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Aging and disease    2018, Vol. 9 Issue (3) : 435-443     DOI: 10.14336/AD.2017.0810
Orginal Article |
Repetitive Element DNA Methylation is Associated with Menopausal Age
Lu Sha1,2, Niu Zheng1, Chen Yueming3, Tu Qiaofeng3, Zhang Yue2, Chen Wenli4, Tong Wenjuan3, Zhang Zhifen1,2,*
1Department of Obstetrics and Gynecology, the Affiliated Hangzhou People’s Hospital of Nanjing Medical University, Hangzhou, China
2Department of Obstetrics and Gynecology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
3Laboratory of Gene Diagnosis, the Affiliated Hangzhou People’s Hospital of Nanjing Medical University, Hangzhou, China
4Department of Obstetrics and Gynecology, the Second People’s Hospital of Tonglu, Hangzhou, China
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Abstract  

To investigate associations between the age of menopause and the DNA methylation levels of two repetitive elements, Alu and LINE-1, we performed plasma DNA extraction on 161 subjects and serum cell-free DNA extraction on 120 subjects. We grouped women by menopausal age as follows: ≤ 48 years (earlier menopause), ≥ 52 years (later menopause), and 48-52 years (control). The DNA methylation levels of Alu and LINE-1 were measured by MethyLight PCR. The results showed that the DNA methylation levels of both Alu and LINE-1 were inversely correlated with menopausal age in the plasma DNA cohort (r = 0.079, P < 0.001 for Alu; r = 0.045, P = 0.007 for LINE-1) as well as in the serum DNA cohort (r = 0.087, P = 0.001 for Alu; r = 0.041, P = 0.026 for LINE-1). Alu methylation levels in both the plasma and serum DNA cohorts and LINE-1 methylation levels in the plasma cohort were remarkably higher in the earlier menopause group than in the later menopause and control groups (P < 0.01 and P < 0.05, respectively). In the serum DNA cohort, the LINE-1 methylation levels in the later menopause group were significantly lower than that in the earlier menopause group and control group (P < 0.05). Therefore, methylation levels of Alu and LINE-1 were significantly associated with menopausal age. Women with earlier menopause showed hypermethylation in both repetitive elements, while women with later menopause showed hypomethylation. These findings suggest that altered DNA methylation in leukocytes and serum cell-free DNA may represent a biomarker of menopausal age.

Keywords DNA methylation      Repetitive elements      menopausal age     
Corresponding Authors: Zhang Zhifen   
About author:

SZ and JZ denote equal first authorship contribution.

Issue Date: 05 June 2018
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Lu Sha
Niu Zheng
Chen Yueming
Tu Qiaofeng
Zhang Yue
Chen Wenli
Tong Wenjuan
Zhang Zhifen
Cite this article:   
Lu Sha,Niu Zheng,Chen Yueming, et al. Repetitive Element DNA Methylation is Associated with Menopausal Age[J]. Aging and disease, 2018, 9(3): 435-443.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0810     OR     http://www.aginganddisease.org/EN/Y2018/V9/I3/435
GenePrimer sequenceRef.
Alu
Forward
Reverse Probe
5′-GCGCGGTGGTTTACGTTT-3′
5′-AACCGAACTAATCTCGAACTCCTAAC-3′ 5′-6FAM-AAATAATCCGCCCGCCTCGACCT-BHQ1-3′
[11]
LINE-1
b-actin
Forward
Reverse Probe Forward Reverse Probe
5′-GGACGTATTTGGAAAATCGGG-3′
5′-AATCTCGCGATACGCCGTT-3′ 5′-6FAM-TCGAATATTGCGTTTTCGGATCGGTTT-BHQ1-3′ 5′-TGGTGATGGAGGAGGTTTAGTAAGT-3′ 5′-AACCAATAAAACCTACTCCTCCCTTAA -3′ 5′-6FAM-ACCACCACCCAACACACAATAACAAACACA-BHQ1 -3′
[11]
[39]
Table 1  Primer and probe sequences for MethyLight PCR
Figure 1.  Correlation between menopausal age and methylation of Alu and LINE-1. Data were adjusted for age, BMI, hypertension, diabetes and education. Significance of correlation coefficients (r) was set at P < 0.05.
Earlier menopause group (n=60)Later menopause group (n=52)Control group (n=49)
Age (years)56.47 ± 8.4457.00 ± 5.8558.33 ± 7.96
Menopausal age (years)46.08 ± 2.0053.47 ± 1.7449.98 ± 0.81
BMI (kg/m2)23.46 ± 3.0824.35 ± 3.4823.97 ± 3.44
Hypertension [n (%)]11 (18.3%)11 (21.15%)13 (26.53%)
Diabetes [n (%)]3 (5.00%)5 (9.62%)5 (10.20%)
Education [n (%)]
 Less than middle school20 (33.33%)22 (42.31%)23 (46.94%)
 Middle school32 (53.33%)25 (48.08%)21 (42.86%)
 More than middle school8 (13.33%)5 (9.62%)5 (10.20%)
Table 2  Participant characteristics of plasma DNA extraction cohort.
Figure 2.  Correlation between methylation of repetitive elements. Each plot represents methylation levels of individuals, and data were adjusted for age, BMI, hypertension, diabetes and education. Significance of correlation coefficients (r) was set at P < 0.05.
Earlier menopause group (n=40)Later menopause group (n=42)Control group (n=38)
Age (years)55.05 ± 6.4857.45 ± 5.6156.47 ± 6.40
Menopausal age (years)45.63 ± 2.6853.17 ± 1.5349.99 ± 0.83
BMI (kg/m2)23.48 ± 3.8624.75 ± 3.3123.94 ± 3.02
Hypertension [n (%)]9 (22.5%)13 (30.95%)10 (26.32%)
Diabetes [n (%)]2 (5.00%)4 (9.52%)4 (9.52%)
Education [n (%)]
 Less than middle school19 (47.50%)22 (52.38%)17 (44.74%)
 Middle school15 (37.50%)16 (38.10%)18 (47.37%)
 More than middle school6 (15.00%)4 (10.53%)3 (7.89%)
Table 3  Participant characteristics of serum DNA extraction cohort.
Figure 3.  Methylation levels of Alu and LINE-1 in different menopausal age groups. Data are represented as box plots. Data were adjusted for age, BMI, hypertension, diabetes and education. * p < 0.05, ** p < 0.01.
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