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Abstract

Background and objective:

The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and renal allograft survival after renal transplantation from the published reports are still debatable. This study was performed to evaluate the relationship between the ACE I/D gene polymorphism and renal allograft survival after renal transplantation using meta-analysis.

Method:

Eligible studies were identified from PubMed and Cochrane Library on 1 November 2014, and eligible studies were recruited and synthesized using a meta-analysis methodology.

Results:

Twelve investigations were included in this meta-analysis for the assessment of the relationship between the ACE I/D gene polymorphism and renal allograft survival. In this meta-analysis, the ACE I/D gene polymorphism was not associated with renal allograft survival after renal transplantation for overall populations, Caucasians, Brazilians and Africans. Interestingly, the ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population.

Conclusions:

ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. However, more studies should be performed to confirm this association.

Keywords

Angiotensin-converting enzyme (ACE)insertion/deletion (I/D)gene polymorphism renal allograft survival renal transplantation meta-analysis

Introduction

End-stage renal disease (ESRD) is an increasing problem worldwide, and it is a major health problem, associated with very high morbidity and mortality.¹ Renal transplantation is the best renal replacement therapy option and is superior to dialysis in patients with ESRD.² The specialty of kidney transplantation has made dramatic strides over the decades, evolving from an experimental procedure to the standard care for the treatment of patients with ESRD.³ However, renal allograft survival after renal transplantation is most important for the patients with ESRD, and is an important indicator to reflect the development of organ transplantation.

In the angiotensin-converting enzyme (ACE) gene, nearly 100 gene polymorphisms have been identified.⁴ Among them, the ACE insertion/deletion (I/D) gene polymorphism is found to be more frequently associated with renal allograft survival after renal transplantation. In past years, several studies have been performed and have found that the ACE I/D gene polymorphism is associated with several renal diseases.^5–10 A well-documented diagnostic approach to predict renal allograft survival after renal transplantation is lacking. Current evidence indicates that gene polymorphism of some genes is associated with renal allograft survival after renal transplantation.

The gene polymorphism factor is reported to be an important factor associated with renal allograft survival after renal transplantation. Most of the epidemiologic investigations studying the relationship between the ACE I/D gene polymorphism and the renal allograft survival after renal transplantation were conducted in recent decades. However, the available evidence is weak, due to the sparseness of data or disagreements among the reported studies. The evidence from meta-analysis might be powerful compared with the individual investigation. We performed this meta-analysis to investigate whether the ACE I/D gene polymorphism is associated with renal allograft survival after renal transplantation.

Materials and methods

Search strategy for the assessment of the relationship between ACE I/D gene polymorphism and renal allograft survival

The relevant studies were searched from the electronic databases of PubMed, and Cochrane Library on 1 November 2014. The retrieval strategy of ‘(renal allograft survival) AND (angiotensin converting enzyme) AND (polymorphism OR variant)’ was entered into these databases. The additional reports were identified through references cited in recruited articles.

Inclusion and exclusion criteria

Inclusion criteria

The outcome had to be renal allograft survival.

There had to be at least two comparison groups (case group vs control group).

Investigation should provide the data of the ACE I/D genotype distribution.

Exclusion criteria

Review articles and editorials.

Case reports.

Preliminary result not on the ACE I/D gene polymorphism or outcome.

Investigating the role of ACE I/D gene expression in disease.

If multiple publications for the same data from the same study group occurred, we only recruited the later paper into our final analysis.

Data extraction and synthesis

The following information from each eligible investigation was extracted independently by two investigators: first author’s surname, year of publication, location of the study performed, control source of the control group and the number of cases and controls for ACE I/D genotypes. The results were compared and disagreement was resolved by discussion.

Statistical analysis

Cochrane Review Manager Version 5 (Cochrane Library, UK) was used to calculate the available data from each investigation. The pooled statistics were counted using the fixed effects model, but a random effects model was conducted when the P value of heterogeneity test was less than 0.1.^8,11 Results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CI) were also calculated. P<0.05 was required for the pooled OR to be statistically significant.^12,13 I² was used to test the heterogeneity between the included studies.

Results

Study characteristics

Twelve investigations^14–25 reporting the relationship between the ACE I/D gene polymorphism and renal allograft survival were recruited into this meta-analysis (Table 1). The data of our interest were extracted for the meta-analysis (Table 1).

Table 1.

Characteristics of the studies evaluating the effects of the ACE I/D gene polymorphism on renal allograft survival.

Author, Year	Ethnicity	Country/	Study style	Case				Control
		Subgroup		DD	ID	II	Total	DD	ID	II	Total
Beige 1997	Caucasian	Germany	Cohort study	11	42	10	63	58	107	41	206
Beige 1998	Caucasian	Germany	Case-control	22	53	12	87	27	41	18	86
Broekroelofs 1998	Caucasian	Netherlands	Case-control	7	14	6	27	11	23	8	42
Viklický 2001	Caucasian	Czekh	Case-control	5	2	6	13	6	8	3	17
Kabat-Koperska 2005	Caucasian	Poland	Case-control	7	10	6	23	5	3	2	10
Ayed 2006	African	Tunisia	Case-control	12	5	6	23	55	12	41	108
Bisalli 2006	Brazilian	Brazil	Case-control	36	60	25	121	39	52	28	119
Zhang 2007	Asian	China	Case-control	7	9	3	19	24	108	55	187
Kedzierska 2008	Caucasian	Poland	Case-control	8	10	6	24	3	3	2	8
Azarpira 2009	Asian	Iran	Case-control	24	32	21	77	5	34	11	50
Fedor 2010	Caucasian	Hungary	Case-control	12	21	5	38	6	24	4	34
Amorim 2013	Brazilian	Brazil	Case-control	59	26	15	100	57	30	13	100

Association of the ACE I/D gene polymorphism with renal allograft survival

In this meta-analysis, we found that the ACE D allele, DD genotype and II genotype were not associated with renal allograft survival (D allele: OR=1.06, 95% CI: 0.90–1.24, P=0.49; DD genotype: OR=1.12, 95% CI: 0.78–1.61, P=0.53; II genotype: OR=0.90, 95% CI: 0.68–1.18, P=0.45; Figure 1 and Table 2).

Figure 1.

Association of the ACE I/D gene polymorphism with renal allograft survival in overall populations.

Table 2.

Meta analysis of the association of the ACE I/D gene polymorphism with renal allograft survival.

Genetic	Group and	Studies	Q test	Model	OR	P
contrasts	subgroups	number	P value	seclected	(95% CI)
D vs I	Overall	12	0.58	Fixed	1.06 (0.90,1.24)	0.49
	Caucasian	7	0.86	Fixed	0.93 (0.74,1.18)	0.56
	Asian	2	0.31	Fixed	1.61 (1.07,2.42)	0.02
	Brazilian	2	0.99	Fixed	1.00 (0.76,1.32)	0.99
	African	1	-	Fixed	1.31 (0.68,2.53)	0.41
DD vs ID+II	Overall	12	0.04	Random	1.12 (0.78,1.61)	0.53
	Caucasian	7	0.52	Fixed	0.79 (0.55,1.14)	0.21
	Asian	2	0.97	Fixed	4.03 (1.91,8.51)	0.0003
	Brazilian	2	0.58	Fixed	0.97 (0.65,1.43)	0.87
	African	1	-	Fixed	1.05 (0.43,2.59)	0.91
II vs ID+DD	Overall	12	0.71	Fixed	0.90 (0.68,1.18)	0.45
	Caucasian	7	0.56	Fixed	0.92 (0.61,1.40)	0.71
	Asian	2	0.16	Fixed	0.92 (0.47,1.78)	0.80
	Brazilian	2	0.28	Fixed	0.88 (0.48,1.64)	0.70
	African	1	-	Fixed	0.85 (0.46,1.56)	0.59

In the Caucasian population, the D allele, DD genotype and II genotype were also not associated with renal allograft survival (D allele: OR=0.93, 95% CI: 0.74–1.18, P=0.56; DD genotype: OR=0.52, 95% CI: 0.55–1.14, P=0.21; II genotype: OR=0.56, 95% CI: 0.61–1.40, P=0.71; Table 2 and Figure 2).

Figure 2.

Association of the ACE I/D gene polymorphism with renal allograft survival in the Caucasian population.

Interestingly, the D allele, and DD genotype were found to be associated with renal allograft survival in the Asian population, but this association was not found for the II genotype (D allele: OR=1.61, 95% CI: 1.07–2.42, P=0.02; DD genotype: OR=4.03, 95% CI: 1.91–8.51, P=0.0003; II genotype: OR=0.92, 95% CI: 0.47–1.78, P=0.80; Table 2 and Figure 3).

Figure 3.

Association of the ACE I/D gene polymorphism with renal allograft survival in Asian population.

Furthermore, the D allele, DD genotype and II genotype were not associated with renal allograft survival in the Brazilian and African populations (Table 2).

Discussion

In recent decades there have been some studies reporting that the ACE I/D gene polymorphism is associated with renal allograft survival. Misra et al.²⁶ conducted a study to investigate the relationship between cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene polymorphism and renal allograft outcome, and reported that CTLA-4 variance was involved in susceptibility to acute allograft rejection. Kloda et al.²⁷ performed a study enrolling 269 Caucasian renal transplant recipients who remained under observation for 5 years, and reported that the rs5498 intercellular adhesion molecule-1 (ICAM-1) GG genotype was correlated with early and long-term allograft failure, and the C allele of the rs1041163 VCAM1 gene was associated with long-term allograft failure and graft loss, as well as increased morbidity after transplantation. Vu et al.²⁸ reported that the -1195C>T in the cyclooxygenase-2 (COX-2) promoter and allograft inflammatory factor-1 (AIF-1) could be potential predictors of allograft rejection in Hispanic kidney transplant recipients.

In this meta-analysis, we found that the ACE I/D gene polymorphism was not associated with renal allograft survival in overall populations. There were 12 included studies for this meta-analysis. There might be no association between the ACE I/D gene polymorphism and renal allograft survival in the overall population, although more eligible studies should be conducted in the future to confirm it. Furthermore, there was also no association between the ACE I/D gene polymorphism and renal allograft survival in Caucasian, Brazilian or African populations. However, the number of included studies for the Brazilian and African populations was small, and more studies should be conducted to explore this relationship. Interestingly, the ACE D allele and DD genotype were associated with renal allograft survival in the Asian population, and there was no notable heterogeneity among the included studies, and a fixed effects model was conducted to calculate the pooled OR. However, the number of included studies for the Asian population was small. More studies for the association between ACE I/D gene polymorphism and renal allograft survival in the Asian population should be performed in the future.

This meta-analysis was the first to study the relationship between the ACE I/D gene polymorphism and renal allograft survival after renal transplantation. This investigation included 12 studies using meta-analysis and reported that the ACE D allele and DD genotype might become valuable indicators to predict renal allograft survival in Asian populations. However, those results should be regarded cautiously for several reasons, for example, small sample size of the included report, heterogeneity of enrolled cases, limited statistical power, variable study designs and different interventions.

To sum up, the ACE D allele and DD genotype might become valuable indicators to predict renal allograft survival in Asian populations. However, more studies are needed to confirm this.

Footnotes

Conflict of interest

None declared.

Funding

This study was supported by the Guangzhou Medical Key Subject Construction Project (2013 -2015).

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Assessment of the relationship between ACE I/D gene polymorphism and renal allograft survival

Abstract

Background and objective:

Method:

Results:

Conclusions:

Keywords

Introduction

Materials and methods

Search strategy for the assessment of the relationship between ACE I/D gene polymorphism and renal allograft survival

Inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

Data extraction and synthesis

Statistical analysis

Results

Study characteristics

Association of the ACE I/D gene polymorphism with renal allograft survival

Discussion

Footnotes

Conflict of interest

Funding

References