Epigenetic regulation of AXL and risk of childhood asthma symptoms

Abstract

Background AXL 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.Conclusions AXL DNA methylation at birth was associated with higher risk for asthma-related symptoms in early childhood.Electronic supplementary materialThe online version of this article (10.1186/s13148-017-0421-8) contains supplementary material, which is available to authorized users.

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“…Epigenome-wide and targeted patterns have also been assessed recently using bloodspots. Gao et al conducted an epigenome-wide analysis using the HumanMethylation 450 array (a predecessor to the MethylationEPIC array) on infant bloodspot specimens and identified a relationship between the epigenetic pattern of a gene known to play a role in asthma and the risk of wheeze by age six [ 64 ]. Another group evaluated bloodspot DNA methylation profiles using the HumanMethylation 450 array and found evidence that gestational folic acid deficiency may influence risk for cleft palate through an epigenetic mechanism [ 65 ].…”

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“…In fact, prominent Th2 cytokines were less methylated in asthmatic patients, resulting in higher expression of these asthma-promoting mediators. Interestingly, also gender-specific methylation structures were found, as CpG hypermethylation of the receptor tyrosine kinase AXL in newborns blood was associated with wheeze at age 6 especially in girls [56]. Epigenome-wide association studies (EWAS) revealed consistently hypomethylated signatures driven by higher numbers of eosinophil, a granular cell type that is known to be centrally involved in allergic inflammatory processes [57].…”