DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood

Eva Morales, Mariona Bustamante, Nadia Vilahur, Georgia Escaramis, Magda Montfort, Rafael De Cid, Raquel Garcia-Esteban, Maties Torrent, Xavier Estivill, Joan O. Grimalt, Jordi Sunyer

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Rationale: Epigenetic changes may play a role in the occurrence of asthma-related phenotypes. Objectives: To identify epigenetic marks in terms ofDNAmethylation 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 usewas obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data. Measurement and Main 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.

Original languageEnglish
Pages (from-to)937-943
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number9
Publication statusPublished - 1 May 2012



  • ALOX12
  • Asthma
  • Dichlorodiphenyldichloroethylene
  • Epigenetics
  • Wheezing

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Morales, E., Bustamante, M., Vilahur, N., Escaramis, G., Montfort, M., De Cid, R., Garcia-Esteban, R., Torrent, M., Estivill, X., Grimalt, J. O., & Sunyer, J. (2012). DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood. American Journal of Respiratory and Critical Care Medicine, 185(9), 937-943. https://doi.org/10.1164/rccm.201105-0870OC