Association of Model-Predicted Epigenetic Age and Female Infertility
Abstract
1. Introduction
2. Results
2.1. Selection of CpG Sites for Biological Age Prediction
2.2. Biological Age Prediction Model
2.3. Testing of a Biological Age Calculation Model Using a Sample of Women with Perinatal Loss and Infertility
3. Discussion
4. Materials and Methods
4.1. Ethics Approval
4.2. The Study Population and Blood Collection
4.3. DNA Extraction
4.4. Bisulfite Conversion
4.5. PCR and Pyrosequencing
4.6. Statistical Analysis
4.7. Development of the Age Prediction Model
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
EAA | epigenetic age acceleration |
EAD | epigenetic age deceleration |
AMH | anti-Müllerian hormone |
FSH | follicle-stimulating hormone |
E2 | estradiol |
AFC | antral follicle count |
ART | assisted reproductive technology |
BMI | body mass index |
RIF | recurrent implantation failure |
MAD | mean absolute deviation |
MAE | mean absolute error |
RMSE | root mean squared error |
SEE | standard error of the estimate |
SE | standard error |
SD | standard deviation |
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Locus | CpG Sites | Spearman’s ρ [95% CI] * |
---|---|---|
KLF14 | C1 | 0.77 [0.67, 0.84] |
FHL2 | C2 | 0.85 [0.79, 0.90] |
TRIM59 | C7 | 0.60 [0.45, 0.72] |
C1orf132 | C1 | −0.92 [−0.95, −0.88] |
ELOVL2 | C5 | 0.94 [0.91, 0.96] |
C7 | 0.88 [0.82, 0.92] |
Age Group, Year (n) | Methylation %, Mean (SD) * | |||||
---|---|---|---|---|---|---|
KLF14 | FHL2 | TRIM59 | C1orf132 | ELOVL2 C5 | ELOVL2 C7 | |
10 (12) | 2.17 (0.39) | 17.7 (2.46) | 11.4 (1.62) | 82.2 (2.52) | 8.08 (1.51) | 30.1 (2.43) |
20 (12) | 2.50 (0.52) ↑ | 23.9 (2.50) ↑ | 17.9 (4.03) ↑ | 74.1 (6.05) ↓ | 13.2 (1.47) ↑ | 46.4 (2.50) ↑ |
30 (12) | 4.92 (1.83) ↑ | 27.5 (2.97) ↑ | 21.6 (4.08) ↑ | 66.7 (7.74) ↓ | 20.2 (2.70) ↑ | 59.8 (4.94) ↑ |
40 (12) | 6.33 (1.92) ↑ | 33.2 (6.19) ↑ | 26.8 (2.45) ↑ | 61.6 (10.0) ↓ | 23.7 (4.27) ↑ | 66.6 (6.96) ↑ |
50 (12) | 5.00 (1.04) ↓ | 45.8 (8.53) ↑ | 20.7 (2.77) ↓ | 40.4 (6.08) ↓ | 25.0 (2.63) ↑ | 66.2 (1.99) ↓ |
60 (12) | 6.50 (1.24) ↑ | 37.8 (4.45) ↓ | 23.5 (3.29) ↑ | 38.1 (6.04) ↓ | 30.7 (3.23) ↑ | 72.8 (3.16) ↑ |
70 (12) | 7.58 (2.43) ↑ | 45.8 (7.19) ↑ | 26.1 (10.4) ↑ | 28.7 (10.1) ↓ | 37.6 (8.37) ↑ | 75.6 (3.55) ↑ |
80 (10) | 7.70 (2.21) ↑ | 46.6 (5.10) ↑ | 30.1 (6.06) ↑ | 29.2 (7.15) ↑ | 37.0 (5.25) ↓ | 72.1 (2.81) ↓ |
Name | Model Equation | SE | Statistical Summary |
---|---|---|---|
Age_predict1 | Age = 24.4506 + 0.1492 × FHL2 + 0.4488 × KLF14 + 0.0114 × TRIM59 + −0.3771 × C1orf132 + 0.3328 × ELOVL2 C5 + 0.3259 × ELOVL2 C7 | 5.727 0.0833 0.3094 0.1432 0.0514 0.2235 0.1148 | R2: 0.954 R2Adjusted: 0.9488 Correlation coefficient: 0.9674 MAE: 2.6158 RMSE: 3.5943 Relative absolute error: 21.42% Root relative squared error: 25.17% AIC: 319 |
Age_predict2 | Age = 24.3118 + 0.1495 × FHL2 + 0.4492 × KLF14 + −0.3755 × C1orf132 + 0.3335 × ELOVL2 C5 + 0.3303 × ELOVL2 C7 | 5.4046 0.0825 0.3065 0.047 0.2212 0.0996 | R2: 0.954 R2Adjusted: 0.94975 Correlation coefficient: 0.9675 MAE: 2.6039 RMSE: 3.5866 Relative absolute error: 21.33% Root relative squared error: 25.12% AIC: 317 |
Group | n | Age, y (SD) | BMI, kg/m2 (SD) | AMH, ng/mL (SD) |
---|---|---|---|---|
Group I. Control group: healthy individuals who have had at least one live birth and have no history of perinatal losses or infertility diagnoses. | 7 | 33.3 (3.5) | 21 (3.7) | 5.2 (3.2) |
Group II. Women with a history of infertility diagnosis or perinatal losses; ART was not applied. | 16 | 33.4 (3.4) | 21 (1.5) | 3.6 (4.1) |
Group III. Women experiencing infertility or perinatal losses and have undergone ART and achieved successful pregnancies, resulting in delivery. | 29 | 34.1 (3.6) | 22 (3.3) | 2.1 (1.5) |
Group IV. Women experiencing infertility, perinatal losses, and assisted reproductive technology (ART), without pregnancy occurrence. | 12 | 34.6 (3.1) | 22 (4.2) | 3.4 (1.4) |
n (%) | ||||
Age: | ||||
24–29 | 6 (9%) | |||
30–34 | 25 (39%) | |||
35–39 | 33 (52%) | |||
BMI abnormal (>18.5 or <25) | 16 (25%) | |||
AMH < 1.2 ng/mL | 17 (27%) |
Group | n | Chronological Age, y | Predicted Age, y | Statistical Significance of Differences Between Chronological and Predicted Age p | EAA/EAD (Differences Between Actual and Predicted Ages) | |||
---|---|---|---|---|---|---|---|---|
Median | p * | Median | p | Median | p | |||
Group I Group II Group III Group IV | 7 16 29 12 | 33.00 33.00 35.00 35.50 | 0.73 | 32.80 33.35 33.30 33.50 | 0.76 | 0.67 0.53 0.30 0.56 | 0.00 −0.15 0.60 0.10 | 0.99 |
ART: yes no | 41 23 | 35.00 33.00 | 0.28 | 33.30 33.20 | 0.33 | 0.19 0.37 | 0.50 −0.10 | 0.86 |
BMI, kg/m2: normal deviation | 48 16 | 35.00 33.50 | 0.31 | 33.40 32.50 | 0.19 | 0.31 0.19 | 0.40 0.20 | 0.54 |
AMH, ng/mL: >1.2 <1.2 | 47 17 | 33.00 35.00 | 0.19 | 33.20 33.30 | 0.26 | 0.47 0.08 | −0.10 1.70 | 0.35 |
Locus | Gene Name | Gene Function | CpG Sites | Chromosome Location (GRCh38) |
---|---|---|---|---|
KLF14 | Kruppel-like factor 14 | Transcription factor | C1 | Chr7: 130734355 |
FHL2 | Four and a half LIM domains protein 2 | Transcription factor | C2 | Chr2: 105399288 |
TRIM59 | Tripartite motif containing 59 | Regulator of immune signaling pathways | C7 | Chr3: 160450199 |
C1orf132 | - | - | C1 | Chr1: 207823681 |
ELOVL2 | ELOVL fatty acid elongase 2 | Synthesis of very long chain polyunsaturated fatty acids | C5 | Chr6: 11044875 |
C7 | Chr6: 11044867 |
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Pozdysheva, E.; Korchagin, V.; Rumyantseva, T.; Ogneva, D.; Zhivotova, V.; Gaponova, I.; Mironov, K.; Akimkin, V. Association of Model-Predicted Epigenetic Age and Female Infertility. Epigenomes 2025, 9, 19. https://doi.org/10.3390/epigenomes9020019
Pozdysheva E, Korchagin V, Rumyantseva T, Ogneva D, Zhivotova V, Gaponova I, Mironov K, Akimkin V. Association of Model-Predicted Epigenetic Age and Female Infertility. Epigenomes. 2025; 9(2):19. https://doi.org/10.3390/epigenomes9020019
Chicago/Turabian StylePozdysheva, Elena, Vitaly Korchagin, Tatiana Rumyantseva, Daria Ogneva, Vera Zhivotova, Irina Gaponova, Konstantin Mironov, and Vasily Akimkin. 2025. "Association of Model-Predicted Epigenetic Age and Female Infertility" Epigenomes 9, no. 2: 19. https://doi.org/10.3390/epigenomes9020019
APA StylePozdysheva, E., Korchagin, V., Rumyantseva, T., Ogneva, D., Zhivotova, V., Gaponova, I., Mironov, K., & Akimkin, V. (2025). Association of Model-Predicted Epigenetic Age and Female Infertility. Epigenomes, 9(2), 19. https://doi.org/10.3390/epigenomes9020019