Background/Purpose: Cardiac manifestations of neonatal lupus (cardiac-NL) which comprise conduction defects and cardiomyopathy, occur in fetuses exposed to maternal anti-Ro antibodies and carry a case fatality rate of nearly 18%. The discordance rate for monozygotic (MZ) twins suggests a role for epigenetic factors in addition to maternal autoantibodies, genetic and environmental influences.  Analysis of MZ twins represents the ideal design to dissect the role of epigenetic factors. Notably, the onset of cardiac-NL can occur within one week of a normal ultrasound and is most often detected between 18-24 wks gestation, and hence, there is very limited confounding due to environmental cues that might occur over decades, as for discordant MZ twins with other autoimmune diseases. As such, the analysis of these twins early in life has unprecedented value to test for disease-associated epigenomic variation and reveal potential metastable epialleles. This study examines an axis of heritable genetic information in human genomic DNA involving cytosine methylation and addresses the hypothesis that susceptibility to cardiac-NL is influenced by epigenetic variability.

Methods: Genomic DNA was extracted from two Caucasian monochorionic MZ male twin pairs who were discordant for cardiac-NL (advanced block).  The source of one pair was umbilical cord blood and the other was saliva from 18-month-olds. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip. Probes with a detection P-value<1.0E-05 were excluded. A paired t-test on the probe-specific β-values was computed and significance was assessed as the intersection of meeting an FDR threshold and mean DNA methylation difference (Δβ)>|0.10|.

Results: Significant hypomethylation in both affected twins was observed in genes with fibrosis and myocyte repair functions. With regard to fibrosis, these include protein phosphatase 1A (PPM1A; Δβ=-0.11, P<1.E-15) a SMAD phosphatase, and a disintegrin and metalloproteinase domain 12 (ADAM12; Δβ=-0.13, P<1.E-15), an enhancer of TGFb1 transcription. For myocyte repair, included are the LIM-protein 1 gene (FHL1; Δβ=-0.14, P=1.2E-30) implicated in cardiomyopathy, the myocardin-like 2 gene (MKL2; Δβ=-0.13, Pβ=-0.33, P=1.2E-78), implicated in hemoglobin biosynthesis. The most significant hypermethylated site is located in the membrane associated guanylate kinase gene MAGI2 (Δβ=0.40, P=1.2E-39).

Conclusion: To our knowledge, this is the first study analyzing global disease-associated methylation patterns in early-life tissue of MZ discordant twins. The data support an epigenetic mechanism underpinning cardiac-NL discordance in MZ twins despite identical DNA sequence and exposure to maternal autoantibody via a shared placenta.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenetic-changes-in-fibrosis-and-myocyte-repair-genes-may-contribute-to-pathogenesis-in-monozygotic-twins-discordant-for-cardiac-manifestations-of-neonatal-lupus/