Association between AXL promoter methylation and lung function growth during adolescence

AXL is one of the TAM (TYRO3, AXL and MERTK) receptor tyrosine kinases and may be involved in airway inflammation. Little is known about how epigenetic changes in AXL may affect lung development during adolescence. We investigated the association between AXL DNA methylation at birth and lung function growth from 10 to 18 years of age in 923 subjects from the Children's Health Study (CHS). DNA methylation from newborn bloodspots was measured at multiple CpG loci across the regulatory regions of AXL using Pyrosequencing. Linear spline mixed-effects models were fitted to assess the association between DNA methylation and 8-year lung function growth. Findings were evaluated for replication in a separate population of 237 CHS subjects using methylation data from the Illumina HumanMethylation450 (HM450) array when possible. A 5% higher average methylation level of the AXL promoter region at birth was associated with a 48.4 ml decrease in mean FEV₁ growth from 10 to 18 years of age in the primary study population (95% CI: -100.2, 3.4), and a 53.9 ml decrease in mean FEV₁ growth from 11 to 15 years of age in the replication population (95% CI: -104.3, -3.5). One CpG locus in the promoter region, cg10564498, was significantly associated with decreased growth in FEV₁, FVC and MMEF from 10 to 18 years of age and the negative associations were observed in a similar age range in the replication population. These findings suggest a potential association between AXL promoter methylation at birth and lower lung function growth during adolescence.