Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity
Abstract
1. Introduction
2. Results
2.1. Participants Characteristics
2.2. Placental DMCs Associated with Obesity Risk in Offspring
2.3. Placental IRS1 Methylation
2.4. Placental IRS1 Expression
2.5. Leukocyte IRS1 Methylation and Expression
2.6. Prediction of Obesity-Related Parameters
3. Discussion
4. Materials and Methods
4.1. Study Participants
4.2. Biological Samples
4.3. Clinical Assessments
4.4. Infinium MethylationEPIC BeadChip Microarray
4.5. Pathway Analysis
4.6. DNA Methylation Assessment
4.7. Gene Expression Assessment
4.8. Statistical Analysis
4.9. Prediction Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Screening | Validation | p-Value | |
---|---|---|---|
Mother (n) | 24 | 147 | |
Age (yr) | 31 ± 1 | 31 ± 1 | NS |
Height (cm) | 164 ± 1 | 163 ± 1 | NS |
Pregestational weight (kg) | 68.5 ± 2.9 | 65.6 ± 1.0 | NS |
Pregestational BMI (kg/m2) | 25.2 ± 1.0 | 24.7 ± 0.3 | NS |
Pregestational obesity (%) | 30 | 34 | NS |
Newborn (n) | 24 | 147 | |
Gender (% female) | 50 | 52 | NS |
Gestational age (wk) | 40 ± 0.1 | 40 ± 0.1 | NS |
Birth weight (kg) | 3.4 ± 0.1 | 3.4 ± 0.1 | NS |
Birth weight-SDS | 0.3 ± 0.1 | 0.2 ± 0.1 | NS |
Birth length (cm) | 50.1 ± 0.2 | 49.7 ± 0.1 | NS |
Birth length-SDS | 0.07 ± 0.1 | 0.01 ± 0.1 | NS |
Offspring at 6 yr (n) | 24 | 147 | |
Age (yr) | 6.2 ± 0.1 | 6.0 ± 0.1 | NS |
Weight (kg) | 23.7 ± 1.0 | 22.4 ± 0.4 | NS |
Weight-SDS | 0.22 ± 0.2 | 0.05 ± 0.1 | NS |
Height (cm) | 120 ± 1 | 116 ± 1 | NS |
Height-SDS | 0.58 ± 0.2 | 0.11 ± 0.1 | NS |
BMI (kg/m2) | 16.3 ± 0.3 | 16.3 ± 0.1 | NS |
BMI-SDS | −0.02 ± 0.1 | 0.01 ± 0.1 | NS |
Δ BW-SDS to weight-SDS | −0.18 ± 0.2 | −0.15 ± 0.1 | NS |
Waist (cm) | 57.1 ± 1.7 | 56.3 ± 0.6 | NS |
Hip (cm) | 61.1 ± 1.8 | 59.6 ± 0.6 | NS |
SBP (mmHg) | 96.9 ± 3.0 | 95.9 ± 1.0 | NS |
DBP (mmHg) | 57.1 ± 1.1 | 57.0 ± 0.7 | NS |
HDL-cholesterol (mg/dL) | 57.0 ± 2.7 | 55.8 ± 0.8 | NS |
Triglycerides (mg/dL) | 49.5 ± 2.7 | 50.8 ± 1.2 | NS |
Glucose (mg/dL) | 85.0 ± 1.7 | 82.9 ± 0.5 | NS |
Insulin (mIU/L) | 6.2 ± 0.5 | 5.2 ± 0.2 | NS |
HOMA-IR | 1.3 ± 0.1 | 1.1 ± 0.1 | NS |
FBM (kg) | 5.9 ± 0.6 | 5.6 ± 0.2 | NS |
LBM (kg) | 18.0 ± 0.6 | 17.0 ± 0.2 | NS |
Subcutaneous fat (cm) | 0.41 ± 0.03 | 0.45 ± 0.02 | NS |
Peritoneal fat (cm) | 0.45 ± 0.04 | 0.46 ± 0.01 | NS |
Visceral fat (cm2) | 5.4 ± 0.2 | 5.2 ± 0.1 | NS |
(A) Hypermethylated DMCs | ||||||
---|---|---|---|---|---|---|
Ilmn ID | Beta Coef. | FDR | OR | Chr | Position | Gene |
cg00406870 | 1.03970511 | 4.35 × 10−43 | 2.82838283 | 11 | 124981741 | TMEM218 |
cg07150062 | 1.03245317 | 2.74 × 10−39 | 2.80794576 | 14 | 104552032 | ASPG |
cg10761315 | 0.98664557 | 7.57 × 10−37 | 2.68222203 | 14 | 104552034 | ASPG |
cg11163620 | 0.97173534 | 5.92 × 10−36 | 2.64252615 | 4 | 157997554 | GLRB |
cg01963620 | 0.97115961 | 6.50 × 10−35 | 2.64100522 | 11 | 124981674 | TMEM218 |
cg08626939 | 0.96229948 | 4.80 × 10−33 | 2.61770892 | 2 | 227656417 | IRS1 |
cg05665562 | 0.96004491 | 5.03 × 10−38 | 2.61181376 | 11 | 124981679 | TMEM218 |
cg14874299 | 0.95164064 | 4.12 × 10−36 | 2.58995536 | 11 | 124981343 | TMEM218 |
cg12163935 | 0.94020019 | 8.88 × 10−32 | 2.56049395 | 2 | 227656057 | IRS1 |
cg05446424 | 0.92323155 | 3.13 × 10−43 | 2.51741242 | 2 | 14772734 | FAM84A |
(B) Hypomethylated DMCs | ||||||
Ilmn ID | Beta Coef. | FDR | OR | Chr | Position | Gene |
cg10324224 | −1.13770315 | 6.06 × 10−11 | 0.32055444 | 1 | 231115997 | TTC13 |
cg24202000 | −1.09504286 | 2.49 × 10−10 | 0.33452527 | 8 | 129551766 | LINC00824 |
cg21240123 | −0.98681175 | 1.42 × 10−08 | 0.37276326 | 3 | 20016987 | RAB5A |
cg14730097 | −0.96058097 | 8.10 × 10−09 | 0.3826705 | 2 | 233632281 | GIGYF2 |
cg18705155 | −0.86117235 | 7.25 × 10−09 | 0.42266628 | 6 | 39194077 | KCNK5 |
cg20401473 | −0.81442859 | 7.13 × 10−07 | 0.44289233 | 6 | 88186912 | SLC35A1 |
cg23691406 | −0.80357486 | 5.41 × 10−17 | 0.44772554 | 14 | 71112909 | TTC9 |
cg10533159 | −0.77469288 | 8.47 × 10−40 | 0.4608453 | 1 | 207991937 | LOC148696 |
cg17325094 | −0.77392864 | 2.08 × 10−20 | 0.46119763 | 1 | 57809419 | DAB1 |
cg04248557 | −0.74101842 | 1.63 × 10−06 | 0.47662826 | 7 | 69196758 | AUTS2 |
Placental IRS1 (CpG2) Methylation | Placental IRS1 Expression | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Offspring at 6 yr | All | Boys | Girls | All | Boys | Girls | ||||||
r | p-Value | r | p-Value | r | p-Value | r | p-Value | r | p-Value | r | p-Value | |
Weight-SDS | 0.227 | 0.006 | 0.254 | 0.03 | 0.249 | 0.02 | 0.054 | Ns | 0.319 | 0.006 | −0.011 | NS |
Height-SDS | 0.160 | 0.05 | 0.214 | NS | 0.142 | NS | 0.134 | NS | 0.150 | NS | 0.091 | NS |
BMI-SDS | 0.221 | 0.007 | 0.245 | 0.04 | 0.237 | 0.03 | 0.062 | NS | 0.118 | NS | −0.016 | NS |
Δ BW-SDS to weight-SDS | 0.190 | 0.02 | 0.236 | 0.05 | 0.201 | NS | 0.039 | NS | 0.153 | NS | −0.063 | NS |
Waist | 0.215 | 0.01 | 0.235 | 0.05 | 0.225 | 0.05 | 0.092 | NS | 0.168 | NS | 0.079 | NS |
Hip | 0.217 | 0.01 | 0.270 | 0.03 | 0.163 | NS | 0.149 | NS | 0.287 | 0.02 | 0.030 | NS |
Waist-to-height ratio | 0.181 | 0.03 | 0.155 | NS | 0.214 | NS | 0.098 | NS | 0.091 | NS | −0.115 | NS |
LBM | 0.185 | 0.03 | 0.240 | 0.05 | 0.201 | NS | 0.168 | 0.05 | 0.317 | 0.01 | 0.123 | NS |
FBM | 0.176 | 0.04 | 0.195 | NS | 0.164 | NS | 0.078 | NS | 0.198 | NS | −0.029 | NS |
Subcutaneous fat | 0.248 | 0.003 | 0.270 | 0.02 | 0.244 | 0.03 | 0.045 | NS | 0.086 | NS | −0.137 | NS |
Preperitoneal fat | 0.171 | 0.03 | 0.282 | 0.01 | 0.066 | NS | 0.086 | NS | 0.032 | NS | −0.182 | NS |
Visceral fat | 0.143 | NS | 0.242 | 0.04 | 0.063 | NS | 0.248 | 0.003 | 0.408 | <0.0001 | 0.057 | NS |
Insulin | 0.103 | NS | −0.041 | NS | 0.241 | 0.03 | 0.167 | 0.05 | 0.178 | NS | 0.249 | 0.03 |
HOMA-IR | 0.063 | NS | −0.086 | NS | 0.204 | NS | 0.159 | 0.05 | 0.179 | NS | 0.264 | 0.02 |
Offspring Leukocyte IRS1 Expression | ||||||
---|---|---|---|---|---|---|
Offspring at 6yr | All | Boys | Girls | |||
r | p-Value | r | p-Value | r | p-Value | |
Weight-SDS | 0.183 | NS | −0.074 | NS | 0.470 | 0.001 |
Height-SDS | 0.094 | NS | 0.012 | NS | 0.186 | NS |
BMI-SDS | 0.148 | NS | −0.152 | NS | 0.444 | 0.002 |
Δ BW-SDS to weight-SDS | 0.028 | NS | −0.177 | NS | 0.283 | 0.05 |
Waist | 0.120 | NS | −0.230 | NS | 0.460 | 0.002 |
Hip | 0.025 | NS | −0.207 | NS | 0.258 | NS |
Waist-to-height ratio | 0.214 | 0.05 | −0.157 | NS | 0.470 | 0.001 |
LBM | 0.043 | NS | −0.109 | NS | 0.252 | NS |
FBM | 0.084 | NS | −0.176 | NS | 0.431 | 0.004 |
Subcutaneous fat | 0.107 | NS | −0.091 | NS | 0.313 | 0.03 |
Preperitoneal fat | 0.100 | NS | 0.007 | NS | 0.178 | NS |
Visceral fat | 0.226 | 0.03 | −0.099 | NS | 0.411 | 0.006 |
Insulin | 0.080 | NS | −0.155 | NS | 0.383 | 0.009 |
HOMA-IR | 0.066 | NS | −0.144 | NS | 0.335 | 0.02 |
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Gómez-Vilarrubla, A.; Niubó-Pallàs, M.; Mas-Parés, B.; Bonmatí-Santané, A.; Martínez-Calcerrada, J.-M.; López, B.; Peñas-Cruz, A.; de Zegher, F.; Ibáñez, L.; López-Bermejo, A.; et al. Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity. Int. J. Mol. Sci. 2025, 26, 3141. https://doi.org/10.3390/ijms26073141
Gómez-Vilarrubla A, Niubó-Pallàs M, Mas-Parés B, Bonmatí-Santané A, Martínez-Calcerrada J-M, López B, Peñas-Cruz A, de Zegher F, Ibáñez L, López-Bermejo A, et al. Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity. International Journal of Molecular Sciences. 2025; 26(7):3141. https://doi.org/10.3390/ijms26073141
Chicago/Turabian StyleGómez-Vilarrubla, Ariadna, Maria Niubó-Pallàs, Berta Mas-Parés, Alexandra Bonmatí-Santané, Jose-Maria Martínez-Calcerrada, Beatriz López, Aaron Peñas-Cruz, Francis de Zegher, Lourdes Ibáñez, Abel López-Bermejo, and et al. 2025. "Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity" International Journal of Molecular Sciences 26, no. 7: 3141. https://doi.org/10.3390/ijms26073141
APA StyleGómez-Vilarrubla, A., Niubó-Pallàs, M., Mas-Parés, B., Bonmatí-Santané, A., Martínez-Calcerrada, J.-M., López, B., Peñas-Cruz, A., de Zegher, F., Ibáñez, L., López-Bermejo, A., & Bassols, J. (2025). Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity. International Journal of Molecular Sciences, 26(7), 3141. https://doi.org/10.3390/ijms26073141