title: Modification of epigenetic patterns in low birth weight children: importance of hypomethylation of the ACE gene promoter.
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.
authors.affiliation: Nephrology Division, School of Medicine, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: Rangel
authors.affiliation: Molecular Biology Laboratory. Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.
authors.forename: Jéssica Cassilla
authors.initials: JC
authors.lastname: dos Santos
authors.affiliation: Molecular Biology Laboratory. Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.
authors.forename: Paula Helena Lima
authors.initials: PH
authors.lastname: Ortiz
authors.affiliation: School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Mario
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Pharmacology Department, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Miriam Galvonas
authors.initials: MG
authors.lastname: Jasiulionis
authors.affiliation: Biophysics Department, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Ronaldo C
authors.initials: RC
authors.lastname: Araujo
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Daniela Filippini
authors.initials: DF
authors.lastname: Ierardi
authors.affiliation: Nephrology Division, School of Medicine, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Maria do Carmo
authors.initials: Mdo C
authors.lastname: Franco
mesh_terms: D001794:Blood Pressure / Q000235:genetics; D015992:Body Mass Index; D002648:Child; D018899:CpG Islands / Q000235:genetics; D003430:Cross-Sectional Studies; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D007230:Infant, Low Birth Weight / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A