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Journal of Peking University (Health Sciences) ›› 2020, Vol. 52 ›› Issue (3): 425-431. doi: 10.19723/j.issn.1671-167X.2020.03.005

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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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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

CLC Number: 

  • R179

Table 1

Demographic characteristics and basic information of related variables among twins"

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)

Figure 1

Manhattan plot of correlation analysis between blood glucose related indicators and DNA methylation of the whole genome The abscissa represents the chromosome, the ordinate represents the negative logarithm with 10 as the base of the original P value, the points above the red line represent P < 5 × 10-8, and the points in green are those which still significant after Bonferroni test. A, fasting blood glucose; B, HbA1c."

Table 2

Association analysis between DNA methylation and indicators of plasma glucose levels among the whole genome"

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

Table 3

Overlapping sites in association analysis between DNA methylation and indictors of plasma glucose level"

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

Figure 2

Q-Q chart of correlation analysis between blood glucose related indexes and DNA methylation of the whole genome The abscissa represents the negative logarithm based on 10 of the predicted P values, and the ordinate represents the negative logarithm based on 10 of the original P values. A, Fasting blood glucose; B, HbA1c."

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