title: DNA methylation and genetic polymorphisms of the Leptin gene interact to influence lung function outcomes and asthma at 18 years of age.
abstract: The leptin gene (LEP) plays a regulatory role in satiety, inflammation, and allergy. Prior findings linking leptin to asthma motivated us to investigate whether DNA methylation (DNA-M) of CpG (cytosine-phosphate-guanine) sites in concert with single nucleotide polymorphisms (SNPs) of LEP can explain the risk of asthma and lung function. Methylation of CpG sites was assessed using the Illumina Infinium Human Methylation 450 beadchip in blood samples collected from 10- and 18-year-old boys and girls from the Isle of Wight (IOW) birth cohort (UK). Four LEP SNPs were genotyped. Linear and log linear models were used for the analysis, adjusting for false discovery rate (FDR). The analyses were repeated in the BAMSE cohort (Sweden). In the IOW study, the interaction of cg00666422 and rs11763517 (CT vs TT and CC) was associated with FEV1 (FDR-adjusted p-value: 0.03), FEV1/FVC ratio (FDR-adjusted p-value: 0.0096), and FEF25-75% (FDR-adjusted p-value: 0.00048) such that they decreased with increasing DNA-M. The interaction of the same CpG-SNP pair was also associated with increased risk of asthma at age 18. We replicated the findings for FEV1/FVC and FEF25-75% in a smaller sample of 34 participants at age 10. Regarding the BAMSE cohort, although, the interaction of cg00666422 and rs11763517 on lung function were not significant, the direction of the effect was the same as in IOW cohort. Thus, penetrance of LEP genotype seems to be modified by methylation at cg00666422 and is linked to airway obstruction and asthma.
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis Memphis, TN, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Mukherjee
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton UK.
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Lockett
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet Box 210 171 77 Stockholm, Sweden.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Merid
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet Box 210 171 77 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet Box 210 171 77 Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Pershagen
authors.affiliation: Human Development and Health, Faculty of Medicine, University of SouthamptonUK; Clinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonUK; NIHR Respiratory Biomedical Research Unit, University Hospital SouthamptonUK.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonUK; NIHR Respiratory Biomedical Research Unit, University Hospital SouthamptonUK; The David Hide Asthma and Allergy Research CentreIsle of Wight, UK.
authors.forename: Syed Hasan
authors.initials: SH
authors.lastname: Arshad
authors.affiliation: Department of Large Animal Clinical Sciences, Michigan State University East Lansing, MI, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Ewart
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis Memphis, TN, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis Memphis, TN, USA.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Karmaus
keywords: CpGs; Epigenetics; FEF25-75%; FEV1; FEV1/FVC ratio; SNPs; asthma; spirometry