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Maternal cardiometabolic factors and genetic ancestry influence epigenetic aging of the placenta

  • Tsegaselassie Workalemahu (a1), Deepika Shrestha (a1), Salman M. Tajuddin (a2) and Fasil Tekola-Ayele (a1)


Disruption of physiological aging of the placenta can lead to pregnancy complications and increased risk for cardiometabolic diseases during childhood and adulthood. Maternal metabolic and genetic factors need to operate in concert with placental development for optimal pregnancy outcome. However, it is unknown whether maternal cardiometabolic status and genetic ancestry contribute to differences in placental epigenetic age acceleration (PAA). We investigated whether maternal prepregnancy obesity, gestational weight gain (GWG), blood pressure, and genetic ancestry influence PAA. Among 301 pregnant women from 4 race/ethnic groups who provided placenta samples at delivery as part of the National Institute of Child Health and Human Development Fetal Growth Studies, placental DNA methylation age was estimated using 62 CpGs known to predict placental aging. PAA was defined to be the difference between placental DNA methylation age and gestational age at birth. Percentage of genetic ancestries was estimated using genotype data. We found that a 1 kg/week increase in GWG was associated with up to 1.71 (95% CI: −3.11, −0.32) week lower PAA. Offspring Native American ancestry and African ancestry were associated, respectively, with higher and lower PAA among Hispanics, and maternal East Asian ancestry was associated with lower PAA among Asians (p < 0.05). Among mothers with a male offspring, blood pressure was associated with lower PAA across all three trimesters (p < 0.05), prepregnancy obesity compared to normal weight was associated with 1.24 (95% CI: −2.24, −0.25) week lower PAA. In summary, we observed that maternal cardiometabolic factors and genetic ancestry influence placental epigenetic aging and some of these influences may be male offspring-specific.


Corresponding author

Address for correspondence: Fasil Tekola-Ayele, Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Email:


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1. Chen, K, Chen, L, Lee, Y. Exploring the relationship between preterm placental calcification and adverse maternal and fetal outcome. Ultrasound Obst Gyn. 2011; 37(3), 328334.
2. Chen, K-H, Chen, L-R, Lee, Y-H. The role of preterm placental calcification in high-risk pregnancy as a predictor of poor uteroplacental blood flow and adverse pregnancy outcome. Ultrasound Med Biol. 2012; 38(6), 10111018.
3. Biron-Shental, T, Sukenik-Halevy, R, Sharon, Y, et al. Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol. 2010; 202(4), 381. e381–381. e387.
4. Maiti, K, Sultana, Z, Aitken, RJ, et al. Evidence that fetal death is associated with placental aging. Am J Obstet Gynecol. 2017; 217(4), 441. e441–441. e414.
5. Sultana, Z, Maiti, K, Aitken, J, Morris, J, Dedman, L, Smith, R. Oxidative stress, placental ageing‐related pathologies and adverse pregnancy outcomes. Am J Reprod Immunol. 2017; 77(5), e12653.
6. Thornburg, K, O’tierney, P, Louey, S. The placenta is a programming agent for cardiovascular disease. Placenta. 2010; 31, S54S59.
7. Arabin, B, Baschat, AA. Pregnancy: an underutilized window of opportunity to improve long-term maternal and infant health—An appeal for continuous family care and interdisciplinary communication. Front Pediatr. 2017; 5, 69.
8. Sultana, Z, Maiti, K, Dedman, L, Smith, R. Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? Am J Obstet Gynecol. 2018; 218(2), S762S773.
9. Polettini, J, Dutta, E, Behnia, F, Saade, G, Torloni, M, Menon, R. Aging of intrauterine tissues in spontaneous preterm birth and preterm premature rupture of the membranes: a systematic review of the literature. Placenta. 2015; 36(9), 969973.
10. Rodier, F, Campisi, J. Four faces of cellular senescence. J Cell Biol. 2011. jcb.201009094.
11. Van Deursen, JM. The role of senescent cells in ageing. Nature. 2014; 509(7501), 439.
12. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 2013; 14(10), 3156.
13. Horvath, S, Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6), 371.
14. Jylhävä, J, Pedersen, NL, Hägg, S. Biological age predictors. EBioMedicine. 2017; 21, 2936.
15. Bell, JT, Tsai, P-C, Yang, T-P, et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLos Genet. 2012; 8(4), e1002629.
16. Christensen, BC, Houseman, EA, Marsit, CJ, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLos Genet. 2009; 5(8), e1000602.
17. Boyd-Kirkup, JD, Green, CD, Wu, G, Wang, D, Han, J-DJ. Epigenomics and the regulation of aging. Epigenomics. 2013; 5(2), 205227.
18. Perna, L, Zhang, Y, Mons, U, Holleczek, B, Saum, K-U, Brenner, H. Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenetics. 2016; 8(1), 64.
19. Zheng, SC, Widschwendter, M, Teschendorff, AE. Epigenetic drift, epigenetic clocks and cancer risk. Epigenomics. 2016; 8(5), 705719.
20. Girchenko, P, Lahti, J, Czamara, D, et al. Associations between maternal risk factors of adverse pregnancy and birth outcomes and the offspring epigenetic clock of gestational age at birth. Clin Epigenetics. 2017; 9(1), 49.
21. Bohlin, J, Håberg, SE, Magnus, P, et al. Prediction of gestational age based on genome-wide differentially methylated regions. Genome Biol. 2016; 17(1), 207.
22. Knight, AK, Craig, JM, Theda, C, et al. An epigenetic clock for gestational age at birth based on blood methylation data. Genome Biol. 2016; 17(1), 206.
23. Mayne, BT, Leemaqz, SY, Smith, AK, Breen, J, Roberts, CT, Bianco-Miotto, T. Accelerated placental aging in early onset preeclampsia pregnancies identified by DNA methylation. Epigenomics. 2017; 9(3), 279289.
24. Knight, AK, Conneely, KN, Smith, AK. Gestational age predicted by DNA methylation: potential clinical and research utility, 2017. Future Medicine.
25. Yang, L, Cartier, J, Drake, A, Reynolds, R. DNA methylation differs between lean and obese placenta and is influenced by maternal environment and fetal sex. In Society for Endocrinology BES 2017, 2017. BioScientifica.
26. Horvath, S, Gurven, M, Levine, ME, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016; 17(1), 171.
27. Cappetta, M, Berdasco, M, Hochmann, J, et al. Effect of genetic ancestry on leukocyte global DNA methylation in cancer patients. BMC Cancer. 2015; 15(1), 434.
28. Zhang, W, Dolan, ME. Ancestry-related differences in gene expression: findings may enhance understanding of health disparities between populations. Pharmacogenomics. 2008; 9(5), 489492.
29. Bryc, K, Durand, EY, Macpherson, JM, Reich, D, Mountain, JL. The genetic ancestry of African Americans, Latinos, and European Americans across the United States. Am J Hum Genet. 2015; 96(1), 3753.
30. Yeganegi, M, Watson, CS, Martins, A, et al. Effect of Lactobacillus rhamnosus GR-1 supernatant and fetal sex on lipopolysaccharide-induced cytokine and prostaglandin-regulating enzymes in human placental trophoblast cells: implications for treatment of bacterial vaginosis and prevention of preterm labor. Am J Obstet Gynecol. 2009; 200(5), 532. e531–532. e538.
31. Simpkin, AJ, Hemani, G, Suderman, M, et al. Prenatal and early life influences on epigenetic age in children: a study of mother–offspring pairs from two cohort studies. Hum Mol Genet. 2015; 25(1), 191201.
32. Grewal, J, Grantz, KL, Zhang, C, et al. Cohort Profile: NICHD Fetal Growth Studies–Singletons and Twins. Int J Epidemiol. 2017; 47(1), 2525l.
33. Buck Louis, GM, Grewal, J, Albert, PS, et al. Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies. Am J Obstet Gynecol. 2015; 213(4), 449. e441–449. e441.
34. Delahaye, F, Do, C, Kong, Y, et al. Genetic variants influence on the placenta regulatory landscape. PLos Genet. 2018; 14(11), e1007785.
35. Teschendorff, AE, Marabita, F, Lechner, M, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2012; 29(2), 189196.
36. Troyanskaya, O, Cantor, M, Sherlock, G, et al. Missing value estimation methods for DNA microarrays. Bioinformatics. 2001; 17(6), 520525.
37. Friedman, J, Hastie, T, Tibshirani, R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010; 33(1), 1.
38. Consortium, GP. A global reference for human genetic variation. Nature. 2015; 526(7571), 68.
39. Li, JZ, Absher, DM, Tang, H, et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science. 2008; 319(5866), 11001104.
40. Alexander, DH, Novembre, J, Lange, K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. 2009; 19, 16551664.
41. Hinkle, SN, Johns, AM, Albert, PS, Kim, S, Grantz, KL. Longitudinal changes in gestational weight gain and the association with intrauterine fetal growth. Eur J Obstet Gynecol Reprod Biol. 2015; 190, 4147.
42. Roberts, VH, Smith, J, McLea, SA, Heizer, AB, Richardson, JL, Myatt, L. Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta. Placenta. 2009; 30(2), 169175.
43. Siveska, E, Jasovic, V. Fetal Growth and Body Proportion during Pre-Eclamptic Pregnancy. Obstet Gynecol Int J. 2015; 2(3), 00038.
44. Hermida, RC, Ayala, DE, Iglesias, M. Predictable blood pressure variability in healthy and complicated pregnancies. Hypertension. 2001; 38(3), 736741.
45. Norwood, KA. Maternal obesity alters fetal development due to impaired placental function and has lasting effects on adult offspring, Theses and Dissertations in Animal Science, 69, UNL Digital Commons, 2013. Accessed 03/12/2019 from
46. Huang, L, Liu, J, Feng, L, Chen, Y, Zhang, J, Wang, W. Maternal prepregnancy obesity is associated with higher risk of placental pathological lesions. Placenta. 2014; 35(8), 563569.
47. Belkacemi, L, Kjos, S, Nelson, D, Desai, M, Ross, M. Reduced apoptosis in term placentas from gestational diabetic pregnancies. J Dev Orig Hlth Dis. 2013; 4(3), 256265.
48. Myatt, L. Placental adaptive responses and fetal programming. J Physiol. 2006; 572(1), 2530.
49. Walker, MG, Hindmarsh, PC, Geary, M, Kingdom, JC. Sonographic maturation of the placenta at 30 to 34 weeks is not associated with second trimester markers of placental insufficiency in low-risk pregnancies. J Obstet Gynaecol Can. 2010; 32(12), 11341139.
50. Sood, R, Zehnder, JL, Druzin, ML, Brown, PO. Gene expression patterns in human placenta. Proc Natl Acad Sci USA. 2006; 103(14), 54785483.
51. Scott, NM, Hodyl, NA, Murphy, VE, et al. Placental cytokine expression covaries with maternal asthma severity and fetal sex. J Immunol. 2009; 182(3), 14111420.
52. Clifton, V. Sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta. 2010; 31, S33S39.
53. Muralimanoharan, S, Maloyan, A, Myatt, L. Evidence of sexual dimorphism in the placental function with severe preeclampsia. Placenta. 2013; 34(12), 11831189.
54. Shrestha, D, Workalemahu, T, Tekola-Ayele, F. Maternal dyslipidemia during early pregnancy and epigenetic aging of the placenta. Epigenetics. 2019; 14(10), 10301039.
55. Steer, PJ, Little, MP, Kold-Jensen, T, Chapple, J, Elliott, P. Maternal blood pressure in pregnancy, birth weight, and perinatal mortality in first births: prospective study. BMJ. 2004; 329(7478), 1312.
56. Ng, PH, Walters, WA. The effects of chronic maternal hypotension during pregnancy. Aust NZ J Obstet Gynaecol. 1992; 32(1), 1416.
57. Melo, NADB, Araujo Júnior, E, Helfer, TM, et al. Assessment of maternal Doppler parameters of ophthalmic artery in fetuses with growth restriction in the third trimester of pregnancy: a case–control study. J Obstet Gynaecol Res. 2015; 41(9), 13301336.
58. Lean, SC, Heazell, AE, Dilworth, MR, Mills, TA, Jones, RL. Placental dysfunction underlies increased risk of fetal growth restriction and stillbirth in advanced maternal age women. Sci Rep. 2017; 7(1), 9677.
59. Shriner, D, Tekola-Ayele, F, Adeyemo, A, Rotimi, CN. Genome-wide genotype and sequence-based reconstruction of the 140,000 year history of modern human ancestry. Sci Rep. 2014; 4, 6055.
60. Galanter, JM, Gignoux, CR, Oh, SS, et al. Methylation analysis reveals fundamental differences between ethnicity and genetic ancestry. BioRxiv. 2016, 036822.
61. Tekola-Ayele, F, Workalemahu, T, Gorfu, G, et al. Sex differences in the associations of placental epigenetic aging with fetal growth. Aging (Albany NY). 2019; 11, 54125432.


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Maternal cardiometabolic factors and genetic ancestry influence epigenetic aging of the placenta

  • Tsegaselassie Workalemahu (a1), Deepika Shrestha (a1), Salman M. Tajuddin (a2) and Fasil Tekola-Ayele (a1)


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