Correlation of ACE gene deletion/insertion polymorphism and risk of pregnancy-induced hypertension: a meta-analysis based on 10,236 subjects

Abstract

Objectives:

To clarify the association of angiotensin-converting enzyme (ACE) gene deletion/insertion polymorphism with risk of pregnancy-induced hypertension.

Methods:

We systematically searched China National Knowledge Infrastructure, Wanfang database, Chongqing WeiPu database and PubMed up to March 2014 to collect related case–control studies. RevMan 5.0 software was used for meta-analysis after evaluating the quality of enrolled studies and extracting the data.

Results:

A total of 45 case–control studies was selected, including 10,236 subjects. The meta-analysis was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) after genotype consolidation. In total, D allele vs I allele: OR 1.57, 95% CI 1.33–1.86; genotype DD vs genotype II + DI: OR 1.86, 95% CI 1.48–2.32; genotype II vs genotype DI + DD: OR 0.65, 95% CI 0.53–0.80. In the Asian population, D allele vs I allele: OR 1.80, 95% CI 1.36–2.38; genotype DD vs genotype II + DI: OR 2.25, 95% CI 1.53–3.30; genotype II vs genotype DI + DD: OR 0.56, 95% CI 0.41–0.76. In the Caucasian population, D allele vs. I allele: OR 1.24, 95% CI 1.08–1.44; genotype DD vs. genotype II + DI: OR 1.25, 95% CI 1.10–1.41; genotype II vs. genotype DI + DD: OR 0.96, 95% CI 0.83–1.11.

Conclusion:

The ACE gene insertion/deletion polymorphism is associated with the risk of pregnancy-induced hypertension.

Keywords

Angiotensin-converting enzyme pregnancy-induced hypertension gene polymorphism meta-analysis

Introduction

Pregnancy-induced hypertension (PIH) seriously affects the life safety and quality of life of mothers and infants. A large-scale study found that the probability of death of mothers diagnosed with PIH after pregnancy was significantly higher than that of normal pregnant women.¹ In addition, PIH is often combined with a number of other diseases, such as pulmonary oedema and liver dysfunction, which also increase the risk of death for pregnant women.² Angiotensin-converting enzyme (ACE) is a key enzyme of the renin–angiotensin system. ACE can convert angiotensin I into a strong vasoconstrictor, angiotensin II, and can inactivate the vasodilator bradykinin peptide, playing an important role in vascular physiological regulation.³ Many studies^4–6 currently show that ACE activity is significantly elevated in the serum of patients with PIH, whereas the ACE gene can modulate ACE activity in serum and tissues.⁷ Therefore, the study of the ACE gene polymorphism has become an important research topic in the pathogenesis of PIH.^{8, 9} However, as a result of the difference in the distribution of the ACE gene in different races and regions, different statistical methods and different sample sizes in each study, the findings are inconsistent.

In this study, we performed a meta-analysis to clarify the correlation between ACE gene polymorphism (insertion/deletion (I/D)) and the risk of PIH.

Materials and methods

Document retrieval

We systematically searched China National Knowledge Infrastructure, Wanfang database, Chongqing WeiPu database and PubMed up to July 2014. We utilized ‘angiotensin-converting enzyme’ or ‘ACE’ and ‘pregnancy-induced hypertension’ or ‘PIH’ and ‘gene polymorphism’ or ‘genetics’ or ‘mutation’ as the search terms to retrieve related documents.

Inclusion criteria

All the included studies had to meet the following criteria: the published literature reported studies of the correlation between the incidence of PIH and ACE gene polymorphism; research methods constituted a case–control study; studies can directly or indirectly provide the frequency distribution of the ACE genotype in cases and controls; genetic polymorphism distribution of controls was in line with Hardy–Weinberg equilibrium; no language or race limitations.

Exclusion criteria

Duplicated literature and literature that did not provide valid data and for which the full text could not be obtained were excluded.

Quality assessment of literature

Referring to the Newcastle–Ottawa Scale,¹⁰ qualities of all the included literature were assessed as to the object selectivity, comparability and exposure; each appropriate entry was described as a star, and each star represented 1 point; object selection accounted for 4 points; comparability accounted for 2 points and exposure accounted for 3 points.

Data extraction

Screening and data extraction of the included literature were conducted by two reviewers (HWM and HG); any inconsistency was resolved by discussion. Data extraction included the following terms: last name of the first author, publication year, country or region, sample size of cases and controls and numbers of each genotype in case and control subjects.

Statistical analysis

RevMan 5.0 software was used for statistical analysis; heterogeneity was detected using the Q test; when I² was less than 50%, a fixed-effect model was use for meta-analysis; when I² was greater than 50%, a random-effect model was used for meta-analysis. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using RevMan software, with a forest plot showing the characteristics of the various findings. In each study, the standard errors of the OR natural logarithm were taken as abscissa and the OR natural logarithm were used for the vertical axis to draw Begg’s funnel plot to examine publication bias. P<0.05 was considered statistically significant.

Results

The characteristics of included studies

As shown in Figure 1, a total of 244 documents was obtained after the initial search; excluding duplicate research and unrelated studies, 45 studies were eventually included the present study.^11–54 The enrolled 45 case–control studies on the ACE gene I/D polymorphism and PIH included 10,236 subjects. Quality assessment showed that the 45 studies had large sample sizes, clear diagnostic criteria and comparability between the case group and the control group; all studies used polymerase chain reaction for genotype testing; the obtained data were clear; and the genetic equilibrium test showed that the gene distribution of the control group was consistent with Hardy–Weinberg equilibrium. The basic characteristics of each included study are shown in Table 1.

Figure 1.

Flow chart of literature identification.

Table 1.

The characteristics of included studies.

Authors	Year	Country	Genotyping methods	HWE	Groups	No.	ACE polymorphism (N)
Authors	Year	Country	Genotyping methods				DD	DI	II
Bai et al.³⁴	2002	China	PCR	Yes	Case	81	8	38	35
					Control	199	31	83	85
Wang et al.³⁵	2004	China	PCR	Yes	Case	99	42	37	20
					Control	54	14	16	24
Zhu et al.⁹	2012	China	PCR	Yes	Case	35	23	7	5
					Control	25	2	10	13
Gao et al.⁴⁵	2002	China	PCR	Yes	Case	110	66	34	10
					Control	81	57	18	6
Hong et al.⁴⁴	2000	China	PCR	Yes	Case	52	34	10	8
					Control	100	16	34	50
Jiang and Fu⁴⁸	2008	China	PCR	Yes	Case	67	13	36	18
					Control	70	8	30	32
Shang et al.⁵¹	2003	China	PCR	Yes	Case	90	31	47	12
					Control	96	15	42	39
Wang et al.⁴³	1999	China	PCR	Yes	Case	61	15	31	15
					Control	70	13	24	33
Wang et al.⁴⁷	2004	China	PCR	Yes	Case	41	16	18	7
					Control	50	9	19	22
Yu and Zhou⁴⁹	1999	China	PCR	Yes	Case	60	39	12	9
					Control	38	4	15	19
Xiang et al.⁵⁰	2001	China	PCR	Yes	Case	110	77	21	12
					Control	117	14	51	52
Yan et al.³³	2011	China	PCR	Yes	Case	113	21	57	35
					Control	113	23	52	38
Yue et al.⁴²	2011	China	PCR	Yes	Case	43	12	8	23
					Control	44	6	14	24
Wu et al.⁵²	2002	China	PCR	Yes	Case	56	21	23	12
					Control	62	12	22	28
Mao et al.⁴⁶	2004	China	PCR	Yes	Case	62	25	24	13
					Control	120	12	46	62
Li et al.³⁶	2005	China	PCR	Yes	Case	54	24	14	16
					Control	100	19	39	42
Li et al.³⁷	2006	China	PCR	Yes	Case	133	37	46	50
					Control	105	25	31	49
Deng et al.⁴¹	2010	China	PCR	Yes	Case	50	20	16	14
					Control	100	20	57	23
Cui and Chen⁴⁰	2008	China	PCR	Yes	Case	63	11	33	19
Cui and Chen⁴⁰					Control	40	4	19	17
Zhan and Zheng³⁹	2008	China	PCR	Yes	Case	120	32	41	47
Zhan and Zheng³⁹					Control	60	10	24	26
Huang et al.⁵⁴	2001	China	PCR	Yes	Case	90	46	32	12
					Control	120	21	47	52
Song et al.³⁸	2007	China	PCR	Yes	Case	45	17	21	7
					Control	45	13	23	9
Kaur et al.¹¹	2005	India	PCR	Yes	Case	50	30	14	6
					Control	50	15	26	9
Aggarwal et al.²⁷	2010	India	PCR	Yes	Case	104	18	45	41
Aggarwal et al.²⁷					Control	118	19	54	45
Roberts et al.¹²	2004	South Africa	PCR	Yes	Case	78	36	38	4
Roberts et al.¹²	2004	South Africa			Control	338	152	142	44
Choi et al.¹³	2004	Korea	PCR	Yes	Case	90	33	34	23
					Control	98	14	51	33
Gurdol et al.¹⁴	2004	Turkey	PCR	Yes	Case	95	47	31	17
					Control	89	31	37	21
Galao et al.¹⁵	2004	Brazil	PCR	Yes	Case	51	16	23	12
					Control	71	21	33	17
Kim et al.¹⁶	2004	Korea	PCR	Yes	Case	104	25	36	33
					Control	114	25	49	31
Heiskanen et al.¹⁷	2001	Finland	PCR	Yes	Case	133	43	59	31
					Control	115	31	58	26
Kobashi et al.¹⁸	2005	Japan	PCR	Yes	Case	122	19	52	51
					Control	291	35	136	120
Morgan et al.¹⁹	1999	UK	PCR	Yes	Case	72	23	31	18
					Control	83	25	36	22
Velloso et al.³⁰	2007	Brazil	PCR	Yes	Case	20	12	7	1
					Control	20	7	12	1
Serrano et al.³¹	2006	Columbia	PCR	Yes	Case	665	140	382	143
					Control	1046	230	607	209
Mello et al.³²	2003	Italy	PCR	Yes	Case	48	25	20	3
					Control	58	26	20	25
Bouba et al.²⁰	2003	Greece	PCR	Yes	Case	41	17	19	5
					Control	102	29	52	21
Dizon-Townson et al.²¹	1995	USA	PCR	Yes	Case	124	49	42	33
					Control	200	65	98	37
Levesque et al.²²	2004	Canada	PCR	Yes	Case	174	50	92	32
					Control	306	97	151	58
Mozgovaia et al.²³	2000	Russia	PCR	Yes	Case	45	21	14	10
					Control	73	28	37	8
Roh et al.²⁴	1997	Korea	PCR	Yes	Case	36	4	11	21
					Control	115	14	62	39
Seremak-Mrozikiewicz et al.²⁵	2000	Poland	PCR	Yes	Case	25	16	7	2
					Control	110	34	61	15
Watanabe et al.²⁶	2001	Japan	PCR	Yes	Case	96	13	48	35
					Control	96	40	46	13
Uma et al.²⁸	2010	UK	PCR	Yes	Case	60	19	27	14
					Control	105	22	61	22
Mandò et al.²⁹	2009	Italy	PCR	Yes	Case	253	100	124	29
					Control	410	151	187	72
Rahimi et al.⁵³	2014	USA	PCR	Yes	Case	198	122	49	25
						100	42	42	16

ACE: angiotensin-converting enzyme; HWE: Hardy–Weinberg equilibrium; PCR: polymerase chain reaction.

The methodological quality of the included studies

In the 45 studies, there were 42 documents with more than 6 points, another three single-centre small sample studies were of lower quality; all the designs of experiments were group-matching; most case definition and criteria were clear; the majority of the controls were from the hospital population.

Meta-analysis

In total, the heterogeneity test showed there was a significant heterogeneity among the various studies (I²=81%, P<0.001), therefore the random-effect model was used to merge the ORs. Meta-analysis showed there was a significant association between ACE I/D polymorphism and PIH in the dominant model (OR 1.86, 95% CI 1.48–2.32, P<0.0001; Figure 2), recessive model (OR 0.65, 95% CI 0.53–0.80, P<0.0001; Figure 3) and allele model (OR 1.57, 95% CI 1.33–1.86, P<0.0001; Figure 4).

Figure 2.

Forest plot of PIH risk associated with ACE I/D polymorphism in total population (DD genotype vs DI + II genotype). The squares and horizontal lines correspond to the study-specific ORs and 95% CIs, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of ORs and 95% CIs. ACE, angiotensin-converting enzyme; PIH, pregnancy-induced hypertension.

Figure 3.

Forest plot of PIH risk associated with ACE I/D polymorphism in total population (II genotype vs DI + DD genotype). The squares and horizontal lines correspond to the study-specific ORs and 95% CIs, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of ORs and 95% CIs. ACE, angiotensin-converting enzyme; PIH, pregnancy-induced hypertension.

Figure 4.

Forest plot of PIH risk associated with ACE I/D polymorphism in total population (D allele vs I allele). The squares and horizontal lines correspond to the study-specific ORs and 95% CIs, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of ORs and 95% CIs. ACE, angiotensin-converting enzyme; PIH, pregnancy-induced hypertension.

In the Asian population, we also found the association of ACE I/D polymorphism with PIH risk in these three models: D allele vs I allele: OR 1.80, 95% CI 1.36–2.38; genotype DD vs genotype II + DI: OR 2.25, 95% CI 1.53–3.30; genotype II vs genotype DI + DD: OR 0.56, 95% CI 0.41–0.76 (Figure 5).

Figure 5.

Forest plot of PIH risk associated with ACE I/D polymorphism in Asian population (A) DD genotype vs DI + II genotype; (B) II genotype vs DI + DD genotype; (C) D allele vs I allele. The squares and horizontal lines correspond to the study-specific ORs and 95% CIs, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of ORs and 95% CIs. ACE, angiotensin-converting enzyme; PIH, pregnancy-induced hypertension.

However, in the Caucasian population, we only found the association of ACE I/D polymorphism with PIH risk in the dominant model and allele model (D vs. I: OR 1.24, 95% CI 1.08–1.44; DD vs II + DI: OR 1.25, 95% CI 1.10–1.41) but not in a recessive model (II vs DI + DD: OR 0.96, 95% CI 0.83–1.11) (Figure 6).

Figure 6.

Forest plot of PIH risk associated with ACE I/D polymorphism in Caucasian population (A) DD genotype vs DI + II genotype; (B) II genotype vs DI + DD genotype; (C) D allele vs I allele. The squares and horizontal lines correspond to the study-specific ORs and 95% CIs, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of ORs and 95% CIs. ACE, angiotensin-converting enzyme; PIH, pregnancy-induced hypertension.

Sensitivity analysis and publication bias

Sensitivity analysis was performed by the exclusion method one by one. We did not find that the combined OR values change significantly, which indicated the meta-analysis was stable and reliable.

Seen from the funnel plot analysis (Figure 7), the symmetry of each genotype funnel plot was good, displaying no publication bias. Evaluation of the funnel plot symmetry with Begg’s test and Egger’s test showed that there was no significant publication bias in the various publications, and the selected studies were more representative.

Figure 7.

Begg’s funnel plot for publication bias test. Each circle denotes an independent study for the indicated association. Log[OR], natural logarithm of OR. Horizontal line stands for mean effect size.

Discussion

In the present study, we found that the ACE genetic polymorphism (I/D) was associated with the risk of PIH. The human ACE gene is located on the long arm of chromosome 17, region 2, zone 3, which is a single copy gene. There is a 287 bp I/D polymorphism in intron 16, and it makes the human ACE gene produce three genotypes, DD, DI and II. At present, it has been found that the ACE gene can regulate the level of human serum ACE concentration. Human serum ACE is at the highest level of activity in DD genotype carriers, and the activity level of human serum ACE with DI genotypes was followed. Human serum ACE is at the lowest level of activity in subjects with the II genotype.^55–58

To date, much research^11–54 has been focused on the ACE gene I/D polymorphism and PIH, but the results are controversial. Aggarwal et al.²⁷ found that although the level of activity of human serum ACE with the DD genotype was higher than that with other genotypes in northern India, in the distribution of genetic frequency there is no difference between the case and control groups. Seremak-Mrozikiewicz et al.²⁵ found that the frequency distribution of the D and I alleles of the ACE gene were inconsistent in cases and control groups, and confirmed that the D allele may be a risk factor for PIH. Bai et al.³⁴ also found in the PIH group the frequency of the D allele was higher than that in the control group. The authors also found the serum concentration of ACE was higher in the PIH group than that in the control group. Kaur et al.¹¹ found that the frequency of the DD genotype in the PIH group was 60%, while it was only 30% in the control group; the difference was significant. And the frequency of the D allele in patients with PIH (74%) was higher than that in the control group (56%). However, they did not find a significant difference in the concentration of serum ACE between the two groups.

In the present study, the meta-analysis showed that the ACE gene I/D polymorphism was associated with the risk of PIH. Both the D allele and DD genotype are risk factors for PIH, while the II genotype may be a protective factor. The present study included 45 studies, involving 10,236 subjects. In these studies, there were three ethnicities including Asian, Caucasian and South African populations. Only one study reported the data for South African individuals, but we did not analyse this study independently. Therefore, in stratification analysis, we divided the studies into Asian and Caucasian populations. We found a similar association, that the D allele carriers have a higher risk of PIH than those with the I allele of the ACE polymorphism with PIH in these two ethnic population. Although we clarified the relation between the ACE polymorphism and PIH, the heterogeneity between each study must be explained. The presence of heterogeneity among the included studies may be associated with the following factors:

The occurrence of PIH may not only be associated with genetic factors but may also be related to environmental factors. In the analysis of included studies, the authors only compared the difference of genotypes between case and control groups, and did not analyse the influence of other risk factors.

Some studies did not consider ethnic and other confounders in the selection of cases, which may also have some impact on the results.

Lack of access to the ethnic, age, occupation and lifestyle of subjects from the included studies, subgroup analysis cannot be further conducted to exclude heterogeneity.

Some of the included publications in the present study had no confirmatory test and there could be genotyping errors, which would impact our results to some extent.

In conclusion, this analysis showed that the subjects with the D allele have a higher risk of having PIH. However, PIH is a complex disease resulting from the interaction between many factors. Our results require verification in a larger sample and more rigorous case–control study or cohort study in the future.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Funai

EF1

Friedlander

Paltiel

. Long-term mortality after preeclampsia. Epidemiology 2005; 16(2): 206–215.

Dildy

Cotton

. Management of severe preeclampsia and eclampsia. Crit Care Clin 1991; 7(4): 829–850.

London

. A second ACE of hearts. J Mol Cell Cardiol 2003; 35(9): 1009–1010.

Brameld

Hold

Pipkin

. Regional variation in angiotensin converting enzyme activity in the human placenta. Placenta 2011; 32(11): 906–908.

Anton

Merrill

Neves L

. Activation of local chorionic villi angiotensin II levels but not angiotensin (1–7) in preeclampsia. Hypertension 2008; 51(4): 1066–1072.

Irani

Xia

. The functional role of the renin–angiotensin system in pregnancy and preeclampsia. Placenta 2008; 29(9): 763–771.

Abbas

Ezzat

Hamdy

. Angiotensin-converting enzyme (ACE) serum levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus. Lupus 2012; 21(1): 103–110.

Chen

Liu

. Meta analysis of correlation of angiotensin-converting enzyme gene deletion/insertion polymorphism and risk of pregnancy-induced hypertension in Chinese women. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013; 38(6): 631–638.

Zhu

Zhang

Nie

. Associations of ACE I/D, AGT M235T gene polymorphisms with pregnancy induced hypertension in Chinese population: a meta-analysis. J Assist Reprod Genet 2012; 29(9): 921–932.

10.

Stang

. Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta analyses. Eur J Epidemiol 2010; 25(9): 603–605.

11.

Kaur

Jain

Khuller

. Association of angiotensin-converting enzyme gene polymorphism with pregnancy-induced hypertension. Acta Obstet Gynecol Scand 2005; 84: 929–933.

12.

Roberts

Rom

Moodley

. Hypertension-related gene polymorphisms in pre-eclampsia, eclampsia and gestational hyper-tension in Black South African women. J Hypertens 2004; 22: 945–948.

13.

Choi

Kang

Yoon

. Association of angiotensin-converting enzyme and angiotensinogen gene polymorphisms with preeclampsia. J Korean Med Sci 2004; 19: 253–257.

14.

Gurdol

Isbilen

Yilmaz

. The association between preeclampsia and angiotensin-converting enzyme insertion/deletion polymorphism. Clin Chim Acta 2004; 341: 127–131.

15.

Galao

de Souza

da Costa

. Angiotensin-converting enzyme gene polymorphism in preeclampsia and normal pregnancy. Am J Obstet Gynecol 2004; 191: 821–824.

16.

Kim

Park

. Associations of polymorphisms of the angiotensinogen M235 polymorphism and angiotensin-converting enzyme intron 16 insertion/deletion polymorphism with preeclampsia in Korean women. Eur J Obstet Gynecol Reprod Biol 2004; 116: 48–53.

17.

Heiskanen

Pirskanen

Hiltunen

. Insertion–deletion polymorphism in the gene for angiotensin-converting enzyme is associated with obstetric cholestasis but not with preeclampsia. Am J Obstet Gynecol 2001; 185: 600–603.

18.

Kobashi

Hata

Shido

. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and preeclampsia in Japanese patients. Semin Thromb Hemost 2005; 31: 346–350.

19.

Morgan

Foster

Hayman

. Angiotensin-converting enzyme insertion–deletion polymorphism in normotensive and pre-eclamptic pregnancies. J Hypertens 1999; 17: 765–768.

20.

Bouba

Makrydimas

Kalaitzidis

. Interaction between the polymorphisms of the renin–angiotensin system in preeclampsia. Eur J Obstet Gynecol Reprod Biol 2003; 110: 8–11.

21.

Dizon-Townson

Lompe

Hastings

. A common genetic variant of the angiotensin converting enzyme is associated with both preeclampsia and chronic hypertension [abstract]. Am J Obstet Gynecol 1995; 172: 374.

22.

Levesque

Moutquin

Lindsay

. Implication of an AGT haplotype in a multigene association study with pregnancy hypertension. Hypertension 2004; 43: 71–78.

23.

Mozgovaia

Malysheva

Ivashchenko

. Genetic predisposition to pre-eclampsia: polymorphism of genes involved in regulation of endothelial functions. Balkan J Med Genetics 2002; 5: 19–26.

24.

Roh

Kim

Yoon

. A common genetic variant of the angiotensin converting enzyme (ACE) gene and pregnancy induced hypertensive disorders. Korean J Obstet Gynecol 1997; 40: 1189–1199.

25.

Seremak-Mrozikiewicz

Drews

Malewski

. Polymorphic genotypes of the angiotensin-converting enzyme in severe pregnancy-induced hypertension. Arch Perinat Med 2000; 6: 22–24.

26.

Watanabe

Hamada

Yamakawa-Kobayashi

. Evidence for an association of the R485K polymorphism in the coagulation factor V gene with severe preeclampsia from screening 35 polymorphisms in 27 candidate genes. Thromb Haemost 2001; 86: 1594–1595.

27.

Aggarwal

Jain

Jha

. Endothelial nitric oxide synthase, angiotensin-converting enzyme and angiotensinogen gene polymorphisms in hypertensive disorders of pregnancy. Hypertens Res 2010; 33: 473–477.

28.

Uma

Forsyth

Struthers

. Polymorphisms of the angiotensin converting enzyme gene in early-onset and late-onset pre-eclampsia. J Matern Fetal Neonatal Med 2010; 23: 874–879.

29.

Mandò

Antonazzo

Tabano

. Angiotensin-converting enzyme and adducin-1 polymorphisms in women with preeclampsia and gestational hypertension. Reprod Sci 2009; 16: 819–826.

30.

Velloso

Vieira

Cabral

. Reduced plasma levels of angiotensin-(1–7) and renin activity in preeclamptic patients are associated with the angiotensin I-converting enzyme deletion/deletion genotype. Braz J Med Biol Res 2007; 40: 583–590.

31.

Serrano

Díaz

Páez

. Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias. PLoS Med 2006; 3: e520.

32.

Mello

Parretti

Gensini

. Maternal–fetal flow, negative events, and preeclampsia: role of ACE I/D polymorphism. Hypertension 2003; 41: 932–937.

33.

Yan

Kulane

Xiang

. Maternal and fetal angiotensin-converting enzyme gene insertion/deletion polymorphism not associated with pregnancy-induced hypertension in Chinese women. J Matern Fetal Neonatal Med 2011; 24(9): 1119–1123.

34.

Bai

Liu

. Angiotensinogen and angiotensin-I converting enzyme gene variations in Chinese pregnancy induced hypertension. Hua Xi Yi Ke Da Xue Xue Bao 2002; 33: 233–237.

35.

Wang

. Relationships between polymorphisms of angiotensin-converting enzyme and methylenetetrahydrofolate reductase genes and genetic susceptibility to pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi 2004; 39: 369–372.

36.

Jiang

. The association between polymorphisms of angiotensin-converting enzyme and apolipoprotein B and left ventricular hypertrophy in patients with preeclampsia and eclampsia. Xian Dai Fu Chan Ke Jin Zhan 2005; 14: 108–114.

37.

. 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 2006; 26: 293–301.

38.

Song

Xie

Tang

. The gene polymorphisms of the rein-angiotensin system in preeclampisa. Shi Yong Yi Xue Za Zhi 2007; 23: 354–357.

39.

Zhan

Zheng

. Relationship between angiotensin converting enzyme gene polymorphism and severe preeclampsia and preeclampsia complication renal dysfunction. Jiang Xi Yi Yao 2008; 43: 782–784.

40.

Cui

Chen

. Relationship between angiotensin converting enzyme gene polymorphism and early-onset severe preeclampsia. Zhong Guo Fu You Bao Jian 2008; 23: 1545–1546.

41.

Deng

You

Cheng

. Correlation between gene polymorphisms of ACE, AT1R, eNOS and severe pre-eclampsia. Zhong Guo Fu You Bao Jian 2010; 25: 5277–5279.

42.

Yue

Liu

. Polymorphisms of angiotensin converting enzyme gene in pre-eclampsia. Med J West China 2011; 23: 850–853.

43.

Wang

Hua

Niu

. Relationship of gene polymorphism of angiotensin-converting enzyme and pregnancy induced hypertension. Zhonghua Fu Chang Ke Za Zhi 1999; 34: 116.

44.

Hong

Lin

. Study on insertion/deletion polymorphis of angiotensin-converting enzyme and pregnancy induced hypertension. Wen Zhou Yi Xue Yuan Xue Bao 2000; 30: 37–38.

45.

Gao

Qiu

. Study on insertion/deletion polymorphism of angiotensin-converting enzyme in women with pregnancy induced hypertension. Zhong Guo Fu You Bao Jian 2002; 17: 738–740.

46.

Mao

Zhao

. Study on MTHFR gene and ACE gene polymorphisms in pregnancy induced hypertension. Zhong Hua Wei Chang Yi Xue Za Zhi 2004; 7: 22–24.

47.

Wang

Liao

. Study on detection of insertion/deletion polymorphism of angiotensin-converting enzyme gene in pregnancy induced hypertension. Jiang Xi Yi Xue Yuan Xue Bao 2004; 44: 77–81.

48.

Jiang

. Angiotensinogen and angiotensin converting enzyme gene variations in pregnancy induced hypertension. Practical Clin Med 2008; 9: 25–28.

49.

Zhou

. Study of the angiotensin converting enzyme gene in pregnancy induced hypertension. Acta Academiae Medicinae Shandong 1999; 37(1): 21–23.

50.

Xiang

Wang

. Study of relationship between the estrogen receptor gene and angiotensin converting enzyme gene of pregnancy induced hypertension. China Contemp Med 2001; 7(11): 78–82.

51.

Shang

Wang

Sun

. Can angiotensin converting enzyme (ACE) and angiotensin II receptor type I (AT(1)-R) gene polymorphisms be used as predictors of pregnancy-induced hypertension. Chinese J Obstet Gynecol 2003; 38(2): 41–42.

52.

Chen

. Relationship of gene polymorphism of angiotensin-converting enzyme and the morbidity of pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi 2002; 37: 30.

53.

Rahimi

Aghaei

. AT2R-1332 G:A polymorphism and its interaction with AT1R 1166 A:C, ACE I/D and MMP-9-1562 C:T polymorphisms: risk factors for susceptibility to preeclampsia. Gene 2014; 538(1): 176–181.

54.

Huang

Liao

Sun

. Study on the relation between the angiotensin converting enzyme gene and pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi 2001; 36: 15–17.

55.

Biller

Ruprecht

Gaede

. Gene polymorphisms of ACE and the angiotensin receptor AT2R1 influence serum ACE levels in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26(2): 139–146.

56.

Firozabad

Tajik

Shafiei

. Interaction of A-240T and A2350G related genotype of angiotensin-converting enzyme (ACE) is associated with decreased serum ACE activity and blood pressure in a healthy Iranian population. Eur J Pharmacol 2011; 668(1–2): 241–247.

57.

Ajala

Almeida

Rangel

. Association of ACE gene insertion/deletion polymorphism with birth weight, blood pressure levels, and ACE activity in healthy children. Am J Hypertens 2012; 25(7): 827–832.

58.

Hosseini

Shafiee

Baluchnejadmojarad

. Garlic extract reduces serum angiotensin converting enzyme (ACE) activity in no diabetic and streptozotocin-diabetic rats. Pathophysiology 2007; 14(2): 109–112.