中国人群外周血MLPH基因高甲基化与冠心病相关

doi:10.12122/j.issn.1673-4254.2025.09.06

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (9): 1859-1866.doi: 10.12122/j.issn.1673-4254.2025.09.06

• • 上一篇

中国人群外周血MLPH基因高甲基化与冠心病相关

金家列¹^,²(), 王菲¹, 朱丽雅¹, 赵晓静³^,⁴, 王金鑫⁵, 朱超⁶(), 杨蓉西¹()

^1.南京医科大学公共卫生学院流行病与卫生统计学系，江苏南京 211166
^2.浙江省疾病预防控制中心，浙江杭州 310051；中国人民解放军总医院3. 军事医学转化实验室
^4.北京市慢性心衰精准医学重点实验室
^5.第二医学中心心内科，北京 100853
^6.首都医科大学北京友谊医院心内科，北京 100050

收稿日期:2025-03-21 出版日期:2025-09-20 发布日期:2025-09-28
通讯作者: 朱超,杨蓉西 E-mail:jljin@cdc.zj.cn;zhuchaodoctor@163.com;rongxiyang@njmu.edu.cn
作者简介:金家列，硕士，E-mail: jljin@cdc.zj.cn
基金资助:
国家自然科学基金(82000311);江苏特聘教授科研基金项目(KY103R201938)

Association between MLPH gene hypermethylation in peripheral blood and coronary heart disease

Jialie JIN¹^,²(), Fei WANG¹, Liya ZHU¹, Xiaojing ZHAO³^,⁴, Jinxin WANG⁵, Chao ZHU⁶(), Rongxi YANG¹()

^1.Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China
^2.Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China
^3.Military Translational Medicine Lab, Medical Innovation Research Division
^4.Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Medical Innovation Research Division
^5.Department of Cardiology, Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
^6.Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China

Received:2025-03-21 Online:2025-09-20 Published:2025-09-28
Contact: Chao ZHU, Rongxi YANG E-mail:jljin@cdc.zj.cn;zhuchaodoctor@163.com;rongxiyang@njmu.edu.cn
Supported by:
National Natural Science Foundation of China(82000311)

摘要/Abstract

摘要：

目的探讨中国人群外周血肿瘤抑制可转移候选基因1（TSSC1）和黑素亲和素（MLPH）基因甲基化水平与冠心病（CHD）之间的关系。方法收集86例CHD患者和95例健康对照，使用定量质谱法检测TSSC1和MLPH基因的CpG位点甲基化水平。使用Mann-Whitney秩和检验比较不同临床特征组间的甲基化水平差异。通过Spearman相关系数和列联系数分别评估甲基化水平与年龄、性别之间的相关性。结果与对照组相比，MLPH基因高甲基化与心肌梗死亚型相关（MLPH_CpG_2.7：P=0.045；MLPH_CpG_3/cg06639874：P=0.049；MLPH_CpG_5：P=0.019）。MLPH基因高甲基化与CHD的相关性在年龄<65岁组（MLPH_CpG_2.7：P=0.014；MLPH_CpG_4：P=0.001）和男性（MLPH_CpG_2.7：P=0.004；MLPH_CpG_3/cg06639874：P=0.044）中更加明显。未观察到外周血TSSC1基因甲基化改变与CHD及其亚型的相关性。结论中国人群外周血中MLPH基因高甲基化与CHD及心肌梗死具有相关性，尤其是65岁以下群体和男性群体。

关键词: 冠心病, TSSC1, MLPH, DNA甲基化, 外周血

Abstract:

Objective To investigate the association between methylation levels of tumor suppressing subtransferable candidate 1 (TSSC1) and melanophilin (MLPH) genes in peripheral blood and coronary heart disease (CHD) in Chinese population. Methods This case-control study was conducted in 86 CHD patients and 95 healthy individuals, whose methylation levels of TSSC1 and MLPH genes in peripheral blood were determined using mass spectrometry. Mann-Whitney U test was used to compare the methylation levels in different subgroups. The correlation of TSSC1 and MLPH gene methylation levels with age and gender were evaluated using Spearman correlation coefficient and contingency coefficient, respectively. Results Compared with the healthy individuals, the CHD patients showed a significant correlation between MLPH hypermethylation and myocardial infarction (MI) (MLPH_CpG_2.7: P=0.045; MLPH_CpG_3/cg06639874: P=0.049; MLPH_CpG_5: P=0.019), and this correlation was even stronger in individuals below 65 years of age (MLPH_CpG_2.7: P=0.014; MLPH_CpG_4: P=0.001) and in male subjects (MLPH_CpG_2.7: P=0.004; MLPH_CpG_3/cg06639874: P=0.044). The methylation level of TSSC1 gene in peripheral blood was not found to correlate with CHD or its subtypes. Conclusion Our findings suggest a correlation of MLPH hypermethylation in peripheral blood with CHD and MI in Chinese population, especially in individuals below 65 years and in male individuals.

Key words: coronary heart disease, TSSC1, MLPH, DNA methylation, peripheral blood

金家列, 王菲, 朱丽雅, 赵晓静, 王金鑫, 朱超, 杨蓉西. 中国人群外周血MLPH基因高甲基化与冠心病相关[J]. 南方医科大学学报, 2025, 45(9): 1859-1866.

Jialie JIN, Fei WANG, Liya ZHU, Xiaojing ZHAO, Jinxin WANG, Chao ZHU, Rongxi YANG. Association between MLPH gene hypermethylation in peripheral blood and coronary heart disease[J]. Journal of Southern Medical University, 2025, 45(9): 1859-1866.

图/表 6

参考文献 36

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Variables	CHD group (n=86)	Control group (n=95)	Z/χ²	P
Gender [n (%)]			3.113	0.078^a
Male	52 (60.5)	45 (47.4)
Female	34 (39.5)	50 (52.6)
Smoking [n (%)]			7.983	0.005^a
Yes	35 (40.7)	20 (21.1)
No	51 (59.3)	74 (77.9)
Drinking [n (%)]			0.034	0.853^a
Yes	23 (26.7)	24 (25.3)
No	63 (73.3)	70 (73.7)
Hypertension [n (%)]			6.004	0.014^a
Yes	55 (64.0)	42 (44.2)
No	31 (36.0)	50 (52.6)
Diabetes [n (%)]			4.314	0.038^a
Yes	34 (39.5)	23 (24.2)
No	52 (60.5)	69 (72.6)
Age (years)	65 (57, 73)	63 (61,68)	-0.364	0.716^b
TC (mmol/L)	3.79 (3.26, 4.41)	4.21 (3.59, 5.02)	-2.608	0.009^b
TG (mmol/L)	1.33 (0.97, 1.86)	1.38 (1.06, 1.92)	-0.562	0.574^b
HDL-C (mmol/L)	1.03 (0.86, 1.29)	1.18 (0.91, 1.41)	-1.829	0.067^b
LDL-C (mmol/L)	2.27 (1.85, 2.76)	2.64 (2.07, 3.35)	-2.794	0.005^b

Variables	CHD group (n=86)	Control group (n=95)	Z/χ²	P
Gender [n (%)]			3.113	0.078^a
Male	52 (60.5)	45 (47.4)
Female	34 (39.5)	50 (52.6)
Smoking [n (%)]			7.983	0.005^a
Yes	35 (40.7)	20 (21.1)
No	51 (59.3)	74 (77.9)
Drinking [n (%)]			0.034	0.853^a
Yes	23 (26.7)	24 (25.3)
No	63 (73.3)	70 (73.7)
Hypertension [n (%)]			6.004	0.014^a
Yes	55 (64.0)	42 (44.2)
No	31 (36.0)	50 (52.6)
Diabetes [n (%)]			4.314	0.038^a
Yes	34 (39.5)	23 (24.2)
No	52 (60.5)	69 (72.6)
Age (years)	65 (57, 73)	63 (61,68)	-0.364	0.716^b
TC (mmol/L)	3.79 (3.26, 4.41)	4.21 (3.59, 5.02)	-2.608	0.009^b
TG (mmol/L)	1.33 (0.97, 1.86)	1.38 (1.06, 1.92)	-0.562	0.574^b
HDL-C (mmol/L)	1.03 (0.86, 1.29)	1.18 (0.91, 1.41)	-1.829	0.067^b
LDL-C (mmol/L)	2.27 (1.85, 2.76)	2.64 (2.07, 3.35)	-2.794	0.005^b

CpG sites	CHD group (n=86)	Control group (n=95)	Z	P*
TSSC1_CpG_1	0.89 (0.82, 0.95)	0.85 (0.77, 0.93)	-1.258	0.208
TSSC1_CpG_6/cg23245316	0.43 (0.33, 0.53)	0.41 (0.32, 0.55)	-0.007	0.994
TSSC1_CpG_7	1.00 (0.98, 1.00)	1.00 (0.97, 1.00)	-0.389	0.697
TSSC1_CpG_8	0.68 (0.60, 0.77)	0.67 (0.59, 0.73)	-1.474	0.140
TSSC1_CpG_12	1.00 (0.89, 1.00)	1.00 (0.91, 1.00)	-0.315	0.753
TSSC1_CpG_14	0.33 (0.26, 0.39)	0.31 (0.24, 0.39)	-0.942	0.346
TSSC1_CpG_15	0.38 (0.33, 0.50)	0.42 (0.32, 0.49)	-0.329	0.742
TSSC1_CpG_16	0.96 (0.92, 0.97)	0.96 (0.93, 0.97)	-0.593	0.553
TSSC1_CpG_17	1.00 (1.00, 1.00)	1.00 (0.98, 1.00)	-1.629	0.103
TSSC1_CpG_18	0.98 (0.95, 0.99)	0.99 (0.96, 0.99)	-0.468	0.640
MLPH_CpG_2.7	0.85 (0.81, 0.93)	0.84 (0.80, 0.90)	-1.715	0.086
MLPH_CpG_3/cg06639874	0.92 (0.84, 0.97)	0.90 (0.87, 0.94)	-0.657	0.511
MLPH_CpG_4	0.94 (0.89, 0.99)	0.94 (0.88, 0.96)	-1.410	0.159
MLPH_CpG_5	0.87 (0.82, 0.95)	0.86 (0.82, 0.90)	-1.763	0.078
MLPH_CpG_6	0.59 (0.37, 0.69)	0.56 (0.36, 0.67)	-1.217	0.224

CpG sites	CHD group (n=86)	Control group (n=95)	Z	P*
TSSC1_CpG_1	0.89 (0.82, 0.95)	0.85 (0.77, 0.93)	-1.258	0.208
TSSC1_CpG_6/cg23245316	0.43 (0.33, 0.53)	0.41 (0.32, 0.55)	-0.007	0.994
TSSC1_CpG_7	1.00 (0.98, 1.00)	1.00 (0.97, 1.00)	-0.389	0.697
TSSC1_CpG_8	0.68 (0.60, 0.77)	0.67 (0.59, 0.73)	-1.474	0.140
TSSC1_CpG_12	1.00 (0.89, 1.00)	1.00 (0.91, 1.00)	-0.315	0.753
TSSC1_CpG_14	0.33 (0.26, 0.39)	0.31 (0.24, 0.39)	-0.942	0.346
TSSC1_CpG_15	0.38 (0.33, 0.50)	0.42 (0.32, 0.49)	-0.329	0.742
TSSC1_CpG_16	0.96 (0.92, 0.97)	0.96 (0.93, 0.97)	-0.593	0.553
TSSC1_CpG_17	1.00 (1.00, 1.00)	1.00 (0.98, 1.00)	-1.629	0.103
TSSC1_CpG_18	0.98 (0.95, 0.99)	0.99 (0.96, 0.99)	-0.468	0.640
MLPH_CpG_2.7	0.85 (0.81, 0.93)	0.84 (0.80, 0.90)	-1.715	0.086
MLPH_CpG_3/cg06639874	0.92 (0.84, 0.97)	0.90 (0.87, 0.94)	-0.657	0.511
MLPH_CpG_4	0.94 (0.89, 0.99)	0.94 (0.88, 0.96)	-1.410	0.159
MLPH_CpG_5	0.87 (0.82, 0.95)	0.86 (0.82, 0.90)	-1.763	0.078
MLPH_CpG_6	0.59 (0.37, 0.69)	0.56 (0.36, 0.67)	-1.217	0.224

CpG sites	Age<65 years (n=101)			Age≥65 year (n=80)
CpG sites	CHD (n=41)	Control (n=0)	P*	CHD (n=45)	Control (n=35)	P *
TSSC1_CpG_1	0.92 (0.82, 0.95)	0.85 (0.76, 0.93)	0.151	0.89 (0.79, 0.95)	0.86 (0.76, 0.95)	0.725
TSSC1_CpG_6/cg23245316	0.42 (0.29, 0.53)	0.40 (0.29, 0.55)	0.730	0.44 (0.34, 0.54)	0.45 (0.36, 0.58)	0.470
TSSC1_CpG_7	1.00 (0.97, 1.00)	1.00 (0.97, 1.00)	0.888	1.00 (0.98, 1.00)	1.00 (0.96, 1.00)	0.419
TSSC1_CpG_8	0.68 (0.56, 0.76)	0.68 (0.59, 0.73)	0.921	0.69 (0.62, 0.77)	0.66 (0.59, 0.73)	0.233
TSSC1_CpG_12	1.00 (0.90, 1.00)	1.00 (0.89, 1.00)	0.687	1.00 (0.89, 1.00)	1.00 (0.93, 1.00)	0.352
TSSC1_CpG_14	0.33 (0.25, 0.39)	0.31 (0.25, 0.38)	0.888	0.34 (0.29, 0.42)	0.32 (0.21, 0.43)	0.384
TSSC1_CpG_15	0.37 (0.31, 0.51)	0.42 (0.31, 0.47)	0.969	0.40 (0.33, 0.50)	0.42 (0.35, 0.50)	0.507
TSSC1_CpG_16	0.96 (0.94, 0.97)	0.96 (0.92, 0.97)	1.000	0.96 (0.90, 0.97)	0.96 (0.93, 0.97)	0.405
TSSC1_CpG_17	1.00 (1.00, 1.00)	1.00 (0.99, 1.00)	0.701	1.00 (1.00, 1.00)	1.00 (0.98, 1.00)	0.051
TSSC1_CpG_18	0.98 (0.94, 0.99)	0.99 (0.95, 0.99)	0.320	0.99 (0.96, 0.99)	0.98 (0.96, 0.99)	0.744
MLPH_CpG_2.7	0.86 (0.83, 0.94)	0.83 (0.80, 0.89)	0.014	0.85 (0.80, 0.91)	0.85 (0.79, 0.93)	0.941
MLPH_CpG_3/cg06639874	0.95 (0.87, 0.98)	0.91 (0.88, 0.96)	0.147	0.89 (0.82, 0.94)	0.89 (0.83, 0.93)	0.930
MLPH_CpG_4	0.97 (0.93, 1.00)	0.93 (0.87, 0.95)	0.001	0.92 (0.86, 0.98)	0.94 (0.89, 0.97)	0.187
MLPH_CpG_5	0.86 (0.81, 0.95)	0.86 (0.82, 0.89)	0.652	0.90 (0.84, 0.95)	0.87 (0.84, 0.91)	0.104
MLPH_CpG_6	0.58 (0.35, 0.71)	0.55 (0.35, 0.67)	0.568	0.62 (0.41, 0.69)	0.57 (0.39, 0.66)	0.284
*The P values were calculated by the Mann-Whitney U test.

中国人群外周血MLPH基因高甲基化与冠心病相关

Association between MLPH gene hypermethylation in peripheral blood and coronary heart disease

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CpG sites	Female (n=84)			Male (n=97)
CpG sites	CHD (n=34)	Control (n=50)	P*	CHD (n = 52)	Control (n = 45)	P*
TSSC1_CpG_1	0.90 (0.83, 0.96)	0.85 (0.75, 0.95)	0.135	0.89 (0.76, 0.95)	0.86 (0.79, 0.93)	0.566
TSSC1_CpG_6/cg23245316	0.44 (0.33, 0.55)	0.38 (0.31, 0.48)	0.160	0.43 (0.32, 0.52)	0.45 (0.35, 0.58)	0.114
TSSC1_CpG_7	1.00 (0.97, 1.00)	1.00 (0.97, 1.00)	0.545	1.00 (0.98, 1.00)	1.00 (0.96, 1.00)	0.298
TSSC1_CpG_8	0.74 (0.68, 0.79)	0.68 (0.59, 0.73)	0.014	0.65 (0.52, 0.72)	0.66 (0.58, 0.72)	0.420
TSSC1_CpG_12	1.00 (0.91, 1.00)	1.00 (0.92, 1.00)	0.467	1.00 (0.88, 1.00)	0.98 (0.90, 1.00)	0.687
TSSC1_CpG_14	0.35 (0.27, 0.41)	0.33 (0.24, 0.43)	0.461	0.33 (0.25, 0.39)	0.30 (0.24, 0.36)	0.349
TSSC1_CpG_15	0.43 (0.34, 0.53)	0.41 (0.31, 0.46)	0.131	0.38 (0.30, 0.46)	0.44 (0.34, 0.52)	0.077
TSSC1_CpG_16	0.96 (0.90, 0.97)	0.96 (0.92, 0.97)	0.447	0.96 (0.93, 0.97)	0.96 (0.93, 0.97)	0.870
TSSC1_CpG_17	1.00 (1.00, 1.00)	1.00 (0.99, 1.00)	0.134	1.00 (1.00, 1.00)	1.00 (0.98, 1.00)	0.290
TSSC1_CpG_18	0.98 (0.96, 0.99)	0.99 (0.96, 0.99)	0.677	0.99 (0.93, 0.99)	0.99 (0.95, 0.99)	0.756
MLPH_CpG_2.7	0.83 (0.77, 0.89)	0.84 (0.80, 0.91)	0.323	0.87 (0.83, 0.94)	0.83 (0.78, 0.88)	0.004
MLPH_CpG_3/cg06639874	0.90 (0.81, 0.95)	0.91 (0.86, 0.96)	0.215	0.94 (0.86, 0.97)	0.90 (0.87, 0.92)	0.044
MLPH_CpG_4	0.93 (0.86, 1.00)	0.93 (0.89, 0.96)	0.966	0.95 (0.90, 0.99)	0.94 (0.88, 0.96)	0.090
MLPH_CpG_5	0.86 (0.82, 0.93)	0.85 (0.82, 0.89)	0.294	0.90 (0.83, 0.95)	0.87 (0.84, 0.91)	0.228
MLPH_CpG_6	0.62 (0.44, 0.69)	0.49 (0.31, 0.64)	0.099	0.58 (0.34, 0.74)	0.58 (0.41, 0.68)	0.981

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