title: Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma.
abstract: Chromosomal region 17q12-q21 is one of the best-replicated genome-wide association study (GWAS) hits and associated with childhood-onset asthma. However, the mechanism by which the genetic association is restricted to childhood-onset disease is unclear. During childhood, more boys than girls develop asthma. Therefore, we tested the hypothesis that the 17q12-q21 genetic association was sex-specific. Indeed, a TDT test showed that in the Saguenay-Lac-Saint-Jean familial collection, the 17q12-q21 association was significant among male, but not among female asthmatic subjects. We next hypothesized that the bias in the genetic association resulted from sex-specific and/or age-dependent DNA methylation at regulatory regions and determined the methylation profiles of five 17q12-q21 gene promoters using the bisulfite sequencing methylation assay. We identified a single regulatory region within the zona pellucida binding protein 2 (ZPBP2) gene, which showed statistically significant differences between males and females with respect to DNA methylation. DNA methylation also varied with age and was higher in adult males compared to boys. We have recently identified two functionally important polymorphisms, both within the ZPBP2 gene that influence expression levels of neighboring genes. Combined with the results of the present work, these data converge pointing to the same 5 kb region within the ZPBP2 gene as a critical region for both gene expression regulation and predisposition to asthma. Our data show that sex- and age-dependent DNA methylation may act as a modifier of genetic effects and influence the results of genetic association studies.
authors.affiliation: Department of Obstetrics and Gynecology, McGill University, Montreal, QC, H3A 1A1, Canada. anna.naoumova@mcgill.ca
authors.forename: Anna K
authors.initials: AK
authors.lastname: Naumova
authors.forename: Abeer
authors.initials: A
authors.lastname: Al Tuwaijri
authors.forename: Andréanne
authors.initials: A
authors.lastname: Morin
authors.forename: Vanessa T
authors.initials: VT
authors.lastname: Vaillancourt
authors.forename: Vanessa T
authors.initials: VT
authors.lastname: Vaillancout
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Madore
authors.forename: Soizik
authors.initials: S
authors.lastname: Berlivet
authors.forename: Hamid-Reza
authors.initials: HR
authors.lastname: Kohan-Ghadr
authors.forename: Sanny
authors.initials: S
authors.lastname: Moussette
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D001249:Asthma / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004527:Egg Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000235:genetics; D056426:Genetic Loci; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D012727:Sex Characteristics
chemical_list: D004527:Egg Proteins; D008565:Membrane Proteins; C479482:ZPBP2 protein, human
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