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      Genome-wide methylation profiling demonstrates hypermethylation in maternal leukocyte DNA in preeclamptic compared to normotensive pregnancies

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          Abstract

          Objective

          To compare genome-wide methylation profiles in maternal leukocyte DNA between normotensive and preeclamptic pregnant women at delivery.

          Methods

          Age, body mass index matched case-control comparison of methylation at 27,578 cytosine—guanine sites in 14,495 genes in maternal leukocyte DNA in women with preeclampsia (PE; n = 14) and normotensive controls ( n = 14).

          Results

          PE was associated with widespread differential methylation favoring hypermethylation. Pathway analysis identified the best matched process as a neuropeptide signaling pathway ( p < 10 −5); best matched disease as eclampsia ( p < 9.97 × 10 −20). Significantly differentially methylated genes ( GRIN2b. GABRA1. PCDHB7, and BEX1) are associated with seizures.

          Conclusion

          Altered maternal leukocyte DNA methylation is associated with PE at delivery, and differential methylation of certain neuronal genes may explain the risk for eclampsia.

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          Most cited references22

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          Epigenome-wide association studies for common human diseases.

          Vardhman Rakyan, Thomas A. Down, David Balding … (2011)
          Despite the success of genome-wide association studies (GWASs) in identifying loci associated with common diseases, a substantial proportion of the causality remains unexplained. Recent advances in genomic technologies have placed us in a position to initiate large-scale studies of human disease-associated epigenetic variation, specifically variation in DNA methylation. Such epigenome-wide association studies (EWASs) present novel opportunities but also create new challenges that are not encountered in GWASs. We discuss EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies. We also discuss how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
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            Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

            Christopher G. Bell, Andrew E. Teschendorff, Vardhman Rakyan … (2010)
            Background Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. Methods We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium® HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. Results Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. Conclusion This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.
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              DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia.

              Ryan Yuen, Maria Peñaherrera, Peter von Dadelszen … (2010)
              Preeclampsia and intrauterine growth restriction (IUGR) are two of the most common adverse pregnancy outcomes, but their underlying causes are mostly unknown. Although multiple studies have investigated gene expression changes in these disorders, few studies have examined epigenetic changes. Analysis of the DNA methylation pattern associated with such pregnancies provides an alternative approach to identifying cellular changes involved in these disorders. We analyzed methylation of 1505 CpG sites associated with 807 genes in 26 placentas from early-onset preeclampsia (EOPET), late-onset preeclampsia, IUGR and control subjects using an Illumina GoldenGate Methylation panel. Thirty-four loci were hypomethylated (false discovery rate 10%) in the early-onset preeclamptic placentas while no and only five differentially methylated loci were found in late-onset preeclamptic and IUGR placentas, respectively. Hypomethylation of 4 loci in EOPET was further confirmed by bisulfite pyrosequencing of 26 independent placental samples. The promoter of TIMP3 was confirmed to be significantly hypomethylated in EOPET placentas (P=0.00001). Our results suggest that gene-specific hypomethylation may be a common phenomenon in EOPET placentas, and that TIMP3 could serve as a potential prenatal diagnostic marker for EOPET.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Hypertens Pregnancy
                Journal ID (iso-abbrev): Hypertens Pregnancy
                Journal ID (publisher-id): hip
                Title: Hypertension in Pregnancy
                Publisher: Informa Healthcare USA, Inc.
                ISSN (Print): 1064-1955
                ISSN (Electronic): 1525-6065
                Publication date (Print): August 2013
                Publication date (Electronic): 19 June 2013
                Volume: 32
                Issue: 3
                Pages: 257-269
                Affiliations
                1Department of OB/GYN, Division of Maternal Fetal Medicine, Mayo Clinic College of Medicine Rochester, MNUSA
                2Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine Rochester, MNUSA
                3Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine Rochester, MNUSA
                Author notes
                Correspondence: Vesna D. Garovic, MDDepartment of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine 200 First Street, Rochester, MN 55905USA. garovic.vesna@ 123456mayo.edu
                Article
                DOI: 10.3109/10641955.2013.796970
                PMC ID: 3741019
                PubMed ID: 23782156
                SO-VID: 5597e61d-f429-4351-a74f-2dbff6a2d4ae
                Copyright © © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.

                History
                Date received : 25 October 2012
                Date revision received : 11 January 2013
                Date accepted : 9 April 2013
                Categories
                Subject: Article

                ScienceOpen disciplines: Obstetrics & Gynecology
                Keywords: dna methylation,epigenetics,leukocyte,maternal,pregnancy,preeclampsia
                Data availability:
                ScienceOpen disciplines: Obstetrics & Gynecology
                Keywords: dna methylation, epigenetics, leukocyte, maternal, pregnancy, preeclampsia

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