White

Learning Objectives ---- At the end of this presentation the learner will be able to:

1. Understand MTHFR C677T gene mutations in relation to pregnancy induced hypertension (PIH) in various race-ethnicity groups in the world. 2. Discuss potential epigenetic factors associated with PIH.

Gene Mutations and Pregnancy Induced Hypertension: A Meta-Analysis Ya-Ling Yang, RN, Ph.D. 1; Shyang-Yun Pamela K. Shiao, PhD, RN, FAAN 2

1 School of Nursing, College of Medicine, National Taiwan University. 2 College of Nursing, Georgia Regents University.

Objectives

To disseminate current evidence on population genome

health and related epigenetic factors, through the meta-

analyses of methylenetetrahydrofolate reductase (MTHFR)

gene in pregnant women who developed hypertension.

Background

PIH including preeclampsia, eclampsia are the leading

causes of maternal and perinatal mortalities.

Genetic and environmental factors contribute to its

development.

Many studies have reported the association between the

MTHFR gene C677T polymorphism and risk of PE, but the

results were inconclusive.

Methods

Cochrane, Embase, PubMed, and Web of Science on-line

databases were searched using related key words.

Progression on Selection of Studies

Presentation at the 43rd Biennial Convention, Honor Society of Nursing, Sigma Theta Tau International, November 7 – 11, 2015, Las Vegas, Nevada, USA.

Potentially relevant studies identified and

screened for retrieval (n = 73)

16 meta-analyses

57 case control studies

9 studies excluded (not English):

2 meta-analyses

7 case control studies

Studies retrieved for more detail evaluations (n = 64)

14 meta-analyses

51 case control studies

14 meta-analyses included:

43 case control studies (16 overlapping; 8

without sufficient information)

Studies with sufficient information fulfilling all inclusion/ exclusion criteria

(n = 52, 2 studies with 3 and 2 additional race groups, respectively)

51 case control studies:

14 papers without sufficient information; 4

papers not focus on pregnancy hypertension

Results Pool Relative Risk of MTHFR 677 Gene Subtypes (57 studies)

Genotype

(number of studies)

PIH Case

N=6463 (n, %)

Control

N=11213 (n, %)

RR (95% CI)

TT Overall (57) 822 (12.72) 1179 (10.51) 1.26 (1.11 – 1.40)***

White (24) 357 (11.86) 610 ( 9.69) 1.16 (1.01 – 1.34)*

Hispanic (4) 236 (21.91) 346 (23.63) 0.98 (0.85 – 1.13)

South American (4) 62 (16.40) 66 (11.89) 1.40 (1.01 – 1.93)*

East Asia (8) 153 (26.15) 163 (13.55) 1.82 (1.49 – 2.23)***

South Asia (5) 16 ( 2.78) 31 ( 3.12) 0.96 (0.51 – 1.84)

Middle Eastern (6) 53 ( 8.31) 38 ( 7.29) 1.16 (0.77 – 1.74)

Africa (6) 20 ( 2.70) 2 ( 0.26) 5.82 (2.06 – 16.5)***

CT Overall (57) 2437 (37.71) 4402 (39.25) 1.00 (0.96 – 1.04)

White (24) 1254 (41.66) 2614 (41.53) 1.01 (0.96 – 1.07)

Hispanic (4) 464 (43.08) 629 (42.96) 1.03 (0.94 – 1.13)

South American (4) 173 (45.77) 258 (46.49) 0.94 (0.81 – 1.08)

East Asia (8) 272 (46.50) 69 ( 4.56) 0.96 (0.86 – 1.07)

South Asia (5) 97 (16.87) 200 (20.12) 0.77 (0.61 – 0.98)*

Middle Eastern (6) 244 (38.24) 185 (35.51) 1.06 (0.92 – 1.24)

Africa (6) 142 (19.16) 152 (19.44) 1.07 (0.88 – 1.30)

CC Overall (57) 3204 (49.57) 5632 (50.22) 0.96 (0.93 – 1.00)

White (24) 1399 (46.48) 3069 (48.76) 0.96 (0.91 –1.01)

Hispanic (4) 377 (35.00) 489 (33.40) 0.98 (0.88 – 1.08)

South American (4) 143 (37.83) 231 (41.62) 0.96 (0.81 – 1.13)

East Asia (8) 160 (27.35) 451 (37.49) 0.74(0.64 – 0.86)***

South Asia (5) 462 (80.35) 763 (76.76) 1.06 (0.95 – 1.17)

Middle Eastern (6) 341 (53.45) 298 (57.20) 0.94 (0.85 – 1.04)

Africa (6) 579 (78.14) 628 (80.31) 0.95 (0.91 – 1.00)

CI = Confidence Interval; P value = *<0.05, ***<0.001

TT + CT subtypes by Country-Race for Case and Control groups (# of studies; # of subjects)

0

0

1

0

0

4

0

4

0

5

11

5

11

13

11

8

13

11

10

14

19

7

13

0

17

16

22

19

8

31

0

11

16

17

19

21

33

32

39

39

36

43

39

38

40

43

39

41

42

39

39

51

48

64

48

51

47

50

61

47

0 10 20 30 40 50 60 70 80

Afro-Caribbean (1, 7)

South Africa (2, 448)

Sri Lanka (1, 171)

Zimbabwe (1, 183)

Indonesia (1, 27)

India (2, 793)

Asian mixeed (1, 3)

Iran (2, 297)

Tunisia (1, 100)

Finland (3, 890)

Brazil (2, 228)

Slovak (1, 40)

UK (3, 190)

USA (4, 599)

Turkey (4, 224)

Denmark (1, 1842)

Croatia (1, 38)

Austria (1, 1397)

Netherland (3, 680)

Australia (1, 79)

Germany (2, 113)

Hungary (2, 174)

Japan (4, 910)

Egypt (1, 44)

Peru (1, 177)

China (4, 293)

Spain (1, 122)

Italy (1, 129)

Ecuador (1, 150)

Mexico (4, 865)

ct 677 tt% ct 677 ct%

0

0

2

1

2

3

7

6

5

6

18

18

11

14

12

12

8

8

13

12

9

12

23

34

20

31

19

30

12

30

21

15

21

16

15

15

21

34

45

35

37

39

39

39

45

45

48

56

45

42

48

47

45

45

50

48

56

44

49

48

0 10 20 30 40 50 60 70 80

Afro-Caribbean (1, 28)

South Africa (2, 454)

Sri Lanka (1, 175)

Zimbabwe (1, 171)

Indonesia (1, 41)

India (2, 345)

Asian mixeed (1, 14)

Iran (2, 390)

Tunisia (1, 44)

Finland (3, 494)

Brazil (2, 105)

Slovak (1, 28)

UK (3, 388)

USA (4, 541)

Turkey (4, 248)

Denmark (1, 263)

Croatia (1, 25)

Austria (1, 25)

Netherland (3, 583)

Australia (1, 156)

Germany (2, 86)

Hungary (2, 284)

Japan (4, 353)

Egypt (1, 44)

Peru (1, 123)

China (4, 232)

Spain (1, 43)

Italy (1, 94)

Ecuador (1, 150)

Mexico (4, 536)

PIH 677 tt% PIH 677 ct%

East Asia

Xt Xc Nt Nc

18 11 34 102

34 32 99 192

12 33 89 182

16 40 51 318

18 9 62 51

17 11 25 53

20 9 33 40

18 18 39 102

Africa

Xt Xc Nt Nc

15 0 29 44

0 0 28 7

2 0 42 100

1 0 104 110

1 2 348 336

1 0 170 183

Xt Xc Nt Nc

14 32 234 643

12 6 121 106

4 7 109 96

31 143 232 1699

7 15 64 64

1 7 14 27

31 12 252 88

11 9 79 81

1 0 14 1

32 11 227 109

21 36 146 367

20 19 137 138

5 2 23 38

2 5 23 33

8 6 112 95

25 6 139 67

2 155 23 1242

28 24 66 105

8 27 35 95

19 11 137 68

13 15 14 15

19 14 104 100

33 41 248 319

10 7 100 88

Conclusion

MTHFR 677 homozygous (TT) mutation genotype was significantly

associated with increased risk of developing PIH (p < 0.001).

MTHFR 677TT subtype was a significant risk of PIH in White race (RR= 1.16, p

< 0.05), South American (RR=1.40, p < 0.05), East Asian (RR= 1.82, p < 0.001)

and in Africa (RR=5.82, p < 0.001) .

Lifestyle factors, body mass index (BMI) before pregnancy (Kg/M2) was an

important predictor for the development of PIH.

Normal weight (BMI < 25) was protective against the development of PIH and

preeclampsia (RR = 0.75, p < 0.0001); whereas, overweight (BMI = 25-29, RR =

1.52, p < 0.0001) and obesity (BMI > 30, RR = 1.80, p < 0.0001) were

associated with increased risk of developing PIH and preeclampsia (376

cases and 2294 controls in 2 studies of Caucasian women).