ = 16.86 pg/mL, IL10 = 11.02 pg/mL, IL17A = 0.00 pg/mL, and CRP = 2.50 pg/mL.