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The Influence of ACE Insertion/Deletion Gene Polymorphism on the Risk of IgA Nephropathy: A Debatable Topic

Published online by Cambridge University Press:  01 January 2024

Fen-Fen Chu Open the ORCID record for Fen-Fen Chu [Opens in a new window] ,
Shi-Kun Yang Open the ORCID record for Shi-Kun Yang [Opens in a new window] ,
Wen-Li Zeng Open the ORCID record for Wen-Li Zeng [Opens in a new window]  and
Hafiz Ishfaq Ahmad
Fen-Fen Chu
Affiliation:
Department of Nephrology, The First Affiliated Hospital of the University of South China, Hengyang 421001, Hunan Province, China
Shi-Kun Yang
Affiliation:
Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
Wen-Li Zeng*
Affiliation:
Department of Nephrology, The First Affiliated Hospital of the University of South China, Hengyang 421001, Hunan Province, China
*
Correspondence should be addressed to Wen-Li Zeng; docwenlizeng@163.com
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Abstract

Background. The connection between angiotensin-converting enzyme insertion/deletion (ACE I/D) gene polymorphisms and IgA nephropathy (IgAN) was conflicting. This pooled analysis was performed to explore this issue. Methods. All eligible investigations were identified from various electronic databases, and the pooled analysis was evaluated using Stata software. Results. 27 studies with 2538 IgAN cases and 3592 controls were included. In overall subjects, ACE D allele, DD, and II genotype were associated with IgAN susceptibility (D vs. I: OR = 1.21, 95% CI: 1.10–1.32, P < 0.001; DD vs. ID + II: OR = 1.38, 95% CI: 1.20–1.60, P < 0.001; and II vs. DD + ID: OR = 0.83, 95% CI: 0.73–0.95, P = 0.007). In Asian and Chinese patients, ACE I/D gene polymorphism was also correlated with IgAN vulnerability. Moreover, ACE D allele, DD, and II genotype were correlated with the progression of IgAN (D vs. I: OR = 1.37, 95% CI: 1.09–1.73, P = 0.008; DD vs. ID + II: OR = 1.57, 95% CI: 1.06–2.31, P =0.024; and II vs. DD + ID: OR = 0.69, 95% CI: 0.49–0.99, P = 0.045). Conversely, in Caucasian subjects, there was no link between ACE I/D gene polymorphism and the risk of IgAN. Conclusion. ACE I/D gene polymorphism was correlated with the vulnerability and progression of IgAN in Asian and Chinese patients, and ACE D allele and DD homozygote genotype could be adverse factors for IgAN, while the II homozygote genotype could be an advantage factor. But, no significant association was found between ACE I/D gene polymorphism and IgAN in Caucasians.

Type
Research Article
Information
Genetics Research , Volume 2021 , 2021 , e7
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
Copyright © 2021 Fen-Fen Chu et al.

1. Introduction

IgA nephropathy (IgAN) is a common type of glomerulonephritis globally; in the Pacific Asian region, the prevalence rate of IgAN is even more high [Reference Rodrigues, Haas and Reich1]. It is a serious public health problem with very high mortality and morbidity, and recent studies have showed that approximately 20% IgAN patients would progress to end-stage renal disease (ESRD) if lacking effective treatment [Reference Soares and Roberts2]. The presence of excessive immune complexes including IgA in the glomerulus was a key mechanism of IgAN. The current therapy was mainly on corticosteroids and immunosuppressors [Reference Yeo, Cheung and Barratt3]. However, these measures were not fully effective. Recent research found that susceptibility to IgAN was influenced by a confluence of some genetic factors, and more importantly, some single-gene polymorphisms were associated with the susceptibility of IgAN [Reference Li and Yu4].

Angiotensin-converting enzyme (ACE) was a key enzyme that converted angiotensin I to angiotensin II. The ACE gene consisted of 26 exons and located on chromosome 17q23 [Reference Tikhomirova, Kost and Kryukova5]. Single-nucleotide polymorphisms (SNPs) frequently occurred in the ACE gene; in the 16th intron of the ACE gene, a 287 bp fragment recognized as insertion/deletion (I/D) polymorphism has been found, and based on this I/D polymorphic marker locus, three genotypes could be defined: DD, II homozygotes, and ID heterozygote [Reference Rigat, Hubert, Alhenc-Gelas, Cambien, Corvol and Soubrier6]. It has been found that serum ACE activity could be affected by ACE I/D gene polymorphisms, and these subjects with the D allele always have higher level of ACE activity [Reference Crisan and Carr7]. Some research studies have demonstrated that ACE I/D polymorphism would affect the vulnerability of IgAN [Reference Teranishi, Yamamoto and Nagasawa8–Reference Qin, Zhou, Su, Lei, Huang and Zhao10]. However, up to now, the role of ACE I/D polymorphism in the occurrence of IgAN is still inconsistent and controversial. So, in this study, we included much more high-quality studies to further assess the influence of ACE I/D gene polymorphism on IgAN susceptibility.

2. Methods

2.1. Study Search and Inclusion Strategy

We searched relevant studies from various electronic databases (e.g., PubMed, Scopus, and CNKI database) for eligible trials (all till Oct 2021). Multiple search keywords were used: IgA nephropathy, renal disease, kidney, nephropathy, ACE, ACE I/D, angiotensin-converting enzyme, insertion/deletion, gene, and gene polymorphism. The inclusion criteria of this study included the following: (1) the study included two comparison groups (IgA patients vs. control subjects or progression IgA patients vs. nonprogression IgA patients). (2) The number of ACE I/D genotypes could to be calculated. (3) The genotype distributions in control group was in accordance with Hardy–Weinberg Equilibrium (HWE).

2.2. Data Analysis

In this study, we used the Stata software to perform this pooled analysis. An odds ratio (OR) was calculated to evaluate the influence of ACE I/D gene polymorphism on IgAN susceptibility, and four different genetic models were used: model 1, allele D vs. allele I; model 2, genotype DD vs. genotype ID + II; model 3, genotype II vs. genotype DD + ID; and model 4, genotype ID vs. genotype DD + II. When a P value was less than 0.05, it was considered as statistically significant for the pooled OR. The heterogeneity among various included studies was evaluated using a Q test. Additionally, Begg’ s test was completed to evaluate the publication bias; when the P value of Begg’ s test was less than 0.05, potential publication bias was most likely to exist [Reference Begg and Mazumdar11].

3. Results

3.1. Characteristics of the Included Studies

As shown in Table 1, 27 studies were finally included in our study [Reference Pawlik, Mostowska, Lianeri, Oko and Jagodziński9,Reference Harden, Rowe and Rodger12–Reference Zheng, Zhang and Li37], but 2 trials were excluded due to the fail to meet the HWE [Reference Liu, Chen and Ding32,Reference Xu, Lv and Shao35]. The main features of the included trials are described in Table 1. 6130 participants with 2538 cases and 3592 controls were included, and 9 of the studies were written in Chinese and 18 in English, from a total of 11 countries. The average age of participants ranged from 6 to 83 years. Additionally, the number of various genotypes were extracted and shown in Table 1.

Table 1 Characteristics of studies included in the meta-analysis.

Note. P: IgA nephropathy subjects; C: control subjects; HB, hospital based; PB: population based; NR: not reported; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism. #Progression of IgAN; ∗nonprogression of IgAN.

3.2. The Link between ACE I/D Gene Polymorphism and IgAN Risk

The influence of ACE I/D gene polymorphism on IgAN risk was reported in 21 trials [Reference Pawlik, Mostowska, Lianeri, Oko and Jagodziński9,Reference Harden, Rowe and Rodger12,Reference Huang, Lin, Li, Wang and Jiang13,Reference Lau, Woo and Choong15,Reference Stratta, Canavese and Ciccone23,Reference Tanaka, Iijima, Murakami, Koide, Nakamura and Yoshikawa26,Reference Yoshida, Mitarai and Kawamura28,Reference Li, Zhang and Kang30,Reference Liao, Li and Guo31,Reference Liu, Chen and Hu33,Reference Song, Xu and Zhao34,Reference You, Yang and Lin36,Reference Zheng, Zhang and Li37]. Our pooled analysis showed that ACE I/D gene polymorphism was associated with IgAN risk in the general populations (allele D vs. allele I: OR = 1.21, 95% CI: 1.10–1.32, P < 0.001, Figure 1; genotype DD vs. genotype ID + II: OR = 1.38, 95% CI: 1.20–1.60, P < 0.001, Figure 2; and genotype II vs. genotype DD + ID: OR = 0.83, 95% CI: 0.73–0.95, P = 0.007, Figure 3 and Table 2).

Figure 1 Forest plot of ACE I/D gene polymorphism linked with IgAN susceptibility (D allele vs. I allele). Pooled analysis indicated that the ACE gene locus D allele was a risk factor of IgAN in the overall and Asian subjects.

Figure 2 Forest plot about the link between ACE I/D gene polymorphism and IgAN risk (genotype DD vs. genotype ID + II). It showed that the ACE gene locus DD genotype was a risk factor of IgAN in the overall and Asian patients.

Figure 3 Forest plot about the link between ACE I/D gene polymorphism and IgAN risk (II genotype vs. DD + ID genotype). Evaluates of pooled OR for IgAN showed that the ACE gene locus II genotype was a protective factor of IgAN in the overall and Asian populations.

Table 2 Meta-analysis of the link between ACE gene locus I/D polymorphisms and the susceptibility and progression of IgAN.

In the Asian patients, we also found a clear correlation between allele D/genotype DD and IgAN susceptibility (allele D vs. allele I: OR = 1.38, 95% CI: 1.22–1.55, P < 0.001, Figure 1; genotype DD vs. genotype ID + II: OR = 1.91, 95% CI: 1.50–2.44, P < 0.001, Figure 2). Conversely, our analysis indicated that the ACE II genotype was a protecting factor against IgAN (genotype II vs. genotype DD + ID: OR = 0.74, 95% CI: 0.63–0.88, P < 0.001, Figure 3 and Table 2).

In Caucasian subjects, the pooled analysis including 8 trials showed that there was no obvious link between ACE I/D gene polymorphism and IgAN risk (allele D vs. allele I: OR = 1.06, 95% CI: 0.94–1.19, P = 0.369, Figure 1; genotype DD vs. genotype ID + II: OR = 1.15, 95% CI: 0.96–1.37, P = 0.137, Figure 2; genotype II vs. genotype DD + ID: OR = 1.02, 95% CI: 0.82–1.26, P = 0.865, Figure 3; and genotype ID vs. genotype DD + II: OR = 0.88, 95% CI: 0.74–1.04, P = 0.125, Figure 4, Table 2).

Figure 4 Forest plot about the link between ACE I/D gene polymorphism and IgAN susceptibility (genotype ID vs. genotype DD + II). Evaluates of pooled OR for IgAN showed that the ACE gene locus ID genotype was not associated with IgAN.

In this study, 8 trials reported the influence of ACE I/D gene polymorphism on IgAN vulnerability in Chinese patients. In line with Asian subjects, the pooled analysis indicated that allele D and genotype DD were risk factors for IgAN (allele D vs. allele I: OR = 1.41, 95% CI: 1.21–1.64, P < 0.001, Figure 1; genotype DD vs. genotype ID + II: OR = 1.89, 95% CI: 1.41–2.55, P < 0.001, Figure 2). Conversely, the ACE II genotype was an advantage factor for IgAN patients (genotype II vs. genotype DD + ID: OR = 0.71, 95% CI: 0.58–0.88, P = 0.001, Figure 3 and Table 2).

3.3. The Link between ACE I/D Gene Polymorphism and IgAN Progression

There were 6 studies evaluating the influence of ACE I/D gene polymorphism on the progression of IgAN [Reference Hunley, Julian and Phillips14,Reference Stratta, Canavese and Ciccone23,Reference Syrjänen, Huang, Mustonen, Koivula, Lehtimäki and Pasternack25,Reference Yoshida, Mitarai and Kawamura28,Reference Hu, Liu and Tang29], and the pooled analysis found that ACE I/D gene polymorphism was associated with IgAN progression (allele D vs. allele I: OR = 1.37, 95% CI: 1.09–1.73, P = 0.008; genotype DD vs. genotype ID + II: OR = 1.57, 95% CI: 1.06–2.31, P = 0.024; and genotype II vs. genotype DD + ID: OR = 0.69, 95% CI: 0.49–0.99, P = 0.045, Table 2).

3.4. Publication Bias

The publication bias has been assessed using Begg’ s test and Funnel plots. Potential publication bias was found in the analysis for the link of genotype DD with IgAN risk (DD vs. ID + II genotype: Begg’ s P = 0.044). Additionally, the funnel plot was asymmetrical (Table 2 and Figure 5).

Figure 5 The funnel plots of different pooled analysis models. (a) Allele D vs. allele I; (b) genotype DD vs. genotype ID + II; (c) genotype II vs. genotype DD + ID; and (d) genotype ID vs. genotype DD + II.

4. Discussion

Our study demonstrated that the ACE I/D polymorphism was associated with the susceptibility and progression of IgAN. Specifically, it showed that the ACE I/D gene D allele and DD genotype were risk factors for IgAN, while the II genotype was an advantageous factor for IgAN.

This study was not the first pooled analysis to explore the relationship between ACE I/D polymorphism and IgAN; a small amount of previous meta-analysis about this controversial issue has been performed. In 2001 and 2006, two meta-analyses including only 5 reports have been completed [Reference Schena, D'Altri, Cerullo, Manno and Gesualdo38,Reference Wiwanitkit39]; these two research studies found that the association between the genetic susceptibility of IgAN and ACE I/D gene polymorphism was not significant. However, another pooled analysis performed by Yong showed that the ACE I/D polymorphism DD genotype was associated with IgAN progression both in Asian and Caucasians patients and the DD genotype was associated with IgAN risk in Asians [Reference Yong, Qing and Hua40]. As the number of included studies in these pooled analyses was small, in order to gain a more credible result, we reexamined the related trials and included 21 studies. We found that the allele D and genotype DD were correlated with IgAN risk and progression only in Asian patients. Similarly, Qin et al. found that the allele D and genotype DD were associated with IgAN susceptibility only in Asians, but there was no significant association between the allele D or genotype DD and the progression of IgAN [Reference Qin, Zhou, Su, Lei, Huang and Zhao10]. Due to the fact that we included much more trials in our analysis compared to the previous research, we believed that our findings were more credible.

IgAN is a common type of glomerulonephritis globally, and it is a major cause of chronic renal failure among East Asian countries. The pathogenesis of IgAN is extremely complex, and immunological renal injury mediated by IgA is traditionally associated with IgAN [Reference Rodrigues, Haas and Reich1,Reference Soares and Roberts2]. It has been demonstrated that IgA immune complexes depositing in the glomerular mesangium could activate inflammatory response, profibrotic cell proliferation, and even the formation of a glomerular crescent [Reference Yeo, Cheung and Barratt3]. But, more and more research suggested that renin-angiotensin-aldosterone system (RAAS) activation played a vital role in the development and occurrence of IgAN. Angiotensin II (AT II) was a pivotal factor of RAAS, and growing evidence indicated that AT II was a potential proinflammatory mediator associated with the renal tubule interstitial fibrosis [Reference Wolf41]. The activation of AT II resulted in the production of various inflammatory cytokines, such as TNF-a, IL-6, IL-8, and TGF-β [Reference Niimi, Nakamura and Yanagawa42]. Consequently, these cytokines could greatly promote the occurrence and development of IgAN.

Recently, the researchers found that IgAN was also influenced by a confluence of environmental and genetic factors. Familial aggregation of IgAN indicated that genetic factor might participate in the pathogenesis of IgN [Reference Scolari, Amoroso and Savoldi43]. With the technological development of genetic studies, especially the Genome Wide Association Study widely used, several SNPs within immune- or hypertension-related genes have been found significantly associated with IgAN. ACE was a pivotal factor of RAAS, the ACE gene contained 26 exons and 25 introns locating on 17q23 [Reference Rigat, Hubert, Alhenc-Gelas, Cambien, Corvol and Soubrier6], and some polymorphic genetic markers of ACE gene have been found. Among these polymorphic markers, insertion or deletion (I/D) polymorphism (rs4340) of a 287 bp Alu in the 16th intron was the most investigated [Reference Rigat, Hubert, Alhenc-Gelas, Cambien, Corvol and Soubrier6]. As mentioned earlier, there was a close relationship between the occurrence of IgAN and RAAS activation, and ACE played a vital role in the activation of angiotensin II. It was worth noting that the ACE level was strongly linked with ACE I/D polymorphism, and in those patients with the ACE DD genotype, the level of ACE expression and activity both in renal tissue and in serum were all markedly increased [Reference Mizuiri, Hemmi and Kumanomidou44,Reference Zeng, Yang, Song and Chu45]. The insertion or deletion of base in the ACE gene might alter the expression or stabilization of ACE via influencing the stability of ACE mRNA. Thus, it could be seen that ACE D allele carriers had higher ACE level and consequently possessed higher risk to IgAN vulnerability.

In this study, the pooled analysis results indicated that the relationship between I/D polymorphism of ACE gene locus and IgAN risk was inconsistent in different races.

In Asian and Chinese patients, we found that the genotype DD, II, and allele D were associated with the vulnerability and progression of IgAN, but there was no evident correlation in Caucasian patients. This might be due to the differences in the environment and genetic backgrounds. Also, ACE inhibitors could affect the analysis results, while some studies in Chinese subjects did not clearly state whether to exclude those patients using ACE inhibitors. In short, the understanding about the ACE I/D genetic susceptibility difference was acquainted scarcely, and future research is needed to explore the specific mechanisms.

Some potential limitations should be discussed in our study. Firstly, the sample sizes in some included trials were small. Secondly, public bias was existed in this meta-analysis. Third, the included trials were from various countries, but the trials were published only in English and Chinese, which would result in reporting bias. Fourth, some included studies did not clearly state whether to exclude those subjects using ACE inhibitors. Finally, our study was mainly focused on ACE I/D genetic alteration, and the relationship between many other genes SNPs and IgAN susceptibility needed to be further explored.

5. Conclusions

Our pooled analysis supported that ACE gene locus I/D polymorphisms were linked with the susceptibility and progression of IgAN in Asian and Chinese individuals. ACE gene locus allele D and genotype DD could be risk factors of IgAN vulnerability. Conversely, those subjects carrying the ACE II genotype would reduce the risk of IgAN susceptibility. However, no obviously correlation was found between ACE I/D gene polymorphism and IgAN in Caucasian patients. In future studies, much more high-quality trials are required to clarify it.

Abbreviations

  • SNPs: Single-nucleotide polymorphisms

  • HWE: Hardy–Weinberg equilibrium

  • OR: Odds ratio

  • CIs: Confidence intervals

Data Availability

The data used to support the findings of this study are available from the first author and corresponding author upon request. Since this is a pooled analysis, data from previous published studies were used.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Shi-kun Yang and Fen-fen Chu analyzed the data for the manuscript and wrote the manuscript. Shi-kun Yang, Fen-fen Chu, and Wen-li Zeng performed the literature search. Wen-li Zeng and Shi-kun Yang edited the manuscript.

Acknowledgments

This study was supported by the Science and Technology Planning Project of Hengyang City (2019jh011012), the Hunan Provincial Health Commission Project (202103050178), and the Hunan Provincial Clinical Medical Technology Innovation Guide Project (2020SK53601).

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Figure 0

Table 1 Characteristics of studies included in the meta-analysis.

Figure 1

Figure 1 Forest plot of ACE I/D gene polymorphism linked with IgAN susceptibility (D allele vs. I allele). Pooled analysis indicated that the ACE gene locus D allele was a risk factor of IgAN in the overall and Asian subjects.

Figure 2

Figure 2 Forest plot about the link between ACE I/D gene polymorphism and IgAN risk (genotype DD vs. genotype ID + II). It showed that the ACE gene locus DD genotype was a risk factor of IgAN in the overall and Asian patients.

Figure 3

Figure 3 Forest plot about the link between ACE I/D gene polymorphism and IgAN risk (II genotype vs. DD + ID genotype). Evaluates of pooled OR for IgAN showed that the ACE gene locus II genotype was a protective factor of IgAN in the overall and Asian populations.

Figure 4

Table 2 Meta-analysis of the link between ACE gene locus I/D polymorphisms and the susceptibility and progression of IgAN.

Figure 5

Figure 4 Forest plot about the link between ACE I/D gene polymorphism and IgAN susceptibility (genotype ID vs. genotype DD + II). Evaluates of pooled OR for IgAN showed that the ACE gene locus ID genotype was not associated with IgAN.

Figure 6

Figure 5 The funnel plots of different pooled analysis models. (a) Allele D vs. allele I; (b) genotype DD vs. genotype ID + II; (c) genotype II vs. genotype DD + ID; and (d) genotype ID vs. genotype DD + II.