Modification of Epigenetic Patterns in Low Birth Weight Children: Importance of Hypomethylation of the ACE Gene Promoter

Author(s)

Rangel, Marina ^[1] ; dos Santos, Jessica Cassilla ^[2] ; Lima Ortiz, Paula Helena ^[2] ; Hirata, Mario ^[3] ; Jasiulionis, Miriam Galvonas ^[4] ; Araujo, Ronaldo C. ^[5] ; Ierardi, Daniela Filippini ^[6] ; Franco, Maria do Carmo ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Sch Med, Div Nephrol, Sao Paulo - Brazil

^[2] Dante Pazzanese Inst Cardiol, Mol Biol Lab, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil

^[6] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 - USA

• Document type: Journal article
• Source: PLoS One; v. 9, n. 8 AUG 29 2014.
• Web of Science Citations: 31

Abstract

There is a growing body of evidence that epigenetic alterations are involved in the pathological mechanisms of many chronic disorders linked to fetal programming. Angiotensin-converting enzyme (ACE) appears as one candidate gene that brings new insights into the epigenetic control and later development of diseases. In this view, we have postulated that epigenetic modifications in the ACE gene might show different interactions between birth weight (BW), blood pressure levels, plasma ACE activity and ACE I/D polymorphism. To explore this hypothesis, we performed a cross-sectional study to evaluate the DNA methylation of 3 CpG sites using pyrosequencing within the ACE gene promoter of peripheral blood leukocytes from 45 LBW children compared with 70 NBW children. Our results have revealed that LBW children have lower methylation levels (P<0.001) in parallel with a higher ACE activity (P=0.001). Adjusting for prematurity, gender, age, body mass index, and family history of cardiovascular disease did not alter these findings. We have also performed analyses of individual CpG sites. The frequency of DNA methylation was significantly different at two CpG sites (site 1: nucleotide position + 555; and site 3: nucleotide position + 563). In addition, we have found a significant inverse correlation between degree of DNA methylation and both ACE activity (P<0.001) and systolic blood pressure levels (P<0.001). We also observed that the methylation level was significantly lower in LBW children who are carriers of the DD genotype compared to NBW children with DD genotype (P<0.024). In conclusion, we are able to demonstrate that the hypomethylation in the 3 CpG sites of ACE gene promoter is associated with LBW in 6 to 12 year-old children. The magnitude of these epigenetic changes appears to be clinically important, which is supported by the observation that discrete changes in DNA methylation can affect systolic blood pressure and ACE protein activity levels. (AU)

• FAPESP's process: 07/58044-2 - Birth weight and cardiovascular diseases: characterization of risk and genetic factors interrelation by identifying genomic imprinting mechanisms as well as genetic polymorphisms in homocysteine and eNOS pathways
• Grantee: Maria Do Carmo Pinho Franco
• Support Opportunities: Research Grants - Young Investigators Grants