Angiotensin-Converting Enzyme Gene Polymorphism Is Correlated to the Progression of Disease in Patients with IgA Nephropathy: A Metaanalysis

Abstract

Angiotensin-converting enzyme (ACE) displays potent vasoconstrictive effects, attenuation of fibrinolysis, and platelet activation and aggregation. Recently it was mentioned that the insertion/deletion polymorphism of the ACE gene is associated with ESRD. The lengthy course of IgA Nephropathy (IgAN) and the possibility of good outcomes without therapy suggest nontoxic therapies such as ACE inhibitors and angiotensin receptor blockers (ARBs). However, the correlation between the ACE gene polymorphism and progression of IgAN still requires further approval. Here, the author performs a summative analysis on the recent previous reports on the ACE gene polymorphism and its correlation to progression of IgAN. The meta-analysis was performed to assess the correlation between the pattern of ACE gene polymorphism and progression of IgAN. From five available studies, 346 and 555 patients with (group 1) and without (group 2) the progression of disease are evaluated. According to this study, the frequency of DD genotype in group 1 is significant higher than group 2 (p < 0.05). In addition, the author first reports a non-significant correlation between the ethnicity and the ACE gene polymorphism.

Keywords:

• angiotensin-converting enzyme
• polymorphism
• IgA nephropathy
• progression

INTRODUCTION

Angiotensin-converting enzyme (ACE) displays potent vasoconstrictive effects, the attenuation of fibrinolysis, and platelet activation and aggregation, thus possibly promoting thromboembolism (VTE).[1] The ACE gene plays an important role in the regulation of ACE.[1] Because the renin/angiotensin system affects hemostasis through different mechanisms, data on the possible role of angiotensin-converting enzyme I/D polymorphism in the pathogenesis of thrombosis are interesting.[1]

IgA nephropathy (IgAN) is initiated by the glomerular deposition of polymeric IgA1(pIgA1).[2] In IgAN, pIgA production is reduced in the mucosal immune system, perhaps mediated by a mucosal gamma delta T-cell defect, and mucosal IgA responses to immunization are impaired.[2] The lengthy course of IgAN and the possibility of good outcomes without therapy suggest nontoxic therapies, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).[3] However, the correlation between the ACE gene polymorphism and progression of IgAN required further exploration. In this study, a summative analysis is performed on recent previous reports of the ACE gene polymorphism and its correlation to progression of IgAN.

MATERIALS AND METHODS

Data Mining

The author performed a literature review on the reports concerning the ACE gene polymorphism in the patients with IgAN using PubMed (http://www.pubmed.com) as a search engine. Only the studies with complete data on comparison of frequency of ACE gene polymorphism between IgAN patients with (group 1) and without (group 2) the progression of diseases (declining or unstable renal function) were selected. The reports with incomplete data were not included. The frequency of ACE gene polymorphism reported from all detected reports were recorded and used as primary data for further analysis.

Assessment for the Correlation between the ACE Gene Polymorphism and ESRD

The frequencies from all reports were analyzed using a meta-analytic method. Briefly, overall frequency in groups 1 and 2 were calculated by pooled descriptive statistic method. Comparison of overall frequency between both groups was performed using proportional T-test. The correlation between the ethnic group population and frequency was also assessed using the regression analysis. A p value equal to or less than 0.05 was accepted as the statistical significant level. The SPSS for Windows (SPSS, Inc., Chicago, Illinois, USA) was used for statistical analysis.

RESULTS

Five available reports with complete data comparing the frequency of ACE gene polymorphism between groups 1 and 2 [4–8] were selected for further analysis in this study. The quoted ACE gene polymorphism pattern is shown in Table 1. From those five studies, the frequency for DD, ID, and II genotype for groups 1 and 2 are 24.1%, 43.2%, and 32.7%; and 20.4%, 41.8% and 37.8%, respectively. The frequency of DD genotype in group 1 is significant higher than group 2 (p < 0.05).

Table 1 Reports on the frequency of ACE gene polymorphism in groups 1 and 2

	Subjects			Frequency of ACE gene polymorphism (%)
		Number		Group 1			Group 2
Author	Country	Group 1	Group 2	DD	ID	II	DD	ID	II
Yoshida et al., 1995[4]	Japan^†	28	25	42.9	28.6	28.5	12.0	44.0	44.0
Hunley et al., 1996[5]	USA	40	24	20.0	60.0	20.0	4.2	58.3	37.5
Ong-Ajyooth et al., 1999[6]	Thailand^†	40	13	8.0	47.0	45.0	6.0	49.0	45.0
Sukuki et al., 2000[7]	Japan^†	156	371	14.3	44.7	41.0	17.9	40.4	41.7
Schmidt et al., 1995[8]	Germany	82	122	46.3	35.4	18.3	34.4	41.8	23.8

*Caucasian, ^†Mongolian.

Concerning ACE gene polymorphism in the patients of different ethnic groups, the frequency of DD genotype in the IgAN patients with progression ranges from 8.0% to 46.3%, with a mean equal to 26.3%. The correlation between the ethnicity and the ACE gene polymorphism cannot be detected (p > 0.05). The Caucasian has a similar ACE gene polymorphism to the Mongolian.

DISCUSSION

IgAN is the most common glomerulonephritis worldwide and remains an important cause of end-stage renal failure.[9] However, the basic molecular mechanism underlying abnormal IgA synthesis, selective mesangial deposition with ensuing mesangial cell proliferation and extracellular matrix expansion, remains poorly understood.[9] The genetic and environmental interplay leading to the nephropathies in IgAN is highlighted.[10] Although findings on the correlation of I/D polymorphism and many disorders are documented,[1] reports on the progression of IgAN are still controversial.[9] It remains to be clarified by multi-center analysis using large numbers of patients whether the gene polymorphism of ACE is related to the progression of IgAN.[10]

Here, the author performed a meta-analysis to investigate the correlation between ACE gene polymorphism and the progression of IgAN. This investigation found that the overall DD genotype frequency in the group 1 is about 1.2 times higher than that of the group 2. These findings are discordant with a recent study that mentioned that ACE gene polymorphism was neither a risk factor for IgA nephropathy nor a predictor for its progression.[11]

This meta-analysis also detected another finding: that ethnicity is not related to the ACE gene polymorphism pattern. This finding has never been proposed and does not support the recent findings of difference in ACE gene pattern in different normal populations.[1] Here, the author tried to select only well-documented case-control studies for the meta-analysis to verify the result of the analysis. However, as this study is a retrospective meta-analysis study, some limitations in case recruitment should be mentioned. Further additional prospective studies are recommended to find the correlation of ACE gene polymorphism and progression of IgAN.