DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood.
BACKGROUND
Epigenetic changes may play a role in the occurrence of asthma-related phenotypes.


OBJECTIVE
To identify epigenetic marks in terms of DNA methylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks.


METHODS
Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) PROJECT: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4-6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement use was obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data.


RESULTS
Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99-1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03-1.37; P = 0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms.


CONCLUSIONS
DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes.
Center for Research in Environmental Epidemiology, Barcelona, Catalonia, Spain. emorales1@creal.cat
Eva
E
Morales
Mariona
M
Bustamante
Nadia
N
Vilahur
Georgia
G
Escaramis
Magda
M
Montfort
Rafael
R
de Cid
Raquel
R
Garcia-Esteban
Maties
M
Torrent
Xavier
X
Estivill
Joan O
JO
Grimalt
Jordi
J
Sunyer
D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000453:epidemiology; D012135:Respiratory Sounds / Q000209:etiology* / Q000235:genetics; D012307:Risk Factors
D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human