Hypomethylation of Interleukin-6 Promoter is Associated with the Risk of Coronary Heart Disease

Zuo, Hong-Peng; Guo, Ying-Yu; Che, Lin; Wu, Xian-Zheng

doi:10.5935/abc.20160124

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Sumário

Original Articles, Epidemiology • Arq. Bras. Cardiol. 107 (2) • Aug 2016 • https://doi.org/10.5935/abc.20160124 copy

Hypomethylation of Interleukin-6 Promoter is Associated with the Risk of Coronary Heart Disease

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

Interleukin-6 (IL-6) is implicated in the pathogenesis of coronary heart disease (CHD), and IL-6 expression has associated with reduced DNA methylation of its gene promoter. However, there are no data on IL-6 promoter methylation and the risk of CHD.

Objective:

To examine whether IL-6 promoter methylation measured in blood leukocyte DNA is associated with CHD risk.

Methods:

A total of 212 cases with CHD and 218 controls were enrolled. Methylation at two CpG sites in IL-6 promoter was measured by bisulfite pyrosequencing, and the mean IL-6 methylation was calculated by averaging the methylation measures of the two CpGs.

Results:

Mean methylation level in IL-6 promoter in CHD cases was significantly lower than that in controls (p = 0.023). Logistic regression analysis showed that IL-6 methylation was inversely associated with the risk of CHD. The odds ratios (ORs) of CHD for subjects in the second and first (lowest) tertile of IL-6 methylation were 1.87 (95% CI = 1.10‑3.20) and 2.01 (95% CI = 1.19-3.38) (p_trend = 0.013), respectively, compared to subjects in the third (highest) tertile. The IL-6 hypomethylation-related risk estimates tended to be stronger for acute myocardial infarction (p_trend = 0.006). CpG position-specific analysis showed that hypomethylation of position 1 conferred a more pronounced increase in CHD risk than that of position 2.

Conclusion:

These findings suggest that DNA hypomethylation of IL-6 promoter is associated with the increased risk for CHD, especially for acute myocardial infarction. The two distinct CpGs in IL-6 may contribute differently to the development of CHD.

Keywords:
Coronary Artery Disease; Interleukin-6; DNA Methylation; Epigenetic Repression

Characteristic	Controls, n (%)	CHD cases, n (%)	*p value^ * p value obtained from a χ2-test comparing cases and Controls.**
Age (years)
< 65	102 (46.8)	108 (50.9)
≥ 65	116 (53.2)	104 (49.1)	0.389
Sex
Female	46 (21.1)	48 (22.6)
Male	172 (78.9)	164 (77.4)	0.699
Body mass index (kg/m²)
< 24	125 (57.3)	96 (45.3)
24-27.9	61 (28.0)	69 (32.5)
≥ 28	32 (14.7)	47 (22.2)	0.029
Ever-smoker
No	100 (45.9)	79 (37.3)
Yes	118 (54.1)	133 (62.7)	0.070
Serum total cholesterol (mmol/L)
< 4.67	73 (33.5)	34 (16.1)
4.67-5.47	75 (34.4)	52 (24.5)
> 5.47	70 (32.1)	126 (59.4)	< 0.001
Family history of CHD
No	214 (98.2)	185 (87.3)
Yes	4 (1.8)	27 (12.7)	< 0.001

Methylation (%5 mC)	Controls	CHD cases
	Controls	All	AMI			Prior MI		Angina
	n (%)	n (%)	*OR (95% CI)^ * Adjusted by body mass index (<24, 24-27.9, ≥28 kg/m2), serum total cholesterol (<4.67, 4.67-5.47, >5.47 mmol/L) and CHD family history (no, yes).**	n (%)	*OR (95% CI)^ * Adjusted by body mass index (<24, 24-27.9, ≥28 kg/m2), serum total cholesterol (<4.67, 4.67-5.47, >5.47 mmol/L) and CHD family history (no, yes).**	n (%)	*OR (95% CI)^ * Adjusted by body mass index (<24, 24-27.9, ≥28 kg/m2), serum total cholesterol (<4.67, 4.67-5.47, >5.47 mmol/L) and CHD family history (no, yes).**	n (%)	*OR (95% CI)^ * Adjusted by body mass index (<24, 24-27.9, ≥28 kg/m2), serum total cholesterol (<4.67, 4.67-5.47, >5.47 mmol/L) and CHD family history (no, yes).**
Mean (Tertile^† † The tertiles of IL-6 methylation measures were based on values among control subjects. )
T3 (> 47.7)	73 (33.5)	42 (19.8)	1.0 (reference)	21 (17.5)	1.0 (reference)	9 (21.4)	1.0 (reference)	12 (24.0)	1.0 (reference)
T2 (40.1-47.7)	71 (32.6)	77 (36.3)	1.87 (1.10-3.20)	41 (34.2)	2.00 (1.01-3.94)	18 (42.9)	2.02 (0.84-4.86)	18 (36.0)	1.76 (0.73-4.24)
T1 (< 40.1)	74 (33.9)	93 (43.9)	2.01 (1.19-3.38)	58 (48.3)	2.57 (1.33-4.95)	15 (35.7)	1.63 (0.66-4.01)	20 (40.0)	1.83 (0.77-4.33)
			p-trend=0.013		p-trend=0.006		p-trend=0.325		p-trend=0.182
Position 1 (Tertile^† † The tertiles of IL-6 methylation measures were based on values among control subjects. )
T3 (> 51.7)	73 (33.5)	44 (20.8)	1.0 (reference)	25 (20.8)	1.0 (reference)	8 (19.1)	1.0 (reference)	11 (22.0)	1.0 (reference)
T2 (43.5-51.7)	71 (32.6)	77 (36.3)	2.04 (1.20-3.49)	38 (31.7)	1.71 (0.88-3.32)	19 (45.2)	2.37 (0.96-5.84)	20 (44.0)	2.50 (1.01-6.17)
T1 (< 43.5)	74 (33.9)	91 (42.9)	2.17 (1.29-3.66)	57 (47.5)	2.44 (1.29-4.62)	15 (35.7)	1.94 (0.77-4.92)	19 (38.0)	2.16 (0.88-5.27)
			p-trend=0.05		p-trend=0.006		p-trend=0.196		p-trend=0.114
Position 2 (Tertile^† † The tertiles of IL-6 methylation measures were based on values among control subjects. )
T3 (> 44.0)	73 (33.5)	51 (24.1)	1.0 (reference)	30 (25.0)	1.0 (reference)	9 (21.4)	1.0 (reference)	12 (24.0)	1.0 (reference)
T2 (35.9-44.0)	71 (32.6)	63 (29.7)	1.25 (0.74-2.12)	28 (23.3)	0.93 (0.48-1.81)	17 (40.5)	2.06 (0.84-5.02)	18 (36.0)	1.74 (0.72-4.20)
T1 (< 35.9)	74 (33.9)	98 (46.2)	1.73 (1.05-2.86)	62 (51.7)	1.81 (0.99-3.29)	16 (38.1)	1.82 (0.74-4.47)	20 (40.0)	1.79 (0.76-4.23)
			p-trend=0.030		p-trend=0.038		p-trend=0.220		p-trend=0.197

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