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EPIGENETIC PATTERNS IN PLACENTAL PROGRAMMING OF PREECLAMPSIA

EPIGENETIC PATTERNS IN PLACENTAL PROGRAMMING OF PREECLAMPSIA. Cindy M. Anderson, PhD, WHNP-BC, FAAN Michelle L. Wright, MS, RN Jody L. Ralph, PhD, RN Eric Uthus , PhD Joyce E. Ohm, PhD University of North Dakota College of Nursing School of Medicine and Health Sciences

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EPIGENETIC PATTERNS IN PLACENTAL PROGRAMMING OF PREECLAMPSIA

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  1. EPIGENETIC PATTERNS IN PLACENTAL PROGRAMMING OF PREECLAMPSIA Cindy M. Anderson, PhD, WHNP-BC, FAAN Michelle L. Wright, MS, RN Jody L. Ralph, PhD, RN Eric Uthus, PhD Joyce E. Ohm, PhD University of North Dakota College of Nursing School of Medicine and Health Sciences USDA ARS Grand Forks Human Nutrition Research Center

  2. Introduction • Preeclampsia • Pregnancy specific condition • De novo onset of hypertension and proteinuria in second half of pregnancy • Initiated in early pregnancy • Characterized by vascular dysfunction and placental insufficiency • Acute perinatal consequences

  3. Introduction • Preeclampsia • No reliable screening • Diagnosis dependent on clinical manifestations of disease • Absence of definitive treatment • Resolves after placenta delivery • Future risk for cardiovascular disease • Heritable risk for hypertension in offspring

  4. Introduction • Epigenetics • Study of heritable changes in gene expression • Modification of DNA without changes in DNA sequence • Above the gene • DNA methylation • Histone modification • Micro RNA regulation

  5. Introduction

  6. Introduction

  7. Promoter Gene CpG Island

  8. Promoter Gene CpG Island N. Shore S. Shore

  9. Promoter Gene CpG Island N. Shore N. Shelf S. Shore S. Shelf

  10. Transcription Factor Gene Promoter CpG Island N. Shore S. Shore N. Shelf S. Shelf

  11. Transcription Factor Gene Promoter CpG Island N. Shore S. Shore N. Shelf S. Shelf

  12. Gene expression Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  13. Gene expression Transcription Factor Gene Promoter CpG Island N. Shore S. Shore N. Shelf S. Shelf Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  14. Gene expression Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  15. Gene expression Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  16. Gene expression Transcription Factor Gene Promoter CpG Island N. Shore S. Shore N. Shelf S. Shelf Gene expression repressed Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  17. Gene expression Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf Gene expression repressed Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  18. Gene expression Transcription Factor Gene Promoter CpG Island N. Shore S. Shore N. Shelf S. Shelf Gene expression repressed Transcription Factor Promoter Gene CpG Island N. Shore S. Shore N. Shelf S. Shelf

  19. Central Hypothesis • Distinct epigenetic patterns of DNA methylation are associated with heritable risk underlying preeclampsia

  20. Methodology • Design • Prospective • Subjects • Nulliparous women recruited (n=55) • Maternal peripheral white blood cells (MPBCs) collected in first trimester of pregnancy • Placental tissue collection at delivery • Medical record abstraction for grouping

  21. Methodology • Genome-wide DNA methylation in women with normal pregnancy and preeclampsia • Maternal white blood cells • Placental chorionic tissue • Method • InfiniumIllumina bead array • Analysis • Significant differences in methylation of individual CpGdinucleotides • Beta score change of 0.2 • Functional classification DAVID v6.7

  22. Differential methylation in maternal peripheral blood (delta-beta > 0.2; n=6/group) Control PE CpGdinucleotides

  23. Mean differential methylation in maternal peripheral blood (delta-beta > 0.2; n=6/group) Preeclampsia Control CpGdinucleotides

  24. Total Number of Differentially Methylated CpG Dinucleotides Maternal Peripheral Blood

  25. Gene location of significantly methylated CpG dinucleotides associated with preeclampsia Maternal Peripheral Blood

  26. Chromosomal Distribution of Differential Methylation Chromosome

  27. DNA Methylation Biomarkers of Preeclampsia from Mother In First Trimester of Pregnancy 36% (n=125) 64% (n=216) Maternal Peripheral Blood Cells

  28. Transmission of DNA Methylation Biomarkers of Preeclampsia from Mother to Child during Pregnancy Placenta 36% 64% Maternal Peripheral Blood Cells

  29. Transmission of DNA Methylation Biomarkers of Preeclampsia from Mother to Child during Pregnancy Placenta Placenta 36% 64% Maternal Peripheral Blood Cells

  30. Disease Categories Associated with Methylation Gain • Neurologic • Chemical dependency • Anorexia • Bipolar disorder • Schizophrenia • Alzheimer’s disease • Immune • Arthritis • Lupus erythematosus • Multiple sclerosis • Celiac disease • Thyroid autoimmunity • Cancer • Bladder • Breast • Colorectal • Endometrial • Head/neck • Cardiovascular • Hypertension • Hypercholesterolemia • Metabolic • Lipid • Fatty acid • cholesterol • Diabetes (type 1 and 2) • Obesity

  31. Disease Categories Associated with Methylation Loss • Neurologic • Chemical dependency • Bipolar disorder • Cognitive function • Asperger syndrome • Schizophrenia • Major depressive disorder • Alzheimer’s disease • Immune • Arthritis • Asthma • Antiphospholipid syndrome • Grave’s disease • Hashimoto thyroiditis • Lupus erythematosus • Multiple sclerosis • Aging • Cardiovascular • MI • Hypertension • Stroke • Hypercholesterolemia • Metabolic • Lipid • Fatty acid • cholesterol • Diabetes (type 1 and 2) • Adiposity

  32. Conclusions • First study to identify common differentially methylated DNA • Early in pregnancies subsequently complicated by preeclampsia • Maternal and fetal origin • Insight into mechanistic underpinnings of preeclampsia and familial risk • Potential for early screening and targeted treatment

  33. Acknowledgements • Funding support • Robert Wood Johnson Nurse Faculty Scholar Award UND New Faculty Scholar Award • UND Research Experience for Medical Students (REMS) • Research team • Jeanine Senti, MS, CNS

  34. Thank you! Thank you!

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