DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non-Atopic Asthma.

Ayoung Jeong,Zdenko Herceg,Deborah Jarvis,Nicole Probst-Hensch,Anne-Elie Carsin,André Amaral,Christian Schindler,Medea Imboden,Alexei Novoloaca,Gianfranco Lovison,Akram Ghantous,Roel Vermeulen,Cyrille Cuenin,Florian Kronenberg,Paolo Vineis,Manolis Kogevinas

doi:10.3390/ijerph16040600

Abstract

A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis that inflammation and/or innate immunity plays a role in the obesity-asthma link. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (p = 0.0023), MAPK signaling (p = 0.013), NF-κB signaling (p = 0.031), and PI3K/AKT signaling (p = 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (p = 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.

Highlights

Obesity and overweight have repeatedly been linked to asthma [1,2], with several studies reporting a stronger association of obesity or overweight with non-atopic compared to atopic asthma [3,4] and with late-onset asthma compared to early-onset asthma [5,6]
Obesity-asthma link, we formally explored whether interaction signals between body mass index (BMI) or BMI change and DNA methylation in peripheral blood on non-atopic adult-onset asthma are enriched for signals mapping to inflammatory pathways
In order to confirm that BMI is related to chronic inflammation, we examined the association between BMI and high-sensitive C-reactive protein within the study subjects (n = 206; one subject was excluded due to missing information on hs-CRP)

Summary

Introduction

Obesity and overweight have repeatedly been linked to asthma [1,2], with several studies reporting a stronger association of obesity or overweight with non-atopic compared to atopic asthma [3,4] and with late-onset asthma compared to early-onset asthma [5,6]. The more likely hypothesis is that this association is not entirely mechanical, but that chronic inflammation related to overweight and obesity contributes to asthma development. While M2 macrophages are predominant in non-obese adipose tissue, pro-inflammatory M1 macrophages increase in obese adipose tissue, leading to low-grade chronic systemic inflammation [12]. An interesting finding in mice experiments pointed to NLRP3 (nucleotide-binding domain, leucine-rich repeats-containing family, pyrin domain-containing-3) inflammasome and interleukin-17 (IL17) producing innate lymphoid cell group 3 (ILC3) cells as a link between obesity and airway hyperresponsiveness (AHR) [13]. IL1B, in turn, activates ILC3 cells to produce IL17, leading to AHR. Kim and her colleagues demonstrated that the NLRP3-IL1B-IL17 axis is crucial in AHR development in obese mice [13]

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