DNA METHYLATION PROFILES OF GENES EFFECTIVE IN PLACENTAL ANGIOGENESIS FOR PREGNANTS WITH GESTATIONAL DIABETES

Year 2019, Volume: 50 Issue: 1, 7 - 12, 14.03.2019

Fatma Selcen Önder Baha Oral

https://doi.org/10.16948/zktipb.421432

Abstract

The reason of absence preventive
processes from GDM and early treatment modalities is unsettled ethiopathologies.
Defining the role of the placenta is important for these pathologies. Fetal
growth is adjusted due to placental genetic and epigenetic factors.

PURPOSE:   DNA methylation
which is an epigenetic mechanism, is modifiable and utiziable for diagnosis and
treatment recently. DNA methylation changes of VEGF, sFLT-1, PIGF genes, have
roles on placentation were evaluated according to GDM

MATERIAL and METHOD: All placental samples had taken from pregnants
who routinely followed at Suleyman Demirel University Gynecology and Obstetrics
Department, compatible with study criteria and diagnosed as GDM (n=15) and
healthy pregnants (n=17). DNA Methylation levels were analysed by ‘New
Generation DNA Sequencing’ method. Data collections analysed via SPSS 23
programme. Because of data distrubution Manny Whitney U tests are used for
means; SPEARMAN correlation analysis is used to reveal relation between datas.

RESULT: The methylation levels were not changed significantly due
to demographic characteristics. The analyses that examine differences in
methylation levels of PIGF were established no statistically significant
difference. There was statistically significant difference in levels of methylation
of sFLT-1 gene at the position of P92186. , P92344. , P92456. primer regions as
hypomethylated and VEGF gene at the position of P92668. , P92710. , P92863.
primer regions as hypermethylated.

CONCLUSION: The findings of our study indicates changes of DNA
methylation in some regions of VEGF, sFLT-1 genes and it is compatible with
literature. But clarifying of related regions of genes via whole genom studies
with a large population is necessary to reach predictive values.

Keywords

DNA Methylation, VEGF, FLT1, Gestational Diabetes, PLACENTA

Plasental Anjiogenezde Rol Alan Genlerin Gestasyonel Diyabeti Olan Gebelerde DNA Metilasyon Profilleri

Abstract

AMAÇ: Gestasyonel diyabet için erken tanı
ve tedavi modalitelerinin geliştirilememesinin nedeni etiyopatolojilerinin
aydınlatılamamış olmasıdır. Bu patolojilerde plasentanın rolünü tanımlamak
önemlidir. Plasenta genetik ve epigenetik faktörlerin etkisinde fetal gelişimi
belirler.

DNA metilasyonu değiştirilebilir
epigenetik mekanizmalardandır. Günümüzde tanı ve tedavi amaçlı
kullanılmaktadır. Çalışmamızda GDM (Gestasyonel Diyabet) gebelerde, plasental
anjiogenezde etkili genlerden VEGF(Vaskuler Endotelyal Büyüme Faktörü), PIGF(Plasental
Büyüme Faktörü) ve sFLT-1(soluble fms like tirozinkinaz)’nin DNA metilasyon
değişiklikleri değerlendirilecektir.

MATERYAL VE METOD: 2016-2017 tarihlerinde Süleyman Demirel Üniversitesi
Kadın Hastalıkları ve Doğum Bölümü’nden takipli; 15 GDM tanılı ve 17 sağlıklı
gebeden plasental örnekler alınmıştır. DNA metilasyon düzeyleri ‘Yeni Nesil
Sekanslama’ ile belirlenmiştir. Verilerin dağılımlarına göre Manny Whitney U
analizi; veriler arasındaki ilişkiler için Spearman korelasyon analizi
kullanılmıştır.

BULGULAR: Genlerin metilasyon oranları ile yaş, gebelik haftası, bebeğin
cinsiyet ve ağırlığı arasında ikililer arasında anlamlı ilişki saptanmamıştır(p>0.05).
Plasenta ağırlığı artarken sFLT-1 geninin P92186.Pozisyondaki promoter
metilasyon düzeyinin azaldığı görülmüştür. PIGF geninin metilasyon değerlerinde
gruplar arasında anlamlı fark bulunmamaktadır. sFLT 1 geninin bölgesel
analizlerine göre P92186. , P92344. , P92456. pozisyonlarındaki primer noktalarının
hipometile; VEGF geninin bölgesel analizlerine göre P92668. , P92710. , P92863.
pozisyonlarındaki primer noktalarının hipermetile olduğu saptanmıştır. 

SONUÇ: Bulgularımız literatürle uyumludur ve anjiogenezde etkili
genlerin bazı lokuslarındaki DNA metilasyon değişimlerinin GDM patogenezindeki
yerine katkı sağlamıştır. Ancak prediktif değere ulaşılabilmesi için, geniş
hasta gruplarıyla yapılacak genom çalışmaları ile ilgili gen bölgeleri
netleştirilmelidir.

Keywords

DNA METILASYONU, Gestasyonel Diyabet, VEGF, s-FLT1, PLASENTA

References

• 1. Galjaard, S., Devlieger, R., & Van Assche, F. A. (2013). Fetal growth and developmental programming. Journal of perinatal medicine, 41(1), 101-105.
• 2. Drake, P. M., Red‐Horse, K., & Fisher, S. J. (2004). Reciprocal chemokine receptor and ligand expression in the human placenta: implications for cytotrophoblast differentiation. Developmental dynamics, 229(4), 877-885.
• 3. Claycombe, K. J., Zeng, H., & Combs Jr, G. F. (2014). 12 Dietary Effects on Adipocyte Metabolism and Epigenetics. Nutrition and Epigenetics, 323.
• 4. Jensen, D. M., Sørensen, B., Feilberg‐Jørgensen, N., Westergaard, J. G., & Beck‐Nielsen, H. (2000). Maternal and perinatal outcomes in 143 Danish women with gestational diabetes mellitus and 143 controls with a similar risk profile. Diabetic Medicine, 17(4), 281-286.
• 5. Franks PW, Looker HC, Kobes S, Touger L, Tataranni PA, Hanson RL, Knowler WC. Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring. Diabetes. 2006;55:460–5.
• 6. Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. Intermediate metabolism in normal pregnancy and in gestational diabetes. Diabetes Metab Res Rev. 2003;19:259–70.
• 7. Dani, C., Bresci, C., Berti, E., Ottanelli, S., Mello, G., Mecacci, F., ... & Luchinat, C. (2014). Metabolomic profile of term infants of gestational diabetic mothers. The Journal of Maternal-Fetal & Neonatal Medicine, 27(6), 537-542.
• 8. Plagemann A. Maternal diabetes and perinatal programming. Early Hum Dev. 2011;87:743–7.
• 9. West NA, Crume TL, Maligie MA, Dabelea D. Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia. 2011;54:504–7.
• 10. Nahum Sacks K, Friger M, Shoham-Vardi I, Abokaf H, Spiegel E, Sergienko R, Landau D, Sheiner E. Prenatal exposure to gestational diabetes mellitus as an independent risk factor for long-term neuropsychiatric morbidity of the offspring. Am J Obstet Gynecol. 2016;215:380.e1-7.
• 11. Van Assche, F. A., Devlieger, R., Harder, T., & Plagemann, A. (2010). Mitogenic effect of insulin and developmental programming. Diabetologia, 53(6), 1243-1243.
• 12. Nelissen, E. C., van Montfoort, A. P., Dumoulin, J. C., & Evers, J. L. (2011). Epigenetics and the placenta. Human reproduction update, 17(3), 397-417.
• 13. Jansson, T., & Powell, T. L. (2007). Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. Clinical science, 113(1), 1-13.
• 14. Finer, S., Mathews, C., Lowe, R., Smart, M., Hillman, S., Foo, L., ... & Hitman, G. A. (2015). Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring. Human molecular genetics, 24(11), 3021-3029.
• 15. Plagemann, A., & Harder, T. (2009). Hormonal programming in perinatal life: leptin and beyond. British Journal of Nutrition, 101(02), 151-152.
• 16. Bouchard L, Hivert MF, Guay SP, St-Pierre J, Perron P, Brisson D. Placental adiponectin gene DNA methylation levels are associated with mothers’ blood glucose concentration. Diabetes. 2012;61:1272–80.
• 17. Ruchat SM, Houde AA, Voisin G, St-Pierre J, Perron P, Baillargeon JP, Gaudet D, Hivert MF, Brisson D, Bouchard L. Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases. Epigenetics. 2013; 8:935–43.
• 18. Del Rosario MC, Ossowski V, Knowler WC, Bogardus C, Baier LJ, Hanson RL. Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metabolism. 2014;6:654–60
• 19. Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest. 2005; 115:485–91.
• 20. Janbakhıshov, T. (2011) Gestasyonel Diyabetes Mellitus, Obezite Ve Travayın Fetal Vasküler Yapıya Etkisinin Araştırılması 13(43)
• 21. Yang, Z., Mo, X., Gong, Q., Pan, Q., Yang, X., Cai, W., ... & Gao, G. (2008). Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose. Apoptosis, 13(11), 1331-1343.
• 22. Su, R., Wang, C., Feng, H., Lin, L., Liu, X., Wei, Y., & Yang, H. (2016). Alteration in Expression and Methylation of IGF2/H19 in Placenta and Umbilical Cord Blood Are Associated with Macrosomia Exposed to Intrauterine Hyperglycemia. PloS one, 11(2), e0148399.
• 23. Lehnen H, Zechner U, Haaf T. Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life. Mol Hum Reprod. 2013;19:415–22.
• 24. Ruchat SM, Houde AA, Voisin G, St-Pierre J, Perron P, Baillargeon JP, Gaudet D, Hivert MF, Brisson D, Bouchard L. Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases. Epigenetics. 2013; 8:935–43.
• 25. Houde AA, Guay SP, Desgagné V, Hivert MF, Baillargeon JP, St-Pierre J, Perron P, Gaudet D, Brisson D, Bouchard L. Adaptations of placental and cord blood ABCA1 DNA methylation profile to maternal metabolic status. Epigenetics. 2013;8:1289–302.
• 26. Sferruzzi-Perri AN, Camm EJ. The programming power of the placenta. Front Physiol. 2016;7(MAR). doi:10.3389/fphys.2016.00033.
• 27. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293(5532):1089-1093. doi:10.1126/science.1063443.
• 28. Januar V, Desoye G, Novakovic B, Cvitic S, Saffery R. Epigenetic regulation of human placental function and pregnancy outcome: considerations for causal inference. Am J Obstet Gynecol. 2015;213(4 Suppl):S182-96. doi:10.1016/j.ajog.2015.07.011.
• 29. Chen C-Y, Tsay W, Tang J-L, et al. SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer. 2003;37(3):300-305. doi:10.1002/gcc.10222.
• 30. Liu L, Zhang X, Rong C, et al. Distinct DNA methylomes of human placentas between pre-eclampsia and gestational diabetes mellitus. Cell Physiol Biochem. 2014;34(6):1877-1889. doi:10.1159/000366386.
• 31. Üstek, D. (2011). Yeni Nesil DNA Dizileme (New Generation DNA Sequencing). Deneysel Tıp Araştırma Enstitüsü Dergisi, 1(1), 11-18.