DNA methylation and genetic polymorphisms of the Leptin gene interact to influence lung function outcomes and asthma at 18 years of age

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

DNA methylation and allergic sensitizations, a genome-scale longitudinal study during adolescence

Background: the presence of allergic sensitization has a major influence on the development and course of common childhood conditions such as asthma and rhinitis. The etiology of allergic sensitization is poorly understood and its underlying biological mechanisms are not well established. Several studies showed that DNA methylation (DNAm) at some CpGs is associated with allergic sensitization. However, no studies have focused on the critical adolescence period.Methods: we assessed the association of pre- and post-adolescence genome-wide DNAm with allergic sensitization against indoor, outdoor and food allergens, using linear mixed models. We hypothesized that DNAm is associated with sensitization in general, and with poly-sensitization status, and these associations are ageand gender-specific. We tested these hypotheses in the IoW cohort (n=376) and examined the findings in the BAMSE cohort (n=267).Results: via linear mixed models, we identified 35 CpGs in IoW associated with allergic sensitization (at false discovery rate of 0.05), of which 33 were available in BAMSE and replicated with respect to the direction of associations with allergic sensitization. At the 35 CpGs except for cg19210306 on C13orf27, a reduction in methylation among atopic subjects was observed, most notably for cg21220721 and cg11699125 (ACOT7). DNAm at cg10159529 was strongly correlated with expression of IL5RA in peripheral blood (p-value=6.76×10-20). Three CpGs (cg14121142, cg23842695, and cg26496795) were identified in IoW with age-specific association between DNAm and allergic sensitization.Conclusion: in adolescence, the status of allergic sensitization was associated with DNAm differentiation and at some CpGs the association is likely to be age-specific

Development of Land Use Regression Models for Particle Composition in Twenty Study Areas in Europe

Land Use Regression (LUR) models have been used to describe and model spatial variability of annual mean concentrations of traffic related pollutants such as nitrogen dioxide (NO₂), nitrogen oxides (NO_<i>x</i>) and particulate matter (PM). No models have yet been published of elemental composition. As part of the ESCAPE project, we measured the elemental composition in both the PM₁₀ and PM_2.5 fraction sizes at 20 sites in each of 20 study areas across Europe. LUR models for eight a priori selected elements (copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V), and zinc (Zn)) were developed. Good models were developed for Cu, Fe, and Zn in both fractions (PM₁₀ and PM_2.5) explaining on average between 67 and 79% of the concentration variance (<i>R</i>²) with a large variability between areas. Traffic variables were the dominant predictors, reflecting nontailpipe emissions. Models for V and S in the PM₁₀ and PM_2.5 fractions and Si, Ni, and K in the PM₁₀ fraction performed moderately with <i>R</i>² ranging from 50 to 61%. Si, NI, and K models for PM_2.5 performed poorest with <i>R</i>² under 50%. The LUR models are used to estimate exposures to elemental composition in the health studies involved in ESCAPE