Association between IL-18/18R gene polymorphisms and coronary artery disease: influence of IL-18/18R genetic variants on cytokine expression

Figures & data

Table 1 Baseline characteristics of the study population

Variables	Controls (n=116)	Patients (n=176)	p-value
Age (years)	74.94±7.43	70.97±12.94	0.723
Gender (M/F)	33/83	98/78	0.000
BMI (kg/m^2)	30.33±6.09	31.05±2.69	0.612
Smoking (yes/no)	7/109	11/165	0.735
Hypertension (yes/no)	63/53	81/95	0.101
Type 2 diabetes mellitus (yes/no)	40/76	60/116	0.746
TC (mmol/L)	5.379±1.46	5.20±1.08	0.384
Tg (mmol/L)	1.705±1.91	1.41±0.69	0.021
LDL-c (mmol/L)	3.294±1.24	3.02±0.98	0.336
HDL-c (mmol/L)	1.64±0.73	1.58±0.52	0.171
CA	2.28±0.41	2.38±0.35	0.368

Notes: p-values <0.05 are shown in bold. Data are presented as mean ± standard deviation.

Abbreviations: BMI, body mass index; CA, coefficient of atherogenicity; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; TC, total cholesterol; Tg, triglyceride.

Table 2 Genotype distributions of different SNPs in patients with and without CAD and their association with risk of CAD development

Variables	Patients without CAD	Patients with CAD	OR (95% Cl)	p-value	pc-value
IL-18	n=116 (%)	n=176 (%)
rs1946518
GG	28 (24.56)	56 (32.18)	1.0
TG	66 (57.89)	90 (51.72)	1.47 (0.84–2.55)	0.174	ns
TT	20 (17.54)	28 (16.09)	1.03 (0.53–1.98)	0.937	ns
Allele
G	122 (53.51)	202 (58.05)	1.0
T	106 (46.49)	146 (41.95)	1.32 (0.95–1.85)	0.102	ns
rs187238
GG	52 (46.43)	86 (48.31)	1.0
GC	48 (42.85)	76 (43.18)	1.01 (0.61–1.59)	0.914	ns
CC	12 (10.71)	14 (7.87)	0.72 (0.31–1.68)	0.444	ns
Allele
G	152 (67.86)	250 (70.22)	1.0	0.538	ns
C	72 (32.14)	102 (28.97)	1.09 (0.76–1.58)	0.538	ns
IL-18R
rs326
AA	76 (66.66)	102 (57.95)	1.0
GA	32 (28.07)	68 (38.64)	0.63 (0.38–1.06)	0.079	ns
GG	6 (5.26)	6 (3.41)	0.47 (0.14–1.57)	0.213	ns
Allele
A	184 (80.70)	272 (77.27)	1.0
G	44 (19.30)	80 (22.73)	0.81 (0.54–1.23)	0.325	ns
rs1169288
TT	34 (29.31)	68 (38.20)	1.0
TG	52 (44.83)	92 (51.69)	1.13 (0.66–1.93)	0.652	ns
GG	30 (25.86)	16 (9.09)	0.33 (0.16–0.66)	0.001	ns
Allele
T	120 (51.72)	220 (63.00)	1.0
G	112 (48.28)	132 (37.00)	1.59 (1.13–2.23)	0.007	ns
rs183130
CC	54 (49.09)	78 (44.32)	1.0
CT	42 (38.18)	70 (39.77)	0.87 (0.52–1.45)	0.587	ns
TT	14 (12.73)	28 (15.91)	1.20 (0.57–2.53)	0.632	ns
Allele
C	150 (68.18)	226 (64.20)	1.0	0.329	ns
T	70 (31.82)	126 (35.80)	0.84 (0.59–1.20)

Notes: p-values, Fisher’s exact test with Yates’s correction; pc-value, after Bonferroni correction. Bold values denote p<0.05.

Abbreviations: CAD, coronary artery disease; IL, interleukin; ns, nonsignificant; OR, odds ratio; SNPs, single-nucleotide polymorphisms.

Table 3 Plasma levels of IL-18 in relation to the IL-18 polymorphisms of the total CAD population

SNP	Genotype	IL-18 (pg/mL)a	p-valueb
rs1946518
	GG	118.27 (65, 157)	>0.065
	TG	86.21 (56, 113)
	TT	139.51 (98, 171)
rs187238
	GG	148.15 (72, 180)	>0.363
	GC	95.35 (53, 123)
	CC	106.45 (68, 149)
rs326
	AA	94.33 (57, 155)	>0.631
	GA	104.31 (74, 146)
	GG	149.52 (119, 180)
rs1169288
	TT	106.24 (78, 154)	>0.453
	TG	90.16 (56, 135)
	GG	104.39 (53, 177)
rs183130
	CC	101.49 (61, 123)	>0.565
	CT	104.24 (58, 164)
	TT	98.50 (64, 200)

Notes:

a Median levels (25th and 75th percentiles);

b Kruskal–Wallis test.

Abbreviations: CAD, coronary artery disease; IL, interleukin; SNP, single-nucleotide polymorphisms.

Table 4 Statistical differences between the controls and patients, irrespective of their genotypes

CAD vs Control	p-value
IL-2	0.874
IL-4	0.196
IL-6	0.485
IL-8	0.000
IL-18	0.404
IL-1β	0.015
IL-10	0.137
IFN-α	0.154
Bilirubin	0.077
IFN-γ	0.066
NT-proBNP	0.058
Myoglobin	0.744
FABP	0.000
Troponin	0.309

Note: p-values <0.05 are shown in bold.

Abbreviations: CAD, coronary artery disease; FABP, fatty acid-binding protein; IFN-γ, interferon gamma; IL, interleukin; NT-proBNP, N-terminal pro B-type natriuretic peptide.

Table 5 Relationships between genotypes from IL-18/IL-18R SNPs between patients with and without CAD in relation to some inflammatory and clinically CAD-associated parameters

(A)	IL-18 rs1946518
	GG	TG	TT
IL-2	0.224	0.054	0.805
IL-4	0.688	0.054	0.999
IL-6	0.670	0.005	0.151
IL-8	0.001	0.000	0.087
IL-18	0.939	0.002	0.627
IL-1b	0.476	0.481	0.056
IL-10	0.431	0.082	0.853
IFN-α	0.307	0.110	0.429
Bilirubin	0.551	0.421	0.422
IFN-γ	0.555	0.629	0.854
NT-proBNP	0.781	0.795	0.900
Myoglobin	0.922	0.172	0.372
FABP	0.843	0.875	0.895
Troponin	0.482	0.112	0.201
(B)	IL-18 rs187238
	CC	GC	GG
IL-2	0.763	0.124	0.321
IL-4	0.725	0.354	0.898
IL-6	0.384	0.036	0.123
IL-8	0.130	0.008	0.000
IL-18	0.365	0.083	0.189
IL-1b	0.053	0.007	0.195
IL-10	0.935	0.513	0.591
IFN-α	0.504	0.331	0.421
Bilirubin	0.511	0.442	0.682
IFN-γ	0.492	0.677	0.428
NT-proBNP	0.245	0.284	0.199
Myoglobin	0.516	0.403	0.367
FABP	0.273	0.108	0.126
Troponin	0.367	0.197	0.241
(C)	IL-18R rs326
	AA	GA	GG
IL-2	0.309	0.183	0.218
IL-4	0.841	0.311	0.240
IL-6	0.121	0.035	0.949
IL-8	0.000	0.000	0.533
IL-18	0.042	0.246	0.801
IL-1b	0.151	0.914	0.460
IL-10	0.983	0.054	0.460
IFN-α	0.239	0.023	0.113
Bilirubin	0.441	0.712	0.505
IFN-γ	0.262	0.361	0.411
NT-proBNP	0.482	0.381	0.272
Myoglobin	0.503	0.455	0.377
FABP	0.706	0.664	0.519
Troponin	0.222	0.199	0.348
(D)	IL-18R rs1169288
	GG	TG	TT
IL-2	0.150	0.171	0.423
IL-4	0.460	0.399	0.818
IL-6	0.378	0.166	0.011
IL-8	0.005	0.005	0.003
IL-18	0.560	0.042	0.403
IL-1b	0.682	0.305	0.516
IL-10	0.488	0.860	0.404
IFN-α	0.987	0.181	0.269
Bilirubin	0.892	0.799	0.461
IFN-γ	0.991	0.891	0.628
NT-proBNP	0.659	0.722	0.502
Myoglobin	0.369	0.428	0.273
FABP	0.264	0.353	0.449
Troponin	0.577	0.664	0.482
(E)	IL-18R rs183130
	CC	CT	TT
IL-2	0.093	0.053	0.550
IL-4	0.251	0.626	0.100
IL-6	0.131	0.011	0.950
IL-8	0.002	0.001	0.081
IL-18	0.077	0.116	0.625
IL-1b	0.198	0.741	0.470
IL-10	0.784	0.227	0.973
IFN-α	0.229	0.081	0.303
Bilirubin	0.144	0.104	0.416
IFN-γ	0.201	0.098	0.229
NT-proBNP	0.163	0.125	0.317
Myoglobin	0.277	0.209	0.169
FABP	0.101	0.146	0.337
Troponin	0.305	0.371	0.178

Notes: (A) for IL-18 rs1946518; (B) for IL-18 rs187238; (C) for IL-18R rs326; (D) for IL-18R rs1169288; (E) for IL-18R rs183130. p-values <0.05 are shown in bold.

Abbreviations: CAD, coronary artery disease; FABP, fatty acid-binding protein; IFN-γ, interferon gamma; IL, interleukin; Nt-proBNP, N-terminal pro B-type natriuretic peptide; SNPs, single nucleotide polymorphisms.

Table 6 Logistic regression analysis for patients

Variables	p-value	OR (95% CI)
Gender	0.029	1.88 (1.15–2.92)
Tg	0.037	2.61 (1.12–3.58)

Note: p-values <0.05 are shown in bold.

Abbreviations: OR, odds ratio; Tg, triglyceride.