• New approaches to early prediction of preeclampsia severity in pregnant women with type 1 diabetes mellitus: evaluation of the possibility of genetic markers’ use 
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New approaches to early prediction of preeclampsia severity in pregnant women with type 1 diabetes mellitus: evaluation of the possibility of genetic markers’ use 

HEALTH OF WOMAN.2015.10(106):28–36; doi 10.15574/HW.2015.106.28 

New approaches to early prediction of preeclampsia severity in pregnant women with type 1 diabetes mellitus: evaluation of the possibility of genetic markers’ use 

Avramenko T. V., Hrybanov A. V., Rossokha Z. I.

SI «Institute of Pediatrics, Obstetrics and Gynecology, NAMS of Ukraine», Kiev

City maternity hospital № 2, Nikolaev

SІ «The Reference center for molecular diagnosis of Ministry of health of Ukraine», Kyiv 

Overall 60 female patients with type 1 diabetes were investigated: pregnancy complicated with mild (n=15), moderate (n=11) and severe (n=4) superimposed preeclampsia was reported in 30 subjects (main study group); no complications were detected among the rest 30 patients (control group). 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 preeclampsia severity in women with pre-existing type 1 diabetes mellitus based on clinical parameters, as well as data about the prevalence of polymorphic variants of genes. The following risk factors were found to be the main contributors to moderate/severe preeclampsia development: presence of vascular complications (diabetic nephropathy and angiopathy of lower extremities), as well as their combinations (nephropathy + retinopathy; nephropathy + angiopathy of lower extremities) at the time of conception; in the presence of diabetic complications – BMI value <23.7 kg/m2; and ACE DD-genotype. In heterozygous carriers of PON1 108CT genotype clinical parameters provide modifying effect: when this genotype is combined with diabetic nephropathy, or duration of diabetes less than 8.5 years, or BMI value less than 23.8 kg/m2 mild preeclampsia develops; in the presence of the same genotype moderate/severe preeclampsia develops when duration of diabetes is over 13.5 years and the value of BMI is over 25.17 kg/m2. Combination of ACE_II/PON1_CC genotypes provides protective effect on preeclampsia development, while ACE_ID/PON1_CT combination is associated with development of mild preeclampsia. Genetic markers defined in our study were found to be helpful in prediction of preeclampsia severity in type 1 diabetic pregnant women. Identification of women at high risk for severe preeclampsia development will let us to implement corresponding preventive measures and to provide closer monitoring, resulting in better pregnancy outcomes.

 

Key words: pregnancy, type 1 diabetes mellitus, preeclampsia; prediction, genetic markers, gene polymorphism. 

REFERENCES

1. Акулова ЛЮ. 2011. Исследование роли полиморфизма генов ренин-ангиотензиновой системы в формировании уровня артериального давления и эхокрадиографических показателей у женщин при беременности. Дисс. д-ра мед. наук: спец. 03.02.07 «Генетика». Белгород:140.

2. Демин ГС. 2008. Анализ ассоциации полиморфизма генов «сосудистой системы» и «эндотелиальной дисфункции с развитием преэклампсии». Дисс. канд. биол. наук: спец. 03.00.03 «Молекулярная биология». Санкт-Петербург:202.

3. Зябліцев СВ, Джоджуа ТВ, Кишеня МС та ін. 2013. Дослідження ролі поліморфізму гена ангіотензинконвертуючого фермента в формуванні артеріальної гіпертензії при прееклампсії. Питання експериментальної та клінічної медицини: Збірник статей 17;2:21–26.

4. Мальцева ЛИ, Павлова ТВ та ін. 2011. Генетические аспекты гестоза. Практическая медицина 6;54:7–11.

5. Нелаева AA, Хасанова ЮВ, Хоботова Е. 2013. Роль провоспалительных цитокинов в развитии и прогрессировании микро- и макроангиопатии у пациентов с сахарным диабетом 2-го типа. Ангиология и сосудистая хирургия 19;3:9–13.

6. Радьков ОВ, Калинкин МН, Заварин ВВ. 2010. Факторы ренин-ангиотензин-альдостероновой системы при гестозе в зависимости от полиморфизма гена ангиотензин-превращающего фермента. Фундаментальная медицина 9:105–111.

7. Радьков ОВ, Калинкин МН, Заварин ВВ. 2011. Ассоциация инсерционно-делеционного полиморфизма гена АСЕ с факторами циркулирующего отдела ренин-ангиотензин-альдостероновой системы и функцией эндотелия микрососудов кожи при формировании гестоза. Бюллетень сибирской медицины 4:32–36.

8. Aggarwal PK, Jain V, Jha V. 2010. Endothelial nitric oxide synthase, angiotensin-converting enzyme and angiotensinogen gene polymorphisms in hypertensive disorders of pregnancy. Hypertens Res. 33; 5:473–477. http://dx.doi.org/10.1038/hr.2010.23; PMid:20186148

9. Aggarwal S, Dimri N, Tandon I et al. 2011. Preeclampsia in North Indian women: the contribution of genetic polymorphism. J Obstet Gynaecol Res. 37;10:1335–1341. http://dx.doi.org/10.1111/j.1447-0756.2010.01523.x; PMid:21564405

10. Alsokary H, Kamel M, Sadek S [et al.]. 2014. Study of angiotensin-converting enzyme and genotype among Egyptian preeclampsia patients. American Journal of Molecular Biology. 4:26–36. http://dx.doi.org/10.4236/ajmb.2014.41005

11. Arrigo FG. 2015. Independent determinants of maternal and fetal outcomes in a sample of pregnant outpatients with normal blood pressure, chronic hypertension, gestational hypertension, and preeclampsia. The Journal of Clinical Hypertension 17;10:777–782. http://dx.doi.org/10.1111/jch.12614; PMid:26173048

12. Backes CH, Markham K, Moorehead P et al. 2011. Maternal preeclampsia and neonatal outcomes. J Pregnancy. 2011;doi:10.1155/2011/214365. http://dx.doi.org/10.1155/2011/214365

13. Bramham K, Rajasingham D. 2012. Pregnancy in diabetes and kidney disease. Journal of Renal Care 38(1):78–89. http://dx.doi.org/10.1111/j.1755-6686.2012.00270.x; PMid:22348367

14. Bose C, Van Marter LJ, Laughon M et al. 2009. Fetal growth restriction and chronic lung disease among infants born before the 28th week of gestation. Pediatrics. 124; 3:e450–e458. http://dx.doi.org/10.1542/peds.2008-3249; PMid:19706590 PMCid:PMC2891899

15. El Bassuoni MA, Younes H, Talaat RM et al. 2009. The association of angiotensin-1 converting enzyme (ACE) serum level and (I/D) polymorphism in Egyptian preeclamptic women. Egyptian Journal of Medical Microbiology. 18;Issue 4:89–96.

16. Elveđi-Gašparović V, Beljan P, Gverić Ahmetašević S et al. 2015. What affects the outcome of severe preeclampsia? Signa Vitae. 10 (Suppl. 1):6–12.

17. Gaugler-Senden IPM. 2011. Severe early-onset preeclampsia: short- and long-term clinical psychosocial and biochemical aspects: PhD Thesis. Rotterdam: Erasmus Universiteit Rotterdam:147.

18. Gьrdцl F, Isbilen E, Yilmaz H et al. 2004. The association between preeclampsia and angiotensin-converting enzyme insertion/deletion polymorphism. Clin Chim Acta. 341;1–2:127–131.

19. Hдupl T, Zimmerman M, Kalus U et al. 2015. 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. 16;2:422–427. http://dx.doi.org/10.1177/1470320314539181; PMid:25155623

20. Li H, Ma Y, Fu Q et al. 2007. Angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor (AT1R) gene polymorphism and its association with preeclampsia in Chinese women. Hypertens Pregnancy. 26;3:293–301. http://dx.doi.org/10.1080/10641950701413676; PMid:17710578

21. Mandу C, Antonazzo P, Tabano S. 2009. Angiotensin-converting enzyme and adducing-1 polymorphisms in women with preeclampsia and gestational hypertension. Reprod Sci. 16;9:819–826. http://dx.doi.org/10.1177/1933719109336612; PMid:19443911

22. Mathiesen ER, Ringholm L, Feldt-Rasmussen B et al. 2012. Obstetric nephrology: pregnancy in women with diabetic nephropathy – the role of antihypertensive treatment. Clinical Journal of the American Society of Nephrology 7;12:2081–2088. http://dx.doi.org/10.2215/CJN.00920112; PMid:22917698

23. Rahimi Z, Rahimi Z, Mozafari H et al. 2013. 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. 14;2:174–180. http://dx.doi.org/10.1177/1470320312448950; PMid:22719026

24. Young BC, Levine RJ, Karumanchi SA. 2010. Pathogenesis of preeclampsia. Annu. Rev. Pathol. Mech. Dis. 5:173–192. http://dx.doi.org/10.1146/annurev-pathol-121808-102149; PMid:20078220