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北京大学学报（医学版） ›› 2020, Vol. 52 ›› Issue (3): 425-431. doi: 10.19723/j.issn.1671-167X.2020.03.005

• 论著 • 上一篇    下一篇

成年双生子空腹血糖、糖化血红蛋白与全基因组DNA甲基化的相关性研究

王兆年1,高文静1,△(),王碧琦1,曹卫华1,吕筠1,余灿清1,逄增昌2,丛黎明3,汪华4,吴先萍5,刘彧6,李立明1   

  1. 1. 北京大学公共卫生学院流行病与卫生统计学系,北京 100191
    2. 青岛市疾病预防控制中心,山东青岛 266033
    3. 浙江省疾病预防控制中心,杭州 310051
    4. 江苏省疾病预防控制中心,南京 210009
    5. 四川省疾病预防控制中心,成都 610041
    6. 黑龙江省农垦总局疾病预防控制中心,哈尔滨 150090
  • 收稿日期:2020-02-15 出版日期:2020-06-18 发布日期:2020-06-30
  • 通讯作者: 高文静 E-mail:pkuepigwj@126.com
  • 基金资助:
    公益性行业科研专项(201502006);公益性行业科研专项(201002007);国家自然科学基金(81573223)

Correlation between fasting plasma glucose, HbA1c and DNA methylation in adult twins

Zhao-nian WANG1,Wen-jing GAO1,△(),Bi-qi WANG1,Wei-hua CAO1,Jun LV1,Can-qing YU1,Zeng-chang PANG2,Li-ming CONG3,Hua WANG4,Xian-ping WU5,Yu LIU6,Li-ming LI1   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Qingdao Municipal Center for Disease Control and Prevention, Qingdao 266033, Shandong, China
    3. Zhejiang Center for Disease Control and Prevention, Hangzhou 310051, China
    4. Jiangsu Center for Disease Control and Prevention, Nanjing 210009, China
    5. Sichuan Center for Disease Control and Prevention, Chengdu 610041, China
    6. Center for Disease Control and prevention, Heilongjiang Agricultural Reclamation Bureau, Harbin 150090, China
  • Received:2020-02-15 Online:2020-06-18 Published:2020-06-30
  • Contact: Wen-jing GAO E-mail:pkuepigwj@126.com
  • Supported by:
    Special Found for Health Scienti-fic Research in the Public Welfare(201502006);Special Found for Health Scienti-fic Research in the Public Welfare(201002007);National Natural Science Foundation of China(81573223)

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摘要：

目的 利用双生子人群分别探索与空腹血糖(fasting plasma glucose,FPG)或糖化血红蛋白(glycated haemoglobin, HbA1c)存在相关性的胞嘧啶-磷酸-鸟嘌呤(cytidine-phosphate-guanosine site,CpG)位点。方法 研究对象来自中国双生子登记系统2013年6月至12月和2017年6月至2018年10月于山东青岛、浙江、江苏、四川及黑龙江五地募集的338人(169对)同卵双生子。甲基化检测分别为Illumina Infinium HumanMethylation450 BeadChip和Illumina Infinium MethylationEPIC BeadChip两种芯片,采用混合效应模型,分别将空腹血糖及HbA1c作为主效应,将甲基化水平(β值)作为因变量,将年龄、体重指数(body mass index, BMI)、血压、血细胞组成成分、用SVA包生成的代理变量等连续变量,及性别、吸烟、饮酒、是否服用降糖药等分类变量作为协变量纳入固定效应模型,将双生子对编号纳入随机效应模型,将截距设置为随机,进行回归分析,找出分别与空腹血糖或HbA1c相关的CpG位点。结果 本研究最终纳入同卵双生子338人(169对),CpG位点412 459个,其中男性同卵双生子114对、女性55对,平均年龄(48.2±11.9)岁。在调整年龄、性别、BMI、血压、吸烟、饮酒、血细胞成分等协变量及多重比较校正后,发现7个与空腹血糖相关的CpG位点(cg19693031、cg01538969、cg08501915、cg04816311、ch.8.1820050F、cg06721411、cg26608667), 其中3个位点(cg08501915、ch.8.1820050F、cg26608667)为本研究新发现的位点;发现10个与HbA1c相关的CpG位点(cg19693031、cg04816311、cg01538969、cg01339781、cg01676795、cg24667115、cg09029192、cg20697417、ch.4.1528651F、cg16097041),其中4个位点(cg01339781、cg24667115、cg20697417、ch.4.1528651F)为本研究新发现的位点。本研究发现,位于TXNIP基因上的cg19693031位点在DNA甲基化与空腹血糖及HbA1c相关分析中均是P值最小的位点(PFPG=2.42×10-19, FD R FPG < 0.001; PHbA1c=1.72×10-19, FD R HbA 1 c < 0.001)。 结论 在验证既往研究发现的同时,本研究利用双生子的天然优势,发现新的与空腹血糖和HbA1c相关的CpG位点,为血糖相关指标的DNA甲基化机制提供一定的线索,但尚需外部样本进一步验证。

关键词: 血糖, 糖化血红蛋白, DNA甲基化, 双生子

Abstract:

Objective: To explore the cytidine-phosphate-guanosine (CPG) sites associated with fas-ting plasma glucose (FPG) and glycated haemoglobin (HbA1c) in twins.Methods: In the study, 169 pairs of monozygotic twins were recruited in Qingdao, Zhejiang, Jiangsu, Sichuan and Heilongjiang in June to December of 2013 and June 2017 to October 2018. The methylation was detected by Illumina Infinium HumanMethylation450 BeadChip and Illumina Infinium MethylationEPIC BeadChip. According to the Linear Mixed Effect model (LME model), fasting plasma glucose and HbA1c were taken as the main effects, the methylation level (β value) was taken as the dependent variable, continuous variables, such as age, body mass index (BMI), blood pressure, components of blood cells, surrogate variables generated by SVA, and categorical variables, such as gender, smoking and drinking status, hypoglycemic drugs taking, were included in the fixed effect model as covariates, and the identity numbers (ID) of the twins was included in the random effect model. The intercept was set as a random. Regression analysis was carried out to find out the CpG sites related to fasting blood glucose or HbA1c, respectively.Results: In this study, 338 monozygotic twins (169 pairs) were included, with 412 459 CpG loci. Among them, 114 pairs were male, and 55 pairs were female, with an average age of (48.2±11.9) years. After adjustment of age, gender, BMI, blood pressure, smoking, drinking, blood cell composition, and other covariates, and multiple comparison test, 7 CpG sites (cg19693031, cg01538969, cg08501915, cg04816311, ch.8.1820050F, cg06721411, cg26608667) were found related to fasting blood glucose, 3 of which (cg08501915, ch.8.1820050f, cg26608667) were the newly found sites in this study; whereas 10 CpG sites (cg19693031, cg04816311, cg01538969, cg01339781, cg01676795, cg24667115, cg09029192, cg20697417, ch.4.1528651F, cg16097041) were found related to HbA1c, and 4 of which(cg01339781, cg24667115, cg20697417, and ch.4.1528651f) were new. We found that cg19693031 in TXNIP gene was the lowest P-value site in the association analysis between DNA methylation and fas-ting plasma glucose and HbA1c (PFPG=2.42×10-19, FDRFPG<0.001; PHbA1c=1.72×10-19, FDRHbA1c<0.001).Conclusion: In this twin study, we found new CpG sites related to fasting blood glucose and HbA1c, and provided some clues that partly revealed the potential mechanism of blood glucose metabolism in terms of DNA methylation, but it needed further verification in external larger samples.

Key words: Fasting plasma glucose, Glycated haemoglobin, DNA methylation, Twin

中图分类号: 

  • R179

表1

双生子人口学特征及相关变量基本信息"

Variables Values
Pair of twins, n 169
Age/years 48.2 ± 11.9
FPG/(mmol/L) 5.9 ± 1.9
HbA1c/% 5.9 ± 1.0
BMI/(kg/m2) 25.0 ± 3.5
SBP/mmHg 135.0 ± 18.7
DBP/mmHg 81.3 ± 11.2
Gender, n(%)
Male 228 (67.5)
Female 110 (32.5)
Type 2 diabetes mellitus, n(%) 35 (10.4)
Hypertension, n(%) 6 (1.8)
Hypoglycemic drug use, n(%) 29 (8.6)
Drinking, n(%)
Never 160 (47.3)
Used to 4 (1.2)
Now 174 (51.5)
Smoking, n(%)
Never 184 (54.4)
Used to 48 (14.2)
Now 106 (31.4)

图1

血糖相关指标与全基因组DNA甲基化间相关性分析的曼哈顿图"

表2

全基因组DNA甲基化与血糖指标相关性分析"

G site Chromosome Position on
chromosome		 Gene Position
on gene		 Relation to
CpG island		 Slope SE P value FDR
FPG
cg19693031 1 145441552 TXNIP 3'UTR OpenSea -1.44×10-2 1.32×10-3 2.42×10-19 <0.001
cg01538969 6 30624636 DHX16 Body OpenSea 4.76×10-3 6.87×10-4 2.68×10-10 <0.001
cg08501915 4 129208894 PGRMC2 1st exon Island 5.80×10-3 8.36×10-4 2.70×10-10 <0.001
cg04816311 7 1066650 C7orf50 Body N_Shore 7.16×10-3 1.04×10-3 3.52×10-10 <0.001
ch.8.1820050F 8 89645708 - - OpenSea 4.12×10-3 6.04×10-4 4.75×10-10 <0.001
cg06721411 2 74753759 DQX1 TSS1500 N_Shelf 4.53×10-3 7.73×10-4 4.73×10-8 0.019
cg26608667 7 1196370 ZFAND2A Body N_Shelf 4.52×10-3 7.96×10-4 1.04×10-7 0.043
HbA1c
cg19693031 1 145441552 TXNIP 3'UTR OpenSea -2.91×10-2 2.66×10-3 1.72×10-19 <0.001
cg04816311 7 1066650 C7orf50 Body N_Shore 1.66×10-2 2.04×10-3 6.00×10-13 <0.001
cg01538969 6 30624636 DHX16 Body OpenSea 9.55×10-3 1.39×01-3 3.31×10-10 <0.001
cg01339781 6 116989657 ZUFSP 5'UTR OpenSea 2.52×10-3 4.03×10-4 7.05×10-9 0.003
cg01676795 7 75586348 POR Body OpenSea 1.21×10-02 1.97×10-3 1.24×10-8 0.005
cg24667115 6 91004482 BACH2 5'UTR N_Shore 1.36×10-2 2.24×10-3 1.90×10-8 0.008
cg09029192 17 76015204 TNRC6C 5'UTR OpenSea 8.13×10-3 1.39×10-3 4.75×10-8 0.020
cg20697417 1 41786797 - - OpenSea 8.82×10-3 1.51×10-3 5.22×10-8 0.021
ch.4.1528651F 4 79200030 FRAS1 Body OpenSea 6.73×10-3 1.17×10-3 6.99×10-8 0.029
cg16097041 1 154965544 FLAD1 3'UTR OpenSea 8.30×10-3 1.44×10-3 7.77×10-8 0.032

表3

全基因组DNA甲基化与血糖指标相关分析重叠位点"

CpG site Chromosome Position on
chromosome		 Gene Position on gene HbA1c FPG
P value FDR P value FDR
cg19693031 1 145441552 TXNIP 3'UTR 1.72×10-19 <0.001 2.42×10-19 <0.001
cg01538969 6 30624636 DHX16 Body 3.31×10-10 <0.001 2.68×10-10 <0.001
cg04816311 7 1066650 C7orf50 Body 6.00×10-13 <0.001 3.52×10-10 <0.001

图2

血糖相关指标与全基因组DNA甲基化间相关性分析的Q-Q图"

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ISSN 1671-167X
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