ACE I/D Gene Polymorphism Can't Pre

ACE I/D Gene Polymorphism Can't Predict the Steroid Responsiveness in Asian Children with Idiopathic Nephrotic Syndrome: A Meta-Analysis
Tian-Biao Zhou,# Yuan-Han Qin,#* Li-Na Su, Feng-Ying Lei, Wei-Fang Huang, and Yan-Jun Zhao
Carmine Zoccali, Editor
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Abstract
Background

The results from the published studies on the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the treatment response to steroid in Asian children with idiopathic nephrotic syndrome (INS) is still conflicting. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and treatment response to steroid in Asian children and to explore whether ACE D allele or DD genotype could become a predictive marker for steroid responsiveness.
Methodology/Principal Findings

Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of September 1, 2010, and eligible investigations were synthesized using meta-analysis method. Five investigations were identified for the analysis of association between ACE I/D gene polymorphism and steroid-resistant nephrotic syndrome (SRNS) risk in Asian children and seven studies were included to explore the relationship between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) susceptibility. Five investigations were recruited to explore the difference of ACE I/D gene distribution between SRNS and SSNS. There was no a markedly association between D allele or DD genotype and SRNS susceptibility or SSNS risk, and the gene distribution differences of ACE between SRNS and SSNS were not statistically significant. II genotype might play a positive role against SRNS onset but not for SSNS (OR = 0.51, P = 0.02; OR = 0.95, P = 0.85; respectively), however, the result for the association of II genotype with SRNS risk was not stable.
Conclusions/Significance

Our results indicate that D allele or DD homozygous can't become a significant genetic molecular marker to predict the treatment response to steroid in Asian children with INS.
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Introduction

Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in childhood [1], and uniformly present as proteinuria, hypoalbuminemia, hyperlipidemia and gravity-dependent edema, with other features like hematuria, hypertension, and decreased glomerular filtration rate [2]. With a benign prognosis, most of INS have a satisfactory response to steroid therapy [3]. According to the clinical response to steroids, INS are divided into steroid-sensitive nephrotic syndrome (SSNS) and non-steroid-sensitive nephrotic syndrome (non-SSNS), and non-SSNS is further divided into steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS) [4]. Age of initial presentation has an important impact on the disease distribution and the response to steroid [5]. Most of children with INS respond to corticosteroid treatment (SSNS), and about 10% of children with INS are mainly steroid-resistant (SRNS) [6]. SRNS is at risk of developing end stage renal disease [7]. In clinical practice, the best prognostic indicator for INS is whether or not the disease responds to steroid treatment [8]. Patients with SSNS or SRNS have a similar clinical manifestation, and there is no specific laboratory indicator to distinguish these two clinical entities [1]. Pathological evaluation of renal cortical tissue, by means of a renal biopsy, has traditionally been used to detect a distinction between SSNS and SRNS [1]. The pathological correlations to SSNS and SRNS are minimal change disease and focal segmental glomerulosclerosis, respectively. However, these histological diagnoses aren't always parallel to patients' clinical response to treatment. Identification of noninvasive biomarkers that accurately distinguish SSNS from SRNS would be most beneficial to the patients with SRNS, preventing their exposure to high-dose, yet ineffective steroid courses [1]. In the past years, some investigations suggested that there might be an association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and treatment response to steroid in children with INS and DD genotype or D allele might become a candidate indicator for predicting the response to corticosteroid treatment.

A variety of recent well-documented evidences indicate that the renin-angiotensin system (RAS) is involved in the pathogenesis of renal disorders [9], [10], [11], [12]. ACE, a key zinc metallopeptidase, catalyses the conversion of angiotensin I to angiotensin II, which is the main active product of the RAS [13]. An increased angiotensin II level causes deleterious effects on renal haemodynamics and induces the expression of different growth factors and cytokines, leading to tubulointerstitial fibrosis and glomerulosclerosis [14]. The ACE gene consists of either an insertion (I) allele or a deletion (D) allele forming three possible genotypes: II, ID and DD [15]. DD homozygous or D allele is associated with elevated circulating and tissue ACE activity compared to I allele [6], [16], [17], [18]. Patients with SRNS eventually receive symptomatic treatment with synergic combinations of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as they seem to produce a nonspecific decrease in the proteinuria and reduce glomerular transcapillary hydrostatic pressure as well as the synthesis of profibrotic cytokines that alter glomerular permeability [19]. There might be an association between ACE and the response to corticosteroid treatment.

The ACE I/D gene polymorphism, correlating with circulating and cellular ACE concentration [16], might be implicated in the etiology of SRNS or SSNS and has been investigated in numerous epidemiologic studies. Most of them were performed in Asian children, and only a few original investigations were conducted in Caucasians or Africans. However, the available evidence is weak for Asians at present, due to sparseness of data or disagreements among the reported investigations. The geographic and race difference is an important factor to effect the association between the gene polymorphism and the susceptibility of renal diseases. So, in this study, we only included the investigations performed in Asians.

The evidence from meta-analysis may be powerful when compared with the individual investigation. In the past years, there were some meta-analyses to explore the association of ACE I/D gene polymorphism with the susceptibility of some diseases in Asians. Some investigators [20],[21], [22] respectively took a meta-analysis to investigated the association of ACE I/D gene polymorphism with immunoglobulin A nephropathy (IgAN) risk, and found that DD homozygous was associated with an increased risk of IgAN in Asians. Ji et al [23] conducted a meta-analysis to explore the association of ACE I/D gene polymorphism with essential hypertension susceptibility in Asians and found that DD homozygous was associated with hypertension risk. Zhang et al [24] performed a meta-analysis to study the relation between ACE I/D gene polymorphism and the onset of asthma, and observed that there was an association between D allele or DD genotype and the asthma susceptibility in Asian population. Whether the ACE I/D gene polymorphism was associated with the response to corticosteroid treatment and could predict the treatment response to steroid in Asian children with INS, there was rare meta-analysis to investigate. We performed this meta-analysis to investigate whether the ACE I/D gene polymorphism could become a valuable indicator to predict the steroid responsiveness in Asian children with INS.