Perinatal obesity is associated with asthma phenotype in children and with a shift of the epithelial DNA methylation clock towards premature epithelial aging

<bold>Background:</bold> Obesity early in life affects the clinical course of asthma. Maternal obesity is a risk factor for childhood obesity, but the impact on asthma phenotypes is unclear. Therefore, we now (i) investigated the influence of perinatal obesity on asthma symptoms and (ii) performed methylome profiling with methylome-derived epigenetic clock in nasal respiratory epithelial cells (REC) of asthmatic children. <bold>Methods:</bold> 221 children with diagnosed asthma/wheeze and 33 controls from the All-Age Asthma Cohort (ALLIANCE) study were investigated. Maternal and children’s metabolic parameters [birthweight; BMI and Body-Fat Fraction (BFF)] were correlated with symptom control, hospital admission rate, FEV1, symptom onset, IgE level and asthma triggers. In 120 asthmatics and controls, methylome profiling with methylome-derived “DNAge” (mDNAge) was assessed in human RECs. <bold>Results:</bold> (1) Maternal BMI during pregnancy was higher in the asthma cohort than in controls. (2) Maternal BMI was higher in asthmatics with higher rate of hospital admission. (3) Birthweight and BFF were higher in patients, who developed wheezing early in life. (4) BFF was linked to worse symptom control and lower FEV1. (5) Higher BMI in patients was linked to higher IgE and allergic triggers. (6) High BMI was associated with higher mDNAge of RECs and obese asthmatics showed higher mDNAge of RECs than non-obese asthmatics. <bold>Conclusion:</bold> Our results highlight the impact of perinatal obesity on asthma triggers, onset and severity in childhood. Obesity-driven premature aging of RECs could be a pathomechanism for epithelial dysfunction, triggering obesity-related asthma.