Associations between antenatal maternal asthma status and placental DNA methylation

Abstract

Introduction: Maternal asthma in pregnancy is associated with adverse perinatal and child health outcomes; however, mechanisms are poorly understood.

Methods: The PRogramming of Intergenerational Stress Mechanisms (PRISM) prospective pregnancy cohort characterized asthma history during pregnancy via questionnaires and quantified placental DNAm using the Illumina Infinium HumanMethylation450 BeadChip. We performed epigenome-wide association analyses (n = 223) to estimate associations between maternal active or inactive asthma, as compared to never asthma, and placental differentially methylated positions (DMPs) and differentially variable positions (DVPs). Models adjusted for maternal pre-pregnancy body mass index, smoking status, parity, age and education level and child sex. P-values were FDR-adjusted.

Results: One hundred and fifty-nine (71.3%) pregnant women reported no history of asthma (never asthma), 15 (6.7%) reported inactive, and 49 (22%) reported active antenatal asthma. Women predominantly self-identified as Black/Hispanic Black [88 (39.5%)] and Hispanic/non-Black [42 (18.8%)]. We identified 10 probes at FDR<0.05 and 4 probes at FDR<0.10 characterized by higher variability in maternal active asthma compared to never asthma mapping to GPX3, LHPP, PECAM1, ATAD3C, and ARHGEF4 and 2 probes characterized by lower variation mapping to CHMP4A and C5orf24. Amongst women with inactive asthma, we identified 52 probes, 41 at FDR<0.05 and an additional 11 at FDR <0.10, with higher variability compared to never asthma; BMP4, LHPP, PHYHIPL, and ZSCAN23 were associated with multiple DVPs. No associations were observed with DMPs.

Discussion: We observed alterations in placental DNAm in women with antenatal asthma, as compared to women without a history of asthma. Further research is needed to understand the impact on fetal development.

Keywords: DNA methylation; Differentially variable positions; Maternal antenatal asthma; Placenta; Sex-specific effects.

Figure 1.

Volcano (a) and Manhattan plot (b) summarizing the topmost DVPs (FDR <0.10) associated with Active Asthma (red). The y-axis corresponds to −log10 p-values from DVP association testing. For (a), β represents the variance ratio comparing variation in placental DNAm for Active and Never Asthma groups.

Figure 2.

Zoom-in plots (a) of gene regions for which multiple DNAm probes were associated with Active Asthma. Probes within a window of 10 KB from the topmost associated probe (red) are yellow or deeper orange if p-values were less than 0.01. (b) Density plots of the topmost DVP for each gene region illustrated in (a).

Figure 3.

Volcano (a) and Manhattan plot (b) summarizing the topmost DVPs (FDR <0.10) associated with Active Asthma (red). The y-axis corresponds to −log10 p-values from DVP association testing. For (a), the x-axis is the log variance ratio comparing variation in placental DNAm for Inactive versus Never Asthma groups.

Figure 4.

Zoom-in plots (a) of gene regions for which multiple DNAm probes were associated with Inactive Asthma. Probes within a window of 10 KB from the topmost associated probe (red) are yellow or deeper orange if p-values were less than 0.01. (b) Density plots of the topmost DVP for each gene region illustrated in (a).

Figure 5.

Volcano and Manhattan plots of DVPs (a-b) and DMPs (c-d) with sex-specific effects for Inactive Asthma (red). The y-axis corresponds to -log10 p-values from DVP/DMP association testing, β represents the variance ratio (a) or difference in fold change (c) comparing males with Inactive Asthma to the Never Asthma group.

Fig. 6.

Zoom-in plots for BMP4 gene region with multiple sex-specific DVPs (a) and DMPs (b) for Inactive Asthma. (b) Density plot for topmost DNAm probe with both sex-specific DVP and DMP associations for BMP4. (c) Heatmap of genes associated with Active and/or Inactive Asthma. M-values correspond to the topmost probe or the topmost common probe (if associated in multiple models).