Association between Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Prognosis of Kidney Transplantation: A Meta-Analysis
Association between Angiotensin I- Converting Enzyme Insertion/Deletion Polymorphism and Prognosis of Kidney Transplantation: A Meta-Analysis
Zhengkai Huang 0 1 2
Bian Wu 0 1 2
Jun Tao 0 1 2
Zhijian Han 0 1 2
Xiao Yang 0 1 2
Lei Zhang 0 1 2
Xuzhong Liu 0 1 2
Zijie Wang 0 1 2
Ruoyun Tan 0 1 2
Min Gu 0 1 2
Changjun Yin 0 1 2
0 Funding: This project was sponsored by the grants from the National Natural Science Foundation of China (81100532;81470981), the Science and Education Health Project of Jiangsu Province for important talent (RC2011055), 333 high level talents project in Jiangsu province (2011 and 2013), Jiangsu province six talents peak from Department of human resources, social security office of Jiangsu Province of China (2010WSN-56 and 2011-WS-033), General program of Department of Health of Jiangsu Province
1 Academic Editor: Michael Bader, Max-Delbruck Center for Molecular Medicine (MDC) , GERMANY
2 Department of Urology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, 210029 , China
ACE I/D polymorphism was found to be associated with acute rejection (AR) in genotypes
DD+ID versus II (OR = 1.62, 95% CI = 1.142.29) and with serum creatinine concentration
after renal transplantation in genotypes DD versus ID (WMD = 13.12, 95% CI = 8.09
18.16). Stratified analysis revealed that recipients transplanted within a year had higher
serum creatinine concentrations in the DD versus ID model. No significant association was
found between hypertension and ACE I/D polymorphism.
ACE I/D polymorphism is associated with AR and allograft function after kidney transplantation.
of China (H2009907), and the Priority Academic
Program Development of Jiangsu Higher Education
Institutions (JX10231801). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
Renal transplantation is considered the best therapeutic approach for patients with end-stage
renal disease because it significantly improves the quality of life of patients . Graft function
is influenced by various immunologic and non-immunologic factors, such as primary disease,
immunosuppressive regimen, metabolic and cardiovascular conditions, episodes of acute
rejection (AR) or chronic rejection (CR), and donor and recipient ages [2, 3]. Genetic factors play
important roles in allografts by affecting blood pressure regulation, vascular proliferation and
inflammatory responses, such as thrombosis, fibrosis or chemotaxis . Under the same
environment, recipients with different genotypes in a specific gene usually have different
outcomes after transplantation. Based on data from the large number of kidney transplantations
performed worldwide and data on long-term survival after the operation, researchers have
established several associations between specific genotypes and graft outcome.
The reninangiotensinaldosterone system (RAS), which regulates homeostasis, vascular
tone, blood pressure and salt balance, plays important roles in renal and cardiovascular
physiologies . Angiotensin I-converting enzyme (ACE) is the key enzyme that influences RAS
activity by converting angiotensin I into vasoactive and aldosterone-stimulating peptide
angiotensin II . Poor renal transplant function and low survival of renal allografts are associated
with RAS over-activation [5, 12]. Thus, ACE is likely to be an important determinant of
prognosis after kidney transplantation.
The gene encoding ACE is located in chromosome 17, and individual patients may exhibit
presence (I allele, insertion) or absence (D allele, deletion) of a 287-base pair Alu repeat
sequence in intron 16 of this gene . Thus, patients can be of three genotypes with regard to
ACE, namely, II, ID and DD. Homozygotes of the D allele express higher levels of ACE
compared with the other genotypes .
Many studies have investigated the association between ACE I/D polymorphism and renal
transplantation, but their results are inconsistent. Considering the decentralised nature of
patient data and inconsistent conclusions amongst the reported articles, it has been extremely
difficult to assess the validity of the proposed theories of associations. Furthermore, a thorough
study of the prognostic aspect of kidney transplantation and ACE I/D polymorphism remains
lacking to date. In this study, we performed a meta-analysis to investigate whether ACE allele
genotype has any influence on the prognosis of kidney transplantation.
Materials and Methods
To obtain relevant literature, a systematic search was performed using the PubMed and
Embase (1966 to March 2014) databases with the following keywords: (ACE or angiotensin
converting enzyme), (polymorphism), (insertion/deletion, deletion/insertion, I/D or D/
I), (transplant or transplantation), (allograft) and (kidney or renal). Only articles written
in English were included in the search. All eligible publications on the association between
kidney transplantation and ACE I/D polymorphisms were searched. The references listed in the
articles found were used as sources of supplementary information. Fig 1 shows the flow
diagram depicting the overall strategy for inclusion of published literature in this study.
Inclusion and Exclusion Criteria
All eligible studies on the association between ACE I/D polymorphisms and kidney
transplantation were considered for inclusion using the following criteria: (1) studies must be published
in English; (2) studies must be a casecontrol or cohort study of renal transplant recipients;
and (3) studies should have provided data on the ACE genotypes II, ID and DD. In particular,
detailed numbers of genotypes must have been provided to calculate the odds ratio (OR) or
weighted mean difference (WMD) and the corresponding 95% confidence intervals (95% CIs).
The exclusion criteria were as follows: (1) studies not evaluating the correlation between ACE
I/D polymorphism and kidney transplantation; (2) animal or cellular studies; (3) reviews,
comments, meta-analysis or abstracts; (4) studies that lack a control group; and (5) paediatric
studies. For studies with overlapping case series, the largest sample sizes were considered.
Information from the publications that met the above criteria was carefully extracted by two
independent investigators (Zhengkai Huang and Bian Wu). A third investigator (Jun Tao)
subsequently reviewed the results. Discussions were personally conducted to reach a consensus in
case of a disagreement. The following items were extracted from each article: first authors
name, publication year, ethnicity, genotyping method, source of controls, numbers of case and
control patients in each genotype, time points, prognostic indicator and HardyWeinberg
equilibrium (HWE) of genotype distribution. Ethnicity was categorised according to research
area. When the data were not directly provided, we calculated the number based on its
percentage and total amount presented by the articles. Only information from one replicate randomly
selected among repeated measurements was used. In addition, serum creatinine level and
blood pressure were converted to identical units of measurement for ease of comparison.
Pooled OR or WMD and the corresponding 95% CIs were calculated to estimate the strength
of association between ACE I/D polymorphism and prognosis of kidney transplantation. A
random- or fixed-effects model of rejection events, serum creatinine concentrations and
hypertension was used in this meta-analysis. ORs were accurately measured for DD versus ID+II,
DD+ID versus II, DD versus II, ID versus II and D allele versus I allele. Meanwhile, WMDs
were determined for DD versus II, DD versus ID and ID versus II. In addition, subgroup
stratification analyses were performed according to ethnicity or time points after transplantation to
explore the association of ACE I/D polymorphism with transplantation outcomes.
Q and I2 statistic tests were used to evaluate heterogeneity. I2 > 50% indicates heterogeneity
. When I2 > 50%, the random-effects model was used; otherwise, the fixed-effects model
was utilised. The allele frequencies of the ACE I/D polymorphism from each included article
were determined through allele counting. Furthermore, HWE was examined using Chi-square
tests. To evaluate publication bias, Beggs test and funnel plot were used [16, 17]. In addition,
sensitivity analysis of the positive results was performed. All statistical analyses were performed
using STATA 10.0 software (StataCorp, College Station, TX, USA).
Using the search strategies mentioned above, 83 articles were initially identified. Of these, 40
articles were selected for full-text review and 43 were excluded according to the
inclusion/exclusion criteria. A total of 27 of the 40 articles were excluded after full-text review because of
paediatric recipients or unavailable information. The total baseline characteristics of the
included studies are shown in Tables 1 and 2. All included articles were published from 1997 to
2013. Three studies investigated CR [1, 18, 19], whereas eight studies focused on AR [1, 18
24]. Ten studies from five publications included serum creatinine concentration [1, 1921, 25].
SC Time Points
1997 Caucasian PCR-RFLP
2013 Caucasian PCR-RFLP
HB: Hospital-based Study; SC: source of controls; HWE: Hardy Weinberg Equilibrium; CR: Chronic rejection; AR: Acute rejection episodes. Case group:
patients occurred acute rejection or chronic rejection or hypertension; Control group: not occurred acute rejection or chronic rejection or hypertension.
* term Brazilian represented Brazilian population.
Ten studies from eight publications considered hypertension [18, 19, 21, 24, 2629]. The
genotype and allele distributions of the included studies about rejections and hypertension are
presented in Table 1. Meanwhile, the genotypes and serum creatinine levels of the included studies
are shown in Table 2. The results of HWE test for ACE I/D genotype distribution in the control
population are also presented in Table 1. Only one of the included studies was not under HWE
Genotype and Rejection Episodes
In this meta-analysis, a significant association was detected between ACE I/D polymorphism
and AR. The genotype model DD+ID versus II (dominant model) showed a significant
difference in AR (OR = 1.62, 95% CI = 1.142.29, fixed-effects model). However, the other genotypes
91 170.0 85.0 187 158.0
59.0 89 171.0
HB: Hospital-based Study; SC: source of controls.
* term Brazilian represented Brazilian population.
20 184.8 65.4 38
20 192.7 83.1 38
35 123.8 26.5 92
35 123.8 26.5 92
35 123.8 26.5 92
113.2 22.1 35 123.8 25.6
185.7 132.6 88 203.3 123.8
42.4 36 160.9
63.7 36 160.0
44.2 88 150.3
35.4 88 141.5
35.4 88 141.5
did not show any association: DD versus II, OR = 2.11, 95% CI = 0.914.00; ID versus II,
OR = 1.39, 95% CI = 0.962.02; DD versus ID+II (recessive model), OR = 1.52, 95% CI = 0.86
2.70; D allele versus I allele, OR = 1.50, 95% CI = 0.922.45 (Table 3, Fig 2). In addition, no
significant association between ACE I/D polymorphisms and CR was found amongst the five
genetic models. When these rejection episodes were compared, no difference was observed
amongst the five genetic models (Table 3). Subgroup analysis revealed high rejection risk
among Brazilian population with the D allele genotype, but not among Caucasians (Table 3).
Genotype and Serum Creatinine
Ten studies measured serum creatinine in the three ACE I/D genotypes after renal
transplantation. Regardless of the time points after transplantation, a significant difference in serum
creatinine level was found in the DD versus ID model (WMD = 13.12, 95% CI = 8.0918.16).
However, this was not found in the DD versus II and ID versus II models (WMD = 9.18, 95%
CI = 3.5121.87 and WMD = 1.93, 95% CI = 11.757.89, respectively; Table 4, Fig 2).
Stratified analysis between polymorphisms and time points after transplantation was performed on
the above models. A significant difference in the same model was detected only in the group
that had undergone transplantation for less than a year (DD versus ID), WMD = 14.81, 95%
CI = 7.5822.05. Furthermore, subgroup analyses revealed the II and DD genotypes to be risk
factors among Caucasians and Brazilian population, respectively (Table 4).
Genotype and Blood Pressure
The results obtained from the meta-analysis of ACE I/D polymorphism and blood pressure are
summarised in Table 5. However, the overall and stratified analyses showed no statistical
DD+ID vs. II (dominant)
DD vs. ID+II (recessive)
D allele vs. I allele
a Random effects estimate
* term Brazilian represented Brazilian population.
difference among the five genetic models. The ethnicity and time points after renal
transplantation were considered in the stratified analyses.
Sensitivity analysis of the positive results was performed to determine the influence of each
study on the pooled ORs or WMDs by sequentially removing one study. No significant change
was found, indicating that the results were reliable (Fig 3).
Publication bias was evaluated using Beggs test and funnel plot. The results of the funnel plot
analyses of groups AR and serum creatinine are shown in Fig 4 (group AR: DD+ID versus II,
P = 0.521; group serum creatinine: DD versus ID, P = 0.073).
Over the last two decades, many studies have investigated the relationship between ACE I/D
gene polymorphism and kidney transplantation to determine if gene polymorphisms have any
influence over patient survival after transplantation. However, the results of these studies have
been inconclusive. Therefore, we performed a meta-analysis to examine the association
between ACE I/D polymorphism and renal transplantation based on clinical data from published
In this study, 21 casecontrol studies with 1497 cases and 2029 controls were included. An
additional ten studies that contained quantitative data on 814 patients were also included. The
results provided strong evidence that ACE I/D polymorphism is associated with patient
prognosis after kidney transplantation. This association is mainly evidenced in AR episodes and
serum creatinine level. However, no objective evidence demonstrated that hypertension after
transplantation is associated with ACE I/D polymorphism.
The DD+ID genotypes were risk factors for the occurrence of AR in the overall study
population. Compared with patients carrying the II genotype, patients carrying the D allele showed
higher risk for AR occurrence despite the lack of statistically significant differences. This result
suggests that the D allele is a risk gene for AR. Considering that AR is an independent risk
factor for graft loss , we can infer that recipients who carry DD+ID genes can incur graft loss
in a short time. This phenomenon may be explained by the D allele increasing levels of ACE
Fig 2. Forest plot of AR and serum creatinine concentration. (A) Forest plot of AR associated with ACE I/D polymorphism (for DD+ID versus II) among all
studies. OR = 1.62, 95% CI = 1.142.29, I2 = 31.6, fixed-effects model. (B) Forest plot of serum creatinine concentration associated with ACE I/D
polymorphism (for DD versus ID) among all included studies. WMD = 13.12, 95% CI = 8.0918.16, I2 = 0.8, fixed-effects model. AR: acute rejection; OR:
odds ratio; WMD: weighted mean difference.
with enhanced conversion of angiotensin I to II . Angiotensin II, the major effector of RAS,
can participate in immunologically induced inflammation via nuclear factor-kappaB and
upregulate TNF- as well as pro-inflammatory mediators such as IL-6 and MCP-1 [31, 32]. TNF-
plays an important role in allograft AR by inducing the expression of histocompatibility
antigens and by affecting the polarization of T cells towards Th1 profile . As a consequence,
recipients carrying the D allele have a higher chance of AR. A similar trend was found for CR but
the results were not statistically significant, which may be attributed to small sample size.
Stratified analysis revealed that Brazilian population have significantly higher risk for rejection
among the five genetic models compared with Caucasians. This result indicates that population
has significant influence on rejection.
Recipients with the DD genotype had extremely higher serum creatinine concentrations
than those with the ID genotype. Furthermore, stratified analysis showed statistically
significant differences between DD and ID genotype patients who had undergone transplantation
less than a year. The results revealed that short-time graft function had larger contribution to
this variance than long-time graft function. Despite the lack of significant difference between
the DD versus II and ID versus II models, the DD genotype had higher serum creatinine level
than the II and ID genotypes after kidney transplantation. Furthermore, different results were
obtained in ethnic subgroup analyses for the three models, probably suggesting that ethnicity is
an important influencing factor for allograft function. Several studies have reported that
recipients with the DD genotype possess deteriorated renal transplant function or high chronic
allograft dysfunction [3, 19, 22]. Fedor et al.  suggested that patients carrying the DD genotype
are at high risk for developing chronic allograft nephropathy. This result can be attributed to
the higher serum ACE concentration or serum ACE activity in patients carrying the DD
genotype than in those carrying the other genotypes . The high levels of ACE stimulating
angiotensin II conversion  can also induce the production of angiotensin II-induced
transforming growth factor- (TGF-). TGF- expression may lead to the development of
glomerulosclerosis and renal fibrosis . In addition, angiotensin II exerts immunoregulatory
DD versus ID
WMD (95% CI)
WMD (95% CI)
WMD (95% CI)
a Random effects estimate
* term Brazilian represented Brazilian population.
a Random effects estimate
DD+ID vs. II
DD vs. ID+II
D allele vs. I allele
effects, including leukocyte adhesion and chemotaxis . These phenomena likely account
for the poor graft function observed among DD genotype recipients. This suggests that when
high serum creatinine concentrations are observed, early identification of the DD genotype
must be achieved to focus on allograft functions of patients.
Cardiovascular complications are major obstacles in increasing survival after renal
transplantation . Hypertension, a common cardiovascular complication, can cause allograft
dysfunction, organ damage and even death . The level of blood pressure under different
genetic models was analysed by comparing the number of patients with hypertension among
the study groups. However, no statistically significant difference was found. This result
suggested that ACE I/D polymorphism may not have any influence on hypertension among
In a genome-wide association study (GWAS), O'Brien, RP. et al.  examined long-term
graft survival and allograft function in kidney transplant recipients. They identified two
variants showing borderline genome-wide significance. Akcay et al.  have reported that ACE I/
D polymorphism is also associated with outcome of allograft function after kidney
transplantation. Unlike O'Briens study, our study focused only on ACE I/D polymorphisms reported in
the literature. Besides, in addition to measuring serum creatinine levels, we also examined two
other parameters, namely rejection and hypertension. Several limitations of the current study
should be noted in interpreting our results. First, original data on the ACE genotypes are
lacking. Therefore, existing data were used to analyse the influence of gene polymorphisms.
Second, this study was restricted to Caucasian, Asian and Brazilian populations, with Caucasians
comprising the majority sub-population. Third, eligible information was extracted from
tabular data rather than individual data of every recipient, which may have contributed to inflation
of standard errors in the pooled analyses. Lastly, genotype distribution among the controls did
not show complete agreement with HWE. However, the only disagreement could be attributed
to Chinese subjects included in the study.
In conclusion, ACE I/D polymorphism is associated with AR and allograft function after
kidney transplantation. Early identification of ACE I/D genotype can significantly improve the
Fig 3. Influential analysis. (A) Influence of each study in the DD+ID versus II model on summary OR. No significant difference was found. (B) Influence of
each study in the DD versus ID model on the summary WMD. No significant difference was found.
outcome of patients. Well-designed and large-scale studies are necessary to further verify the
S2 Checklist. Meta-analysis on genetic association studies checklist.
Conceived and designed the experiments: RT MG. Performed the experiments: Z. Huang BW.
Analyzed the data: Z. Huang BW JT. Contributed reagents/materials/analysis tools: Z. Han XY
LZ. Wrote the paper: Z. Huang. Checked and polished the article: XL ZW CY.
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