Abstract

BackgroundAXL is one of the TAM (TYRO3, AXL and MERTK) receptor tyrosine kinases and may affect numerous immune-related health conditions. However, the role for AXL in asthma, including its epigenetic regulation, has not been extensively studied.MethodsWe investigated the association between AXL DNA methylation at birth and risk of childhood asthma symptoms at age 6 years. DNA methylation of multiple CpG loci across the regulatory regions of AXL was measured in newborn bloodspots using the Illumina HumanMethylation450 array on a subset of 246 children from the Children’s Health Study (CHS). Logistic regression models were fitted to assess the association between asthma symptoms and DNA methylation. Findings were evaluated for replication in a separate population of 1038 CHS subjects using Pyrosequencing on newborn bloodspot samples. AXL genotypes were extracted from genome-wide data.ResultsHigher average methylation of CpGs in the AXL gene at birth was associated with higher risk of parent-reported wheezing, and the association was stronger in girls than in boys. This relationship reflected the methylation status of the gene-body region near the 5′ end, for which a 1% higher methylation level was significantly associated with a 72% increased risk of ever having wheezed by 6 years. The association of one CpG locus, cg00360107 was replicated using Pyrosequencing. Increased AXL methylation was also associated with lower mRNA expression level of this gene in lung tissue from the Cancer Genome Atlas (TCGA) dataset. Furthermore, AXL DNA methylation was strongly linked to underlying genetic polymorphisms.ConclusionsAXL DNA methylation at birth was associated with higher risk for asthma-related symptoms in early childhood.

Highlights

  • AXL is one of the TAM (TYRO3, AXL and MERTK) receptor tyrosine kinases and may affect numerous immune-related health conditions

  • Given the known associations between prenatal tobacco smoke exposure and asthma risk, as well as prenatal tobacco smoke and Deoxyribonucleic acid (DNA) methylation in AXL, we sought to investigate whether methylation in AXL at birth was associated with childhood asthma or asthma-related symptoms

  • We investigated the association between methylation of multiple Cytosine-guanine dinucleotide sites (CpG) sites across the regulatory regions of AXL at birth and risk of childhood asthma symptoms, taking into consideration the underlying genetic variation in AXL

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Summary

Introduction

AXL is one of the TAM (TYRO3, AXL and MERTK) receptor tyrosine kinases and may affect numerous immune-related health conditions. Asthma is the most common chronic disease in childhood [1, 2]. We and others have shown that early life exposure to tobacco smoke and air pollution are associated with increased risk of childhood asthma and asthma symptoms [12,13,14,15,16,17]. We identified a gene—AXL, one of the TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases—in which methylation status of certain. Given the known associations between prenatal tobacco smoke exposure and asthma risk, as well as prenatal tobacco smoke and DNA methylation in AXL, we sought to investigate whether methylation in AXL at birth was associated with childhood asthma or asthma-related symptoms

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