Maternal cardiovascular-related single nucleotide polymorphisms, genes, and pathways associated with early-onset preeclampsia

Autoři: Paula Benny aff001;  Kelly Yamasato aff002;  Breck Yunits aff001;  Xun Zhu aff003;  Travers Ching aff003;  Lana X. Garmire aff004;  Marla J. Berry aff005;  Dena Towner aff002
Působiště autorů: University of Hawaii Cancer Center, Honolulu, Hawai’i, United States of America aff001;  Department of Obstetrics, Gynecology, and Women’s Health, John A Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawai’i, United States of America aff002;  Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawai’i, United States of America aff003;  Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America aff004;  Department of Cell and Molecular Biology, John A Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawai’i, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222672



Preeclampsia is a medical condition complicated with hypertension and proteinuria during pregnancy. While preeclampsia affects approximately 5% of pregnancies, it remains without a cure. In addition, women who had preeclampsia during pregnancy have been reported to have an increased risk for cardiovascular disease later in life. However, the disease etiology and molecular mechanisms remain poorly understood. The paucity in the literature on preeclampsia associated maternal cardiovascular risk in different ethnic populations also present a need for more research. Therefore, the objective of this study was to identify cardiovascular/metabolic single nucleotide polymorphisms (SNPs), genes, and regulatory pathways associated with early-onset preeclampsia.

Materials and methods

We compared maternal DNAs from 31 women with early-onset preeclampsia with those from a control group of 29 women without preeclampsia who delivered full-term normal birthweight infants. Women with multiple gestations and/or known medical disorders associated with preeclampsia (pregestational diabetes, chronic hypertension, renal disease, hyperthyroidism, and lupus) were excluded. The MetaboChip genotyping array with approximately 197,000 SNPs associated with metabolic and cardiovascular traits was used. Single nucleotide polymorphism analysis was performed using the SNPAssoc program in R. The Truncated Product Method was used to identify significantly associated genes. Ingenuity Pathway Analysis and Ingenuity Causal Network Analysis were used to identify significantly associated disease processes and regulatory gene networks respectively.


The early-onset preeclampsia group included 45% Filipino, 26% White, 16% other Asian, and 13% Native Hawaiian and other Pacific Islanders, which did not differ from the control group. There were no SNPs associated with early-onset preeclampsia after correction for multiple comparisons. However, through gene-based tests, 68 genes and 23 cardiovascular disease-related processes were found to be significantly associated. Associated gene regulatory networks involved cellular movement, cardiovascular disease, and inflammatory disease.


Multiple cardiovascular genes and diseases demonstrate associations with early-onset preeclampsia. This unfolds new areas of research regarding the genetic determinants of early-onset preeclampsia and their relation to future cardiovascular disease.

Klíčová slova:

Cardiovascular diseases – Genetic networks – Genetics of disease – Human genetics – Hypertension – Preeclampsia – Gene regulatory networks – Genetic predisposition


1. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009;33(3):130–7. doi: 10.1053/j.semperi.2009.02.010 19464502

2. Steegers E, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376:633–44.

3. Cnattingius S, Reilly M, Pawitan Y, Lichtenstein P. Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study. Am J Med Genet A. 2004;130A(4):365–71. doi: 10.1002/ajmg.a.30257 15384082

4. Chappell S, Morgan L. Searching for genetic clues to the causes of pre-eclampsia. Clin Sci. 2006;110(4):443–58. doi: 10.1042/CS20050323 16526948

5. Nishizawa H, Pryor-Koishi K, Kato T, Kowa H, Kurahashi H, Udagawa Y. Microarray analysis of differentially expressed fetal genes in placental tissue derived form early and late onset severe-preeclampsia. Placenta. 2007;28(5–6):487–97. doi: 10.1016/j.placenta.2006.05.010 16860862

6. Bendetto C, Marozio L, Ciccone G, Ghieppa G, Quaglia M, Matullo G. Synergistic effect of renin-angiotensin system and nitric oxide synthase genes polymorphisms in pre-eclampsia. Acta Obstetrica et Gynecologica. 2007;86(6):678–82.

7. Nakagawa K, Lim E, Harvey S, Miyamura J, Juarez DT. Racial/Ethnic Disparities in the Association Between Preeclampsia Risk Factors and Preeclampsia Among Women Residing in Hawaii. Matern Child Health J. 2016;20(9):1814–24. doi: 10.1007/s10995-016-1984-2 27000850

8. Ching T, Ha J, Song MA, Tiirikainen M, Molnar J, Berry M, et al. Genome-scale hypomethylation in the cord blood DNAs associated with early onset preeclampsia. Clin Epigenetics. 2015;7(1):21.

9. Ching T, Song M, Tiirikainen M, Molnar J, Berry M, Towner D, et al. Genome-wide hypermethylation coupled with promoter hypomethylation in the chorioamniotic membranes of early onset pre-eclampsia. Mol Hum Reprod. 2014;20(9):885–904. doi: 10.1093/molehr/gau046 24944161

10. University of Hawaii John A Burns School of Medicine. University of Hawaii Biorepository 2014 [cited 19 March 2018].

11. Voight B, Kang HM, Ding J, Palmer CD, Sidore C, Chines PS et al. The Metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 2012;8(8):e1002793. doi: 10.1371/journal.pgen.1002793 22876189

12. Gonzalez J, Armengol L, Sole X, Guino E, Mercader JM, Estivill X, et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007;23(5):644–5. doi: 10.1093/bioinformatics/btm025 17267436

13. Wojcik G, Kao WHL, Duggal P. Relative performance of gene- and pathway-level methods as secondary analyses for genome-wide association studies. BMC Genet. 2015;16:34. doi: 10.1186/s12863-015-0191-2 25887572

14. Gene. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information [cited 3 February 2016].

15. Brown M, Best KE, Pearce MS, Waugh J, Robson SC, Bell R. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol. 2013;28(1):1–19. doi: 10.1007/s10654-013-9762-6 23397514

16. Bellamy L, Casas J, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. Br Med J. 2007;335(7627):974.

17. Zhang G, Zhao J, Yi J, Luan Y, Wang Q. Association Between Gene Polymorphisms on Chromosome 1 and Susceptibility to Pre-Eclampsia: An Updated Meta-Analysis. Med Sci Monit. 2016;22:2202–14. doi: 10.12659/MSM.896552 27348238

18. Sharma S, Yadav S, Chandiok K, Sharma RS, Mishra V, Saraswathy KN. Protein signatures linking history of miscarriages and metabolic syndrome: a proteomic study among North Indian women. PeerJ. 2019;7:e6321. doi: 10.7717/peerj.6321 30783564

19. Mishra J, Talwar S, Kaur L, Chandiok K, Yadav S, Puri M, et al. Differential global and MTHFR gene specific methylation patterns in preeclampsia and recurrent miscarriages: A case-control study from North India. Gene. 2019;704:68–73. doi: 10.1016/j.gene.2019.04.036 30986448

20. Holobotovskyy V, Chong YS, Burchell J, He B, Phillips M, Leader L, et al. Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia. Sci Transl Med. 2015;7(290):290ra88. doi: 10.1126/scitranslmed.aaa5038 26041705

21. Shaarawy M, El Meleigy M, Rasheed K. Maternal serum transforming growth factor beta-2 in preeclampsia and eclampsia, a potential biomarker for the assessment of disease severity and fetal outcome. J Soc Gynecol Investig. 2001;8(1):27–31. 11223354

22. Liu L, Zhang M, Min X, Cai L. Low Serum Levels of ABCA1, an ATP-Binding Cassette Transporter, Are Predictive of Preeclampsia. Tohoku J Exp Med. 2015;236(2):89–95. doi: 10.1620/tjem.236.89 26004638

23. Rani U, Praveen Kumar KS, Munisamaiah M, Rajesh D, Balakrishna S. Atrial fibrillation associated genetic variation near PITX2 gene increases the risk of preeclampsia. Pregnancy Hypertens. 2018;13:214–7. doi: 10.1016/j.preghy.2018.06.023 30177054

24. Loset M, Johnson MP, Melton PE, Ang W, Huang RC, Mori TA, et al. Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22. Pregnancy Hypertens. 2014;4:178–85. doi: 10.1016/j.preghy.2014.03.005 26104425

25. Johnson MP, Brennecke SP, East CE, Dyer TD, Roten LT, Proffitt JM, et al. Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease. Mol Hum Reprod. 2013;19(7):423–37. doi: 10.1093/molehr/gat011 23420841

26. Tuteja G, Cheng E, Papadakis H, Bejerano G. PESNPdb: A comprehensive database for SNPs studied in association with pre-eclampsia. Placenta. 2012;33(12):1055–57. doi: 10.1016/j.placenta.2012.09.016 23084601

27. Kaartokallio T, Cervera A, Kyllonen A, Laivuori K, Group. FCI. Gene expression profiling of pre-eclamptic placentae by RNA sequencing. Sci Rep. 2015;5:14107. doi: 10.1038/srep14107 26388242

28. Kleinrouweler CE, van Uitert M, Moerland PD, Ris-Stalpers C, van der Post JA, Afink GB. Differentially expressed genes in the pre-eclamptic placenta: a systematic review and meta-analysis. PLoS One. 2013;8(7):e68991. doi: 10.1371/journal.pone.0068991 23874842

29. Kawasaki K, Kondoh E, Chigusa Y, Ujita M, Murakami R, Mogami H, et al. Reliable pre-eclampsia pathways based on multiple independent microarray data sets. Mol Hum Reprod. 2015;21(2):217–24. doi: 10.1093/molehr/gau096 25323968

30. Sitras V, Fenton C, Acharya G. Gene expression profile in cardiovascular disease and preeclampsia: A meta-analysis of the transcriptome based on raw data from human studies deposited in Gene Expression Omnibus. Placenta. 2015;36(2):170–8. doi: 10.1016/j.placenta.2014.11.017 25555499

31. Murphy MSQ, Bytautiene E, Saade G, Smith GN. Alterations to the maternal circulating proteome after pre-eclampsia. Am J Obstet Gynecol. 2015;213:853.e1–9.

32. Vance C, Taylor RN, Craven TE, Edwards MS, Corriere MA. Increased prevalence of preeclampsia among women undergoing procedural intervention for renal artery fibromuscular dysplasia. Ann Vasc Surg. 2015;29(6):1105–10. doi: 10.1016/j.avsg.2015.03.037 26004957

33. Gordon J, Kahn AM, Burns JC. When children with Kawasaki disease grow up: Myocardial and vascular complications in adulthood. J Am Coll Cardiol. 2009;54(21):1911–20. doi: 10.1016/j.jacc.2009.04.102 19909870

34. Oudejans C, van Dijk M, Oosterkamp M, Lachmeijer A, Blankenstein MA. Genetics of preeclampsia: paradigm shifts. Hum Genet. 2007;120(5):2007.

35. Stekkinger E, Zandstra M, Peeters LLH, Spaanderman MEA. Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome. Obstet Gynecol. 2009;114(5):1076–84. doi: 10.1097/AOG.0b013e3181b7b242 20168110

36. Boyd H, Tahir H, Wohlfahrt J, Melbye M. Associations of personal and family preeclampsia history with the risk of early-, intermediate- and late-onset preeclampsia. Am J Epidemiol. 2013;178(11):1611–9. doi: 10.1093/aje/kwt189 24049162

37. Ramalingam U, Forsyth SJ, Struthers AD, Fraser CG, Godfrey V, Murphy DJ. Polymorphisms of the angiotensin converting enzyme gene in early-onset and late-onset pre-eclampsia. J Matern Fetal Neonatal Med. 2010;23(8):874–9. doi: 10.3109/14767050903456667 20044877

38. Rao A, Daniels K, El-Sayed YY, Moshesh MK, Caughey AB. Perinatal outcomes among Asian American and Pacific Islander women. Am J Obstet Gynecol. 2006;195(3):834–8. doi: 10.1016/j.ajog.2006.06.079 16949421

39. Sun C, Zhang L, Zhang WY. Gene expression profiling of maternal blood in early onset severe preeclampsia: identification of novel biomarkers. J Perinat Med. 2009;37(6):609–16. doi: 10.1515/JPM.2009.103 19681734

Článek vyšel v časopise


2019 Číslo 9