Perinatal & Pediatric
DNA methylation of the Lamin A/C gene is associated with congenital heart disease Nandini Mukherjee* Nandini Mukherjee Elijah H. Bolin Amna H. Qasim Mohammed S. Orloff Philip J. Lupo Wendy N. Nembhard
Background: Prior studies report maternal serum Lamin A, encoded by the LMNA gene, to be linked to fetal congenital heart disease (CHD). It is unknown whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites in LMNA impacts CHDs. We investigated the associations of LMNA DNAm with CHDs in a cross-sectional study.
Methods: We used publicly available data of CHD cases (n= 197) and controls (n= 134) from the Gene Expression Omnibus repository with accession numbers GSE159930 and GSE36054, respectively. Peripheral blood DNAm was measured using Illumina Infinium Methylation 850K BeadChip for cases and 450K BeadChip for controls. We tested 31 LMNA CpGs to identify differences in DNAm between cases and controls using linear regression correcting for multiple testing with false discovery rate (FDR). In a case-only analysis, we tested the variations in LMNA DNAm between CHD subtypes. To identify consistency across tissue types we compared peripheral blood (n= 197) and heart tissue DNAm (n= 20) in CHD cases.
Results: We detected significant differences in 17 among the 31 LMNA CpGs between CHD cases and controls adjusting for sex, age, and cell types at FDR p-value <=0.05. DNAm of cg09820673 located at 3’UTR exhibited lower methylation for Hypoplastic Left Heart Syndrome compared to other Left-sided lesions, Lateralities, and Conotruncal defects. DNAm of three CpGs was consistent between peripheral blood and heart tissue in CHD cases.
Conclusion: We demonstrate that LMNA DNAm may influence CHD susceptibility. The findings inform future studies to explore associations of maternal LMNA DNAm with CHDs to develop preventive interventions.