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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.

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

Abstract

Objectives:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and methods

Document retrieval

Inclusion criteria

Exclusion criteria

Quality assessment of literature

Data extraction

Statistical analysis

Results

The characteristics of included studies

The methodological quality of the included studies

Meta-analysis

Sensitivity analysis and publication bias

Discussion

Footnotes

Conflict of interest

Funding

References