GENETIC PREDISPOSITION TO PRE-ECLAMPSIA: POLYMORPHISM OF GENES INVOLVED IN REGULATION OF ENDOTHELIAL FUNCTIONS
Mozgovaia EV, Malysheva OV, Ivashchenko TE, Baranov VS*
*Corresponding Author: Professor Dr. Vladislav S. Baranov, Laboratory of Prenatal Diagnosis of Inherited Disorders, D.O. Ott Research Institute of Obstetrics and Gynecology, Russian Academy of Medical Sciences, Mendeleevskaya line 3, St. Petersburg 199034, Russia; Tel/Fax: +07-812-328-0487; E-mail: baranov@vb2475. spb.edu
page: 19

CONCLUSIONS

Our data substantiate existing opinions that PE repre­sents a complex syndrome which include various patholog­ical conditions that produce similar clinical traits, but developing in different ways. Far from being considered as a single clinical diagnosis, PE should be divided into different subgroups according to its metabolic and genetic bases.

The present data show that particular genotypes of the tested genes are associated with the development of par­ticular clinical forms of PE, and thus contribute to the genetic background of this disease. The following geno­types: I/I (PLAT), 4G/4G (PAI-1), 4a/4a (eNOS), A/G (TNF-a, and 1c/1c (GSTP1) should be considered as mar­kers of unfavorable prognosis at onset of PE, if they are combined with arterial hypertension, kidney disorders or with diabetes mellitus. Progression of pPE is also associ­ated with particular polymorphisms of the same genes, although usually with some other genotypes such as D/D (ACE), 4b/4b (eNOS), G/G (TNF-a, and 1a/1a (GSTP1). Correlation of certain genotypes for PLAT, PAI and espe­cially TNF-a, with endothelial dysfunction induced by some other diseases which existed before pregnancy, is also quite obvious. In these cases, PE comes as a primary clinical manifestation of a previous chronic endothelial dysfunction acquired before pregnancy. However, a final conclusion about the actual impact of some unfavorable combinations of the genes participating in endothelial function in the origin of PE should be considered prema­ture and deserves further study.

Analysis of other gene groups involved in the possible pathogenesis of PE should be undertaken. These could include: 1) genes whose products are responsible for im­munological and intercellular interactions during implan­tation and placentation, and 2) genes responsible for pla­cental growth such as vascular endothelial growth factor (VEGF), placental growth factor (PGF), angiopoietins and angiostatins [16]. According to the present data, early testing for genetic polymorphisms relevant to endothelial dysfunction could be rather important for presymptomatic identification of women at high risk for PE.

 

Table 2. Polymorphisms of the ACE, eNOS and TNF-a genes in pregnant women with pre-eclampsia.

 

 

ACE Polymorphism

 

n

 

Genotype
I/I (%)

 

Genotype
I/D (%)

 

Genotype
D/D (%)

 

c2

 

OR

 

Control group

 

73

 

10.9

 

50.6

 

38.3

 

Pure PE

  • nephropathia I & II
  • severe

 

45
34
11

 

22.2
23.5
18.1

 

31.1
20.5
63.6

 

46.6
55.8
18.1

 

5.25 (p<0.25)
9.18 (p<0.05)
1.81

 

1.4
2.04
0.35
1.7

 

Combined PE

  • mild with mild AH
  • mild with severe AH
  • severe with mild AH
  • severe with heavy AH
  • with kidney disease
  • with type 1 diabetes
  • with type 2 diabetes

 

73
21
12
12
11
16
9
4

 

20
28.5
25.0
46.1
0.0
12.5
22.2
25.0

 

46.2
33.3
25.0
38.4
45.4
56.2
77.7
25.0

 

33.7
38.0
50.0
15.3
54.5
31.2
0.0
50.0

 

2.37 (p<0.5)
4.45 (p<0.25)
3.36 (p<0.5)
10.4 (p<0.05)
1.87
0.29
5.38 (p<0.25)

 

0.81
0.99
1.6
0.32
1.9

3.41.6

 

eNOS Polymorphism

 

n

 

Genotype
4a/4a (%)

 

Genotype
4a/4b (%)

 

Genotype
4b/4b (%)

 

c2

 

OR

 

Control group

 

73

 

2.7

 

33.3

 

63.8

 

Pure PE

  • nephropathia I & II
  • severe

 

42
31
11

 

0.0
0.0
0.0

 

30.9
40.0
0.0

 

69.1
60.0
100.0

 

1.35
0.19
8.2 (p<0.05)

 

0.89
1.47

 

Combined PE

  • mild with mild AH
  • mild with severe AH
  • severe with mild AH
  • severe with severe AH
  • with kidney disease
  • with type 1 diabetes
  • with type 2 diabetes
  • with gestational diabetes

 

76
17
12
12
12
14
10
4
5

 

3.9
11.2
0.0
0.0
0.0
0.0
10.0
0.0
0.0

 

38.1
50.0
50.0
58.3
25.0
28.5
30.0
50.0
40.0

 

57.8
38.8
50.0
41.6
75.0
71.4
60.0
50.0
60.0

 

0.6
4.87 (p<0.25)
1.45
2.9 (p<0.5)
0.75
0.51
1.3

 

1.46
4.38
2.0
2.8
0.67

3.89
2.0
1.33

 

 

TNF-a Polymorphism

 

n

 

Genotype
(238) G/G (%)

 

Genotype
(238) A/G (%)

 

c2

 

OR

 

Control group

 

73

 

91.7

 

8.2

 

Pure PE

  • nephropathia I & II
  • severe

 

41
26
15

 

92.6
88.4
100.0

 

7.3
11.5
0.0

 

0.036
0.011
0.345

 

0.85
1.46

 

Combined PE

  • nephropathia I with mild AH
  • nephropathia II & III with mild AH
  • real PE with mild AH
  • with severe AH
  • heavy with kidney disease
  • with gestational diabetes

 

76
22
11
4
25
10
5

 

84.0
63.6
85.7
75.0
100.0
50.0
80.0

 

16.0
36.3
14.2
25.0
0.0
50.0
20.0

 

1.44 (p<0.5)
8.53 (p<0.05)
0.07

0.18
9.97 (p<0.05)

 

1.75
6.38
1.6
3.72

11.2
2.79

 

 

 

GSTP1 Polymorphism

 

n

 

Genotype
1a/1a (%)

 

Genotype
1a/1b (%)

 

Genotype
1a/1c (%)

 

Genotype
1b/1b (%)

 

Genotype
1b/1c (%)

 

Genotype
1c/1c (%)

 

c2

 

OR

 

Control group

 

73

 

53.3

 

26.0

 

9.5

 

6.8

 

4.1

 

0.0

 

Pure PE

  • nephropathia I and II
  • severe

 

45
30
15

 

48.8
40.0
62.5

 

35.5
43.3
25.0

 

8.8
6.6
12.5

 

0.0
0.0
0.0

 

2.2
3.3
0.0

 

4.6
6.6
0.0

 

4.35 (p<0.5)
5.12 (p<0.5)
2.07

 

1.57
2.17
1.45

 

Combined PE

  • mild with mild AH
  • mild with severe AH
  • severe with mild AH
  • severe with severe AH

 

  • with kidney disease

 

  • with type 2 diabetes and gestational diabetes

 

77
19
12

12
12

 

16

9

 

46.7
42.1
50.0

75.0
25.0

 

62.6

22.2

 

24.6
26.3
25.0

0.0
25.0

 

12.5

33.3

 

19.4
26.3
16.6

16.6
33.3

 

18.7

33.3

 

5.1
5.2
8.3

0.0
8.3

 

0.0

0.0

 

2.5
0.0
0.0

0.0
8.3

 

6.2

0.0

 

1.2
0.0
0.0

8.3
0.0

 

0.0

11.1

 

4.24
4.45 (p<0.05)
1.04

5.78 (p<0.5)
6.6 (p<0.05)

 

3.42

6.4 (p<0.5)

 

2.29
3.37
1.89
1.24ƒ
1.89
4.71
1.24ƒ
2.12
2.18
1.56
4.7

Table 3. Polymorphisms of the GSTP1 genes in pregnant women with pre-eclampsia.




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