ABSTRACT
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.
Acknowledgments
We would like to express our sincere gratitude to Steve Graham and Robin Cooley at the California Biobank Program and Genetic Disease Screening Program within the California Department of Public Health for their assistance and advice regarding newborn bloodspots. The biospecimens and/or data used in this study were obtained from the California Biobank Program, (SIS request number(s) 479)” Section 6555(b), 17 CCR. The California Department of Public Health is not responsible for the results or conclusions drawn by the authors of this publication.
This research was supported by NIEHS grants 4R01ES022216, K01ES017801 and P30ES007048.
Disclosure statement
No potential conflict of interest was reported by the authors.
Competing financial interests
The authors declare that they have no competing interests.
Author contributions
CB conceived and designed the study. CB, JM, KS, LD, and RU supervised the project. LG analyzed the data and wrote the manuscript. All authors edited and approved the manuscript.
Data availability
Please contact author for data requests.
Supplementary material
Supplementary material data can be accessed here.