Background Birth weight and prematurity are important obstetric outcomes linked to lifelong health. We studied a large birth cohort to look for evidence of epigenetic involvement in birth outcomes. Methods We investigated the association between birth weight, length, placental weight and duration of gestation and four candidate variants in 1,236 mothers and 1,073 newborns; DNMT1 (rs2162560), DNMT3A (rs734693), DNMT3B (rs2424913) and DNMT3L (rs7354779). We measured methylation of LINE1 and the imprinted genes, PEG3, SNRPN, and IGF2, in cord blood. Results The minor DNMT3L allele in the baby was associated with higher birth weight (+54 95% CI 10,99 g; p = 0.016), birth length (+0.23 95% CI 0.04,0.42 cm; p = 0.017), placental weight, (+18 95% CI 3,33 g; p = 0.017), and reduced risk of being in the lowest birth weight decile (p = 0.018) or requiring neonatal care (p = 0.039). The DNMT3B minor allele in the mother was associated with an increased risk of prematurity (p = 0.001). Placental size was related to PEG3 (p<0.001) and IGF2 (p<0.001) methylation. Birth weight was related to LINE1 and IGF2 methylation but only at p = 0.052. The risk of requiring neonatal treatment was related to LINE1 (p = 0.010) and SNRPN (p = 0.001) methylation. PEG3 methylation was influenced by baby DNMT3A genotype (p = 0.012) and LINE1 by baby 3B genotype (p = 0.044). Maternal DNMT3L genotype was related to IGF2 methylation in the cord blood but this effect was only seen in carriers of the minor frequency allele (p = 0.050). Conclusions The results here suggest that epigenetic processes are linked birth outcome and health in early life. Our emerging understanding of the role of epigenetics in health and biological function across the lifecourse suggests that these early epigenetic events could have longer term implications.
References
[1]
Barker DJ (2007) The origins of the developmental origins theory. J Intern Med 261: 412–417 JIM1809 [pii];10.1111/j.1365-2796.2007.01809.x [doi].
[2]
Scientific Advisory Committee on Nutrition (2007) The influence of maternal fetal and child nutrition on the development of chronic disease in later life. A report of the SACN subgroup on Maternal and Child Nutrition.
[3]
Risnes KR, Vatten LJ, Baker JL, Jameson K, Sovio U, et al. (2011) Birthweight and mortality in adulthood: a systematic review and meta-analysis. Int J Epidemiol 40: 647–661.
[4]
Silva IS, De SB, McCormack V (2008) Birth size and breast cancer risk: re-analysis of individual participant data from 32 studies. PLoS Med 5: e193 08-PLME-RA-0764 [pii];10.1371/journal.pmed.0050193 [doi].
[5]
Elovainio M, Ferrie JE, Singh-Manoux A, Shipley M, Batty GD, et al. (2011) Socioeconomic Differences in Cardiometabolic Factors: Social Causation or Health-related Selection? Evidence From the Whitehall II Cohort Study, 1991–2004. Am J Epidemiol.
[6]
Matte TD, Bresnahan M, Begg MD, Susser E (2001) Influence of variation in birth weight within normal range and within sibships on IQ at age 7 years: cohort study. BMJ 323: 310–314.
[7]
Richards M, Hardy R, Kuh D, Wadsworth ME (2001) Birth weight and cognitive function in the British 1946 birth cohort: longitudinal population based study. BMJ 322: 199–203.
[8]
Calvin CM, Deary IJ, Fenton C, Roberts BA, Der G, et al. (2011) Intelligence in youth and all-cause-mortality: systematic review with meta-analysis. Int J Epidemiol 40: 626–644.
[9]
Swamy GK, Ostbye T, Skjaerven R (2008) Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth. JAMA 299: 1429–1436.
[10]
Clausson B, Lichtenstein P, Cnattingius S (2000) Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 107: 375–381.
[11]
Czerwinski SA, Lee M, Choh AC, Wurzbacher K, Demerath EW, et al. (2007) Genetic factors in physical growth and development and their relationship to subsequent health outcomes. Am J Hum Biol 19: 684–691.
[12]
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753 nature08494 [pii];10.1038/nature08494 [doi].
[13]
Hattersley AT, Tooke JE (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353: 1789–1792.
[14]
Sebert S, Sharkey D, Budge H, Symonds ME (2011) The early programming of metabolic health: is epigenetic setting the missing link? Am J Clin Nutr. ajcn.110.001040 [pii];10.3945/ajcn.110.001040 [doi].
[15]
Waterland RA, Jirtle RL (2004) Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20: 63–68.
[16]
Waterland RA (2009) Is epigenetics an important link between early life events and adult disease? Horm Res 71 Suppl 113–16 000178030 [pii];10.1159/000178030 [doi].
[17]
Woodfine K, Huddleston JE, Murrell A (2011) Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenetics Chromatin 4: 1 1756-8935-4-1 [pii];10.1186/1756-8935-4-1 [doi].
[18]
Campbell D, Hall M, Lemon J, Carr-Hill R, Pritchard C, et al. (1993) Clinical birthweight standards for a total population in the 1980s. Br J Obstet Gynaecol 100: 436–445.
[19]
Haggarty P, McCallum H, McBain H, Andrews K, Duthie S, et al. (2006) Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 367: 1513–1519.
[20]
Balding DJ (2006) A tutorial on statistical methods for population association studies. Nat Rev Genet 7: 781–791.
[21]
de VS, Wouters KA, Gottschalk RW, van Schooten FJ, de Goeij AF, et al. (2011) Dietary methyl donors, methyl metabolizing enzymes, and epigenetic regulators: diet-gene interactions and promoter CpG island hypermethylation in colorectal cancer. Cancer Causes Control 22: 1–12 10.1007/s10552-010-9659-6 [doi].
[22]
Bao Q, He B, Pan Y, Tang Z, Zhang Y, et al. (2011) Genetic variation in the promoter of DNMT3B is associated with the risk of colorectal cancer. Int J Colorectal Dis 26: 1107–1112 10.1007/s00384-011-1199-3 [doi].
[23]
Liu Z, Wang L, Wang LE, Sturgis EE, Wei Q (2008) Polymorphisms of the DNMT3B gene and risk of squamous cell carcinoma of the head and neck: A case-control study. Cancer Lett.
[24]
Coppede F, Bosco P, Tannorella P, Romano C, Antonucci I, et al. (2013) DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome. Hum Reprod 28: 545–550 des376 [pii];10.1093/humrep/des376 [doi].
[25]
Borghese B, Santulli P, Hequet D, Pierre G, de ZD, et al. (2012) Genetic Polymorphisms of DNMT3L Involved in Hypermethylation of Chromosomal Ends Are Associated with Greater Risk of Developing Ovarian Endometriosis. Am J Pathol 180: 1781–1786 S0002-9440(12)00100-9 [pii];10.1016/j.ajpath.2012.01.009 [doi].
[26]
Huang JX, Scott MB, Pu XY, Zhou-Cun A (2012) Association between single-nucleotide polymorphisms of DNMT3L and infertility with azoospermia in Chinese men. Reprod Biomed Online 24: 66–71 S1472-6483(11)00492-5 [pii];10.1016/j.rbmo.2011.09.004 [doi].
[27]
Haggarty P, Hoad G, Harris SE, Starr JM, Fox HC, et al. (2010) Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. PLoS One 5: e11329.
[28]
El-Maarri O, Kareta MS, Mikeska T, Becker T, az-Lacava A, et al. (2009) A systematic search for DNA methyltransferase polymorphisms reveals a rare DNMT3L variant associated with subtelomeric hypomethylation. Hum Mol Genet 18: 1755–1768.
[29]
Levin HL, Moran JV (2011) Dynamic interactions between transposable elements and their hosts. Nat Rev Genet 12: 615–627 nrg3030 [pii];10.1038/nrg3030 [doi].
[30]
Dupont JM, Tost J, Jammes H, Gut IG (2004) De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem 333: 119–127 10.1016/j.ab.2004.05.007 [doi];S0003269704004130 [pii].
[31]
Feng W, Marquez RT, Lu Z, Liu J, Lu KH, et al. (2008) Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer 112: 1489–1502 10.1002/cncr.23323 [doi].
[32]
White HE, Durston VJ, Harvey JF, Cross NC (2006) Quantitative analysis of SNRPN(correction of SRNPN) gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome. Clin Chem 52: 1005–1013 clinchem.2005.065086 [pii];10.1373/clinchem.2005.065086 [doi].
[33]
Leonardi-Bee J, Smyth A, Britton J, Coleman T (2008) Environmental tobacco smoke and fetal health: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 93: F351–F361.
[34]
Arnaud P, Hata K, Kaneda M, Li E, Sasaki H, et al. (2006) Stochastic imprinting in the progeny of Dnmt3L(？/？) females. Hum Mol Genet 15: 589–598.
[35]
Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, et al. (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429: 900–903.
[36]
Kaneda M, Hirasawa R, Chiba H, Okano M, Li E, et al. (2010) Genetic evidence for Dnmt3a-dependent imprinting during oocyte growth obtained by conditional knockout with Zp3-Cre and complete exclusion of Dnmt3b by chimera formation. Genes Cells. GTC1374 [pii];10.1111/j.1365-2443.2009.01374.x [doi].
[37]
Aapola U, Liiv I, Peterson P (2002) Imprinting regulator DNMT3L is a transcriptional repressor associated with histone deacetylase activity. Nucleic Acids Res 30: 3602–3608.
[38]
Deplus R, Brenner C, Burgers WA, Putmans P, Kouzarides T, et al. (2002) Dnmt3L is a transcriptional repressor that recruits histone deacetylase. Nucleic Acids Res 30: 3831–3838.
[39]
Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH (2001) Dnmt3L and the establishment of maternal genomic imprints. Science 294: 2536–2539.
[40]
Lucifero D, Mann MRW, Bartolomei MS, Trasler JM (2004) Gene-specific timing and epigenetic memory in oocyte imprinting. Human Molecular Genetics 13: 839–849.
[41]
Hata K, Okano M, Lei H, Li E (2002) Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129: 1983–1993.
[42]
Trasler JM (2006) Gamete imprinting: setting epigenetic patterns for the next generation. Reprod Fertil Dev 18: 63–69.
[43]
Reik W, Constancia M, Fowden A, Anderson N, Dean W, et al. (2003) Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol 547: 35–44.
[44]
Allegrucci C, Thurston A, Lucas E, Young L (2005) Epigenetics and the germline. Reproduction 129: 137–149.
[45]
Constancia M, Pickard B, Kelsey G, Reik W (1998) Imprinting mechanisms. Genome Res 8: 881–900.
[46]
Walter J, Hutter B, Khare T, Paulsen M (2006) Repetitive elements in imprinted genes. Cytogenet Genome Res 113: 109–115.
[47]
Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10: 691–703 nrg2640 [pii];10.1038/nrg2640 [doi].
[48]
Michels KB, Harris HR, Barault L (2011) Birthweight, maternal weight trajectories and global DNA methylation of LINE-1 repetitive elements. PLoS One 6: e25254 10.1371/journal.pone.0025254 [doi];PONE-D-11–10322 [pii].
[49]
Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7: 21–33 nrg1748 [pii];10.1038/nrg1748 [doi].
[50]
Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6: 597–610.
[51]
Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128: 683–692.
[52]
Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105: 17046–17049 0806560105 [pii];10.1073/pnas.0806560105 [doi].
[53]
Reik W, Davies K, Dean W, Kelsey G, Constancia M (2001) Imprinted genes and the coordination of fetal and postnatal growth in mammals. Novartis Found Symp 237: 19–31.
[54]
Tycko B, Morison IM (2002) Physiological functions of imprinted genes. J Cell Physiol 192: 245–258.
[55]
Wilkinson LS, Davies W, Isles AR (2007) Genomic imprinting effects on brain development and function. Nat Rev Neurosci 8: 832–843.
