Genetic markers for prediction of early and late onset preeclampsia in pregnant women with preexisting type 1 diabetes mellitus

Т. В. Авраменко, А. В. Грибанов, З. И. Россоха

Abstract


The study compared the profile of polymorphic variants of genes that determine the basic pathogenesis of pre-eclampsia in groups of patients with type 1 diabetes. Overall, 60 female patients with type 1 diabetes were investigated: pregnancy complicated with early-onset (n = 15) and late-onset (n = 15) superimposed preeclampsia was reported in 30 subjects; no complications were detected among the rest 30 patients. Besides standard clinical investigation, each patient underwent molecular genetic testing with detection of the following polymorphic variants of genes: А1166С-AT2R1, C108T-PON1, Thr83Ala- and T138C-MGP, 4b/4a- and G894T-eNOS, as well as I/D-ACE.

On completion of our study we established differential prognostic models for prediction of early-and late-onset preeclampsia development in women with pre-existing type 1 diabetes mellitus based on the data about the prevalence of polymorphic variants of genes and gene-gene interactions.

The following risk factors were found to be the main contributors to early-onset (< 32 weeks) preeclampsia development: long duration of diabetes; presence of vascular complications at the time of conception (in particular, diabetic angiopathy of lower extremities and diabetic nephropathy); and ACE ID-genotype. The most significant genotype combinations associated with early-onset preeclampsia development were as follows: ACE (ID) / AT2R1 (1166АА), ACE (ID) / AT2R1 (1166АС), ACE (I/D) / eNOS (4b/4b), ACE (I/D) / eNOS (894GG). Genetic factor influenced the development of late-onset preeclampsia (≥ 32 weeks) to a much lesser extent; only one statistically significant combination of genotypes was detected to be associated with preeclampsia debut after 32 weeks of pregnancy – ACE (ID) / MGP (138TC). Genotype combination ACE (II) / PON1 (108CC) significantly reduced the risk of preeclampsia development during the entire pregnancy.

Important genetic markers found in our study will allow predicting different forms of preeclampsia in type 1 diabetic pregnant women. Identification of women at high risk for early-onset preeclampsia development will let us to implement treatment and preventive measures and to provide closer monitoring, resulting in better pregnancy outcomes.


Keywords


pregnancy; type 1 diabetes mellitus; early- and late-onset preeclampsia; prediction; genetic markers; gene polymorphism; gene-gene interactions

References


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21. Ekbom, P., Damm, P., Andersson, A.M., et al. “Serum levels of activin A and inhibin A are not related to the increased susceptibility to pre-eclampsia in type I diabetic pregnancies.” Acta Obstet Gynecol Scand, 2 (Vol. 85) (2006): 143–147.

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23. El-Sherbiny, W.S., Nasr, A.S., Soliman, A. “Endothelial nitric oxide synthase (eNOS) (Glu298Asp) and urotensin II (UTS2 S89N) gene polymorphisms in preeclampsia: prediction and correlation with severity in Egyptian families.” Hypertens Pregnancy, 3 (Vol. 32) (2013): 292–303.

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25. Gong, F.F., Hu, C.Y., Lu, S.S., et al. “Associations of angiotensin-converting enzyme insertion/ deletion, angiotensin II receptor A1166C, and endothelial nitric oxide synthase 4b/4a gene polymorphisms with pregnancy hypertensive disorders: a meta-analysis.” J Clin Hypertens (Greenwich), 2015. DOI: 10.1111/jch.12606

26. Häupl, T., Zimmerman, M., Kalus, U., et al. “Angiotensin converting enzyme intron 16 insertion/deletion genotype is associated with plasma C-reactive protein concentration in uteroplacental dysfunction.” Journal of Renin- Angiotensin-Aldosterone System, 2 (Vol. 16) (2015): 422–427.

27. Holmes, V.A., Young, I.S., Patterson, C.C., et al. “The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes.” Diabetes Care, 11 (Vol. 36) (2013): 3671–3677. DOI: 10.2337/dc13-0944

28. Junus, K., Centlow, M., Wikström, A.-K., et al. “Gene expression profiling of placentae from women with early- and late-onset pre-eclampsia: down-regulation of the angiogenesis-related genes ACVRL1 and EGFL7 in early-onset disease.” Mol Hum Reprod, 3 (Vol. 18) (2012): 146–155.

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30. Mackness, B., Turkie, W., Mackness, M. “Paraoxonase-1 (PON1) promoter region polymorphisms, serum PON1 status and coronary heart disease.” Arch Med Sci, 1 (Vol. 9) (2013): 8–13.

31. Mandó, C., Antonazzo, P., Tabano, S. “Angiotensin-converting enzyme and adducing-1 polymorphisms in women with preeclampsia and gestational hypertension.” Reprod Sci, 9 (Vol. 16) (2009): 819–826.

32. Mathiesen, E.R., Ringholm, L., Feldt-Rasmussen, B., et al. “Obstetric nephrology: pregnancy in women with diabetic nephropathy – the role of antihypertensive treatment.” Clinical Journal of the American Society of Nephrology, 12 (Vol. 7) (2012): 2081–2088.

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34. Misković, B., Sertić, J., Stavljenić-Rukavina, A. “Association of angiotensin-converting enzyme insertiondeletion polymorphism with preeclampsia.” Coll Antropol, 2 (Vol. 31) (2008): 239–243.

35. Perlik, M., Seremak-Mroikiewicz, M.A., Barlik, M., et al. “Genetic variants of endothelial nitric synthase in gestational hypertension and preeclampsia.” Ginekol Pol, 9 (Vol. 83) (2012): 652–659.

36. Procopciuc, L.M., Caracostea, G., Zaharie, G., et al. “Maternal/newborn genotype contribution of the renninangiotensin system (Met235Thr, Thr174Met, I/D-ACE, A2350G-ACE, A1166C-AT2R1, C3123A-AT2R2, 83A/G-REN) to the risk of pre-eclampsia: a Romanian study.” J Renin Angiotensin Aldosterone System, 4 (Vol. 12) (2011): 539–548.

37. Qi, H.P., Fraser, W.D., Luo Z.C., et al. “Endothelial nitric oxide synthase gene polymorphisms and risk of preeclampsia.” Am J Perinatol, 10 (Vol. 30) (2013): 795–804.

38. Qiong, J.M. Analysis on gene polymorphism between hypertensive disorder complicating pregnancy and the RAS: Master’s thesis. Nanchang University, 2008.

39. Rahimi, Z., Rahimi, Z., Aghaei, A., et al. “AT2R – 1332 G:A polymorphism and its interaction with AT1R 1166 A:C and MMP-9 – 1562 C:T polymorphisms: risk factors for susceptibility to preeclampsia.” Gene, 1 (Vol. 538) (2014): 176–181.

40. Rahimi, Z., Rahimi, Z., Mozafari, H., et al. “Preeclampsia and angiotensin converting enzyme (ACE) I/D and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms: association with ACE I/D polymorphisms.” J Renin Angiotensin Aldosterone Syst, 2 (Vol. 14) (2013): 174–180.

41. Ringholm, L., Pedersen-Bjergaard, U., Thorsteinsson, B., et al. “A high concentration of prorenin in early pregnancy is associated with development of pre-eclampsia in women with type 1 diabetes.” Diabetologia, 7 (Vol. 54) (2011): 1615–1619. DOI: 10.1007/s00125-011-2087-7

42. Ringholm, L. “Atrial natriuretic peptide (ANP) in early pregnancy is associated with development of preeclampsia in type 1 diabetes.” Diabetes Res Clin Pract, 3 (Vol. 93) (2011): 106–109.

43. Sakar, M.N., Atay, A.E., Demir, S., et al. “Association of endothelial nitric oxide synthase gene G894T polymorphism and serum nitric oxide levels in patients with preeclampsia and gestational hypertension.” J Matern Fetal Neonatal Med, 16 (Vol. 28) (2015): 1907–1911.

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DOI: http://dx.doi.org/10.18370/2309-4117.2015.26.56-65

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