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. 2023 Dec 21;62(6):2300714.
doi: 10.1183/13993003.00714-2023. Print 2023 Dec.

Novel insights into the whole-blood DNA methylome of asthma in ethnically diverse children and youth

Esther Herrera-Luis  1   2 , Carlos Rosa-Baez  1 , Scott Huntsman  3 , Celeste Eng  3 , Kenneth B Beckman  4 , Michael A LeNoir  1   5 , Jose R Rodriguez-Santana  1   6 , Jesús Villar  7   8   9 , Catherine Laprise  10   11 , Luisa N Borrell  12 , Elad Ziv  13   14 , Esteban G Burchard  3   14   15 , Maria Pino-Yanes  16   8   15   17
Affiliations

Novel insights into the whole-blood DNA methylome of asthma in ethnically diverse children and youth

Esther Herrera-Luis et al. Eur Respir J. .

Abstract

Background: The epigenetic mechanisms of asthma remain largely understudied in African Americans and Hispanics/Latinos, two populations disproportionately affected by asthma. We aimed to identify markers, regions and processes with differential patterns of DNA methylation (DNAm) in whole blood by asthma status in ethnically diverse children and youth, and to assess their functional consequences.

Methods: DNAm levels were profiled with the Infinium MethylationEPIC or HumanMethylation450 BeadChip arrays among 1226 African Americans or Hispanics/Latinos and assessed for differential methylation per asthma status at the CpG and region (differentially methylated region (DMR)) level. Novel associations were validated in blood and/or nasal epithelium from ethnically diverse children and youth. The functional and biological implications of the markers identified were investigated by combining epigenomics with transcriptomics from study participants.

Results: 128 CpGs and 196 DMRs were differentially methylated after multiple testing corrections, including 92.3% and 92.8% novel associations, respectively. 41 CpGs were replicated in other Hispanics/Latinos, prioritising cg17647904 (NCOR2) and cg16412914 (AXIN1) as asthma DNAm markers. Significant DNAm markers were enriched in previous associations for asthma, fractional exhaled nitric oxide, bacterial infections, immune regulation or eosinophilia. Functional annotation highlighted epigenetically regulated gene networks involved in corticosteroid response, host defence and immune regulation. Several implicated genes are targets for approved or experimental drugs, including TNNC1 and NDUFA12. Many differentially methylated loci previously associated with asthma were validated in our study.

Conclusions: We report novel whole-blood DNAm markers for asthma underlying key processes of the disease pathophysiology and confirm the transferability of previous asthma DNAm associations to ethnically diverse populations.

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Conflict of interest statement

Conflict of interest: E. Herrera-Luis was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by the European Social Fund (ESF) “Investing in your future” (PRE2018-083837). C. Rosa-Baez reports support for the present manuscript from the Ministry of Education and Vocational Training. M. Pino-Yanes was funded by the Ramón y Cajal Program (RYC-2015-17205) by MCIN/AEI/10.13039/501100011033 and by the ESF “Investing in your future”. She reports a grant from MCIN/AEI/10.13039/501100011033, and grant support from the EAACI Allergopharma Award 2021 and from GlaxoSmithKline, Spain, paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias for a project outside the submitted work. J. Villar and M. Pino-Yanes were also supported by CIBERES, Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación and Unión Europea–European Regional Development Fund (CB06/06/1088). J. Villar also reports funding by ISCIII and the European Regional Development Fund “A way of making Europe”. E.G. Burchard reports grants from the National Institutes of Health, the Tobacco-Related Disease Research Program, the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, and from the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II. C. Laprise is the director of the Centre Intersectoriel en Santé Durable, codirector of the Environment, Genetics and Cancer axis of the Respiratory Health Network, investigator of CHILD Study, member of the InFAC consortium, and chairholder of the Canada Research Chair in Asthma and Allergic Diseases Genomics. The remaining authors declare they have no competing interests or other interests that might be perceived to influence the interpretation of the article.

Figures

Figure 1.
Figure 1.
Workflow of the multi-ancestry meta-analysis of epigenome-wide association studies of asthma in whole blood samples from Hispanics/Latinos (GALA II) and African American (SAGE) children and young adults recruited between 2006–2014.
Figure 2.
Figure 2.. Miami plot of hypermethylated (top) and hypomethylated (bottom) probes in whole blood between subjects with and without asthma in a) the combined results of Hispanics/Latinos (GALA II) and Africans Americans (SAGE), b) Hispanics/Latinos, and c) Africans Americans.
The statistical significance of association results (−log10 p) is represented for each CpG site as a dot (y-axis) along the autosomal chromosomes (x-axis). The threshold for the genome-wide significance (p=9×10−8) is represented by a dark grey line. The closest gene corresponding to some of the genome-wide significant hyper or hypomethylated CpGs in subjects with asthma compared with controls are shown.
Figure 3.
Figure 3.. Volcano plot of differentially methylated probes in whole blood between subjects with and without asthma, highlighting those probes hypermethylated in red and hypomethylated in blue, in a) the combined results of Hispanics/Latinos (GALA II) and Africans Americans (SAGE), b) Hispanics/Latinos, and c) Africans Americans.
The statistical significance of association results (−log10 p) is represented for each CpG site as a dot (y-axis) along the regression coefficient for the comparison of individuals with and without asthma (x-axis). The threshold for the genome-wide significance (p=9×10−8) is represented by a dark grey line. The closest gene corresponding to some of the genome-wide significant hyper or hypomethylated CpGs in subjects with asthma compared with controls are shown.
Figure 4.
Figure 4.. Enrichment analysis of 113 CpGs differentially methylated between subjects with and without asthma at a false discovery rate-adjusted p≤0.05 in Hispanics/Latinos (GALA II) and African American (SAGE) children and young adults. A) CpG-trait association enrichment analysis B) Genomic location enrichment analysis.
In Figure 4A, the x-axis represents the significance of the association, while the y-axis shows the top traits for which the CpG set is enriched. The diameter of the dot stands for the number of CpGs within the set associated with a certain trait, and their colors represent the p-value of the enrichment in -log10 scale. In Figure 4B, the x-axis displays the effect sizes estimates for each functionally relevant location shown in the y-axis. The color of the bars represents the FDR.
Figure 5.
Figure 5.. Circos plot of the differentially methylated region (DMRs) between subjects with and without asthma across the autosomes of Hispanics/Latinos (GALA II) and African American (SAGE) children and young adults.
The outer track shows the GRCh37/hg19 cytoband, followed by the p-values in -log10 scale for each DMR. The inner track shows the association p-values in -log10 scale for CpGs within each DMR. Orange and blue circles represent hyper and hypomethylation of the CpGs, respectively. The gene symbols corresponding to the genes harbored by previously asthma-related DMRs are indicated.
Figure 6.
Figure 6.. Notched boxplot of blood DNA methylation levels for top selected CpGs that were replicated or exhibited more than absolute 15%-fold change in effect size estimates in sensitivity analyses.
Hispanics/Latinos (GALA II) and African American (SAGE) children and young adults recruited between 2006–2014 with DNA methylation available were considered.
See this image and copyright information in PMC

Comment in

References

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