A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy
Abstract Background While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e....
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Epigenetics Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s43682-022-00014-w |
| _version_ | 1811175978258399232 |
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| author | Shuwei Liu Haoyi Fu Mitali Ray Lacey W. Heinsberg Yvette P. Conley Cindy M. Anderson Carl A. Hubel James M. Roberts Arun Jeyabalan Daniel E. Weeks Mandy J. Schmella |
| author_facet | Shuwei Liu Haoyi Fu Mitali Ray Lacey W. Heinsberg Yvette P. Conley Cindy M. Anderson Carl A. Hubel James M. Roberts Arun Jeyabalan Daniel E. Weeks Mandy J. Schmella |
| author_sort | Shuwei Liu |
| collection | DOAJ |
| description | Abstract Background While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls). Results In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample. Conclusions The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase. |
| first_indexed | 2024-04-10T19:45:39Z |
| format | Article |
| id | doaj.art-c5c35e1db21045b7bdeac7182c030bde |
| institution | Directory Open Access Journal |
| issn | 2730-7034 |
| language | English |
| last_indexed | 2024-04-10T19:45:39Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics Communications |
| spelling | doaj.art-c5c35e1db21045b7bdeac7182c030bde2023-01-29T12:05:17ZengBMCEpigenetics Communications2730-70342023-01-013111610.1186/s43682-022-00014-wA longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancyShuwei Liu0Haoyi Fu1Mitali Ray2Lacey W. Heinsberg3Yvette P. Conley4Cindy M. Anderson5Carl A. Hubel6James M. Roberts7Arun Jeyabalan8Daniel E. Weeks9Mandy J. Schmella10Department of Human Genetics, School of Public Health, University of PittsburghDepartment of Biostatistics, School of Public Health, University of PittsburghDepartment of Health Promotion and Development, School of Nursing, University of PittsburghDepartment of Human Genetics, School of Public Health, University of PittsburghDepartment of Human Genetics, School of Public Health, University of PittsburghMartha S. Pitzer Center for Women, Children and Youth, College of Nursing, The Ohio State UniversityMagee-Womens Research Institute and FoundationMagee-Womens Research Institute and FoundationMagee-Womens Research Institute and FoundationDepartment of Human Genetics, School of Public Health, University of PittsburghDepartment of Health Promotion and Development, School of Nursing, University of PittsburghAbstract Background While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls). Results In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample. Conclusions The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase.https://doi.org/10.1186/s43682-022-00014-wPreeclampsiaPre-eclampsiaDNA methylationEpigeneticsHypertensive disorder of pregnancySurrogate variable analysis |
| spellingShingle | Shuwei Liu Haoyi Fu Mitali Ray Lacey W. Heinsberg Yvette P. Conley Cindy M. Anderson Carl A. Hubel James M. Roberts Arun Jeyabalan Daniel E. Weeks Mandy J. Schmella A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy Epigenetics Communications Preeclampsia Pre-eclampsia DNA methylation Epigenetics Hypertensive disorder of pregnancy Surrogate variable analysis |
| title | A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy |
| title_full | A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy |
| title_fullStr | A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy |
| title_full_unstemmed | A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy |
| title_short | A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy |
| title_sort | longitudinal epigenome wide association study of preeclamptic and normotensive pregnancy |
| topic | Preeclampsia Pre-eclampsia DNA methylation Epigenetics Hypertensive disorder of pregnancy Surrogate variable analysis |
| url | https://doi.org/10.1186/s43682-022-00014-w |
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