Common cfDNA Methylation Profiles in Hypertensive Disorders of Pregnancy

Introduction Hypertensive disorders in pregnancy (HDP), including preeclampsia (PE) and gestational or chronic hypertension (HT), are associated with an increased risk for long-term cardiovascular disorders for both mother and infant[1]. There is increased evidence that HDP are vascular disorders with a shared predisposition. Specifically, HDP appear to induce epigenetic changes. These are changes in DNA methylation profiles in CpG dinucleotides that can occur in the fetal/placental and maternal compartment[2]. Although cell-free DNA (cfDNA) assessments have become an important part of prenatal care, the use of cfDNA methylation patterns to detect HDP in early pregnancy is still largely unexplored. Hence, we aimed to test cardiovascular predisposition for HDP using cfDNA methylation profiles.

Material/Methods Samples from the Liquid Biobank Bern previously collected at our clinic were assigned to 3 different cohorts with 5 patients per group: PE group (low risk for PE but subsequent PE), HT group (chronic hypertension with high risk for PE but no subsequent PE) and Control group (low risk for PE and no subsequent PE). Risk stratification for PE was based on the FMF screening algorithm in the first trimester[3]. We performed cfDNA extraction and whole-genome cfDNA methylation sequencing on our first trimester samples. Furthermore, we assessed unbiased determination of the tissue origins of cfDNA using deconvolution and identified differentially methylated regions (DMRs) and annotated genes. DMRs are regions in the genome where different DNA methylation patterns can point to specific diseases. We used Student's t tests and one-way analysis of variance and Holm-Sidak test. We considered p<0.05 to be statistically significant.

Results Clinical characteristics at inclusion in early pregnancy of our three cohorts differed only in FMF risk stratification for PE and incidence of chronic hypertension. Global cfDNA methylation changes and potential cfDNA methylation origin point towards a homogenous PE/HT group. We detected 86 DMRs in PE/HT (75 genes) compared to PE/Ctr (DMRs: 139 and 75 genes) and HT/Ctr (DMRs: 140 and 74 genes) groups. Analysis of specific genes point towards an association with cardiovascular disorders. Furthermore, placental methylation origin of cfDNA appears to be low.

Discussion The cfDNA methylation profile in the first trimester supports the pivotal role of the cardiovascular system in HDP pathogenesis. Using cfDNA methylation profiles, we envision a personalized approach crucial to prophylaxis and treatment of HPD and chronic cardiovascular diseases in pregnancy and beyond.

Publication History

Article published online:
26 November 2021

• References

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