DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight

Abstract

Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. Results Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E−11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. Conclusions These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Epigenetic signature of very low birth weight in young adult life

“…43 Differential methylation of EBF4 has been positively associated with gestational age, also in adolescence, 18 but in opposite direction to our study. Cameron et al report four CpG-sites associating with EBF4 being differentially methylated between VLBW participants and term controls in 28-year-olds 22 ; four of these sites (cg24263062, cg05857996, cg13518079, and cg05825244) overlap with our results.…”

“…Cameron et al also report hypomethylation in three sites associating with HIF3A in 28year-old VLBW individuals when compared to term controls. 22 Our sites are among these. Differential methylation of HIF3A has been associated with gestational age in cord blood.…”

“…Cameron et al report hypermethylation in one CpG site associating with GLI2 (cg20219891), which is one of the sites seen in our discovery cohort and validation meta-analysis. 22 Differential methylation of GLI2 has been associated with gestational age in a meta-analysis in cord blood. 18 None of the five validated CpGs from our study examining birth weight were reported as differentially methylated.…”

“…21 A recent study by Cameron et al compared DNAm at birth (109 VLBW individuals, 52 controls) and in 28-year-olds (215 VLBW individuals, 96 controls). 22 No robust DMPs across these studies have emerged. There is little evidence of overlap of DMPs between studies examining VLBW and LBW individuals.…”

Reduced DNMT1 levels induce cell apoptosis via upregulation of METTL3 in cardiac hypertrophy

“…Meder et al analyzed plasma-treated hiPSC-CMs and cardiac biopsies using array-based DNA methylation analysis and revealed prevalent alterations in cardiac DNA methylation; they further revealed that hypomethylation of the ATG promoter could serve as a diagnostic marker of HF [ 16 ]. Cameron et al found large differences in DNA methylation at over 16,400 CpG methylation sites, particularly in the canonical signaling pathway of Cardiac Hypertrophy in neonates [ 17 ]. However, further studies are needed to elucidate the involvement and function of DNA methylation in cardiac hypertrophy.…”