Infectious Disease

Atopy mediates association between DNA methylation at birth, adolescent asthma

September 08, 2023

5 min read


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Key takeaways:

  • Researchers identified 126 cytosine-phosphate-guanine (CpG) sites for atopy and 93 for asthma in males.
  • In females, 196 were identified for atopy and 182 were identified for asthma.

DNA methylation among newborns was associated with asthma acquisition in adolescence, partially mediated by pre-adolescent atopy, according to a letter published in Clinical & Experimental Allergy.

Also, cytosine-phosphate-guanine (CpG) at birth may be a potential biomarker for atopic and nonatopic asthma and explain asthma heterogeneity, Aniruddha Rathod, PhD, MPH, MBBS, postdoctoral researcher at the Peter O’Donnell Jr. School of Public Health of University of Texas Southwestern Medical Center, and colleagues wrote.

DNA methylation may explain why proportions of asthma prevalence among boys and girls switches from childhood to adolescence. Image: Adobe Stock

“This study was prompted by the need to better understand the complex relationship between DNA methylation (DNAm), atopy and the development of asthma in children,” Rathod told Healio.

Serving as a reflection of prenatal exposures, DNAm patterns could potentially serve as early biomarkers for asthma development later in life, he explained, adding that asthma can manifest as atopic or nonatopic.

Aniruddha Rathod

“The specific role of DNAm in newborns via preadolescent atopy in the context of asthma development remained poorly understood,” Rathod said. “We aimed to investigate whether childhood atopy acts as a mediator between DNAm in newborns and the onset of asthma in later life leveraging data from the Isle of Wight Birth Cohort (IOWBC).”

Boys are more prone to asthma than girls during childhood, according to the researchers, but that switches with more asthma development among girls than boys during adolescence.

With atopy known as a risk factor for asthma, the researchers continued, longitudinal changes in DNAm at specific CpG sites have been associated with risks for atopy and asthma.

Study design, results

The researchers enrolled 1,456 infants born between Jan. 1, 1989, and Feb. 28, 1990, and followed up with them at ages 1 year and 2, 4, 10 and 18 years. Also, the researchers assessed gene expression levels via peripheral blood samples collected at age 26 years.

Genome-wide screening identified 126 CpGs for atopy and 93 CpGs for asthma acquisition among males as well as 196 CpGs for atopy and 182 CpGs for asthma acquisition among females. There were no common CpGs between atopy and asthma in either sex, nor were there any overlapping CpGs between males and females.

“Some particularly significant findings from the study include the identification of specific CpG sites associated with asthma acquisition through both indirect and direct effects,” Rathod said.

Next, the researchers analyzed DNAm at the genome scale to identify differentially methylated regions (DMRs) corresponding with asthma acquisition. Further analysis of 223 CpGs in males and 378 CpGs in females for their enrichment in pathways or biological processes identified 153 biological processes in males and 215 in females (P < .05), with no common biological processes between the sexes.

Controlling for confounders yielded 68 CpGs in males and 41 CpGs in females that were indirectly associated with asthma acquisition through atopy, with statistically significant indirect effects with 60 of the CpGs in males and 37 of the CpGs in females.

With 21 of these male CpGs and 18 of these female CpGs, the researchers continued, there was an indirect association between higher DNAm and increased risk for asthma acquisition due to an increased risk for atopy.

The researchers additionally said there was a direct association between asthma acquisition between age 10 and 18 years and DNAm in newborns at 99 CPGs in males and 192 CpGs in females.

Only direct effects were significant at 91 of these CpGs in males and 188 of these CpGs in females, with a direct association between an increase in DNAm and an increase in the risk for asthma acquisition at 50 of these CpGs in males and 72 of these CpGs in females.

Also, the researchers tested these indirect associations in the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC), including newborn DNAm data for 41 of the 68 male CpGs and 18 of the 41 female CpGs from the IOWBC.

Among these CpGs, 20 in the male group and 10 in the female group had a direction of indirect effects that was consistent with those CpGs in the IOWBC, the researchers found, but none of these CpGs were statistically significant in the ALSPAC. However, these 20 male CpGs and 10 female CpGs all only showed indirect effects in the IOWBC.

Among the 99 male CpGs and 192 female CpGs that showed direct effects in the IOWBC, ALSPAC had DNAm for 54 male CpGs and 113 female CpGs. Twenty-five of these male CpGs and 78 of these female CpGs from ALSPAC had the same directions of association as their counterparts in IOWBC, with one male CpG and 11 female CpGs achieving statistical significance, the researchers said.

At age 26 years, the researchers also assessed the association between DNAm at the identified 133 CpGs and the expression of neighboring genes. There were significant effects of DNAm at 35 CpGs on associations with 213 neighboring genes in males. In females, significant effects of DNAm were observed at 61 CpGs with 357 neighboring genes.

Noting that more than 40% of these 96 CpGs were located in the promoter region of their mapped genes, the researchers said that increased DNAm was associated with increased gene expression for 289 (130 in males) of these 570 (213 in males) neighboring genes.

Based on these findings, the researchers noted that there were consistent mediation effects between the IOWBC and ALSPAC cohorts at 20 CpG sites in males and 10 CpG sites in females, although they were indirect effects only, and the effects were not statistically significant in ALSPAC.

However, the researchers continued, these 30 CpGs may be markers linked to atopic asthma development attributable to atopy mediation. Conversely, the researchers added, the sole direct effects of the 103 CpGs may contribute to the occurrence of nonatopic asthma since the atopic states of individuals did not have any influence on the associations between DNAm and asthma acquisition in newborns.

Conclusions, next steps

“These findings highlight the potential importance of these specific CpG sites as epigenetic markers in understanding asthma development,” Rathod said.

The study also suggests that epigenetic modifications in early life could play a critical role in determining a child’s susceptibility to asthma in adolescence, he said.

“The identification of direct and indirect effects on asthma acquisition provides a nuanced understanding of the mechanisms underlying the disease, which could eventually lead to more precise diagnostic and therapeutic strategies for children at risk of developing asthma,” Rathod said.

Rathod also said it was interesting to see that some CpG sites were directly associated with asthma development, whereas childhood atopy mediated the association for other CpGs.

Among DNAm directly associated with asthma acquisition, there was a direct association between an increase in DNAm and an increase in risk for asthma acquisition at 51% CpGs in males and 38% CpGs in females, Rathod continued.

“Among DNAm indirectly associated with asthma acquisition via atopy, a higher DNAm was indirectly associated with an increased risk of asthma acquisition via an increased risk of atopy at 31% CpGs in males and 44% CpGs in females,” he continued.

These findings do not support any immediate clinical applications, Rathod said, but doctors can use them to enhance their understanding of the early predictors of asthma development in children.

“Incorporating DNAm analysis in newborns could enable the early identification of individuals at a higher risk of developing asthma later in life, especially in distinguishing between atopic and nonatopic asthma,” Rathod said.

For example, these findings could contribute to more targeted and personalized interventions or preventive measures for children at higher risk for developing asthma, Rathod said.

“However, further research and clinical validation are essential before widespread implementation in health care settings,” he said.

The researchers called for future studies into the role of DNAm at these CpGs as a mediator in the association between exposures during fetal development and asthma and allergic conditions.

Next, Rathod and his colleagues aim to further investigate and validate these findings in different populations.

“We can conduct more extensive studies to replicate the associations between DNAm, atopy, and asthma acquisition,” he said.

Rathod said that he and his colleagues also can explore the potential use of these CpG sites as biomarkers for predicting asthma risk in children.

“Ultimately, the goal is to translate these research findings into practical clinical applications for improving the prevention and management of asthma in children,” he said.

For more information:

Aniruddha Rathod, PhD, MPH, MBBS, can be reached at [email protected].


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