journal of renin angiotensin aldosterone system 2011 zhou 601 10

1 Department of Pediatrics, The First Affiliated Hospital of GuangXi Medical University, NanNing, China

2 Department of Experimental Pathology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China

3 Department of Internal Medicine, Township Health Centers of ShilLing in LongQuan district, ChengDu, China

*These authors are joint first authors

Corresponding author:Tian-Biao Zhou, Department of Pediatrics, The First Affiliated Hospital of GuangXi Medical University, NanNing 530021, China. Email: [email protected]

Journal of the Renin-Angiotensin-Aldosterone System12(4) 601 610 The Author(s) 2011Reprints and permission: sagepub.co.uk/journalsPermissions.navDOI: 10.1177/1470320311422578jra.sagepub.com

Article

Association of angiotensin converting enzyme insertion/deletion gene polymorphism with idiopathic nephrotic syndrome susceptibility in children: a meta-analysis

Tian-Biao Zhou1*, Chao Ou2*, Yuan-Han Qin1*, Li-Na Su1, Feng-Ying Lei1, Wei-Fang Huang1, Yan-Jun Zhao1, Yu-Sheng Pang1 and Kun-Peng Yang3

AbstractBackground and objective: Angiotensin converting enzyme (ACE) gene contains either an insertion (I) allele or a deletion (D) allele forming three potential genotypes: II, ID and DD. The D allele or DD genotype has been reported to be associated with higher plasma ACE level. An assessment of the association between ACE I/D gene polymorphism and idiopathic nephrotic syndrome (INS) susceptibility in children is still controversial. This meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and the onset of INS.Method: A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases, and eligible investigations were synthesized using the meta-analysis method.Results: Nine investigations were identified for the analysis of association between ACE I/D gene polymorphism and INS risk in children, including six in Asians, one study for Caucasians and two for Africans. There was positive association between D allele or DD genotype and INS susceptibility in Asians (OR = 1.75, p = 0.01; OR = 2.01, p = 0.02), but not for Caucasian children and Africans (for Caucasians, D: OR=1.35, p = 0.27, DD: OR = 0.95, p = 0.91; for Africans, D: OR = 1.70, p = 0.56, DD: OR = 1.60, p = 0.73). Furthermore, II homozygous seemed to play a positive role against INS onset for Asians (OR = 0.59, p = 0.02), but the link between II genotype and INS risk was not observed in Caucasian children and Africans (Caucasians: OR = 0.31, p = 0.06; Africans: OR = 0.50, p = 0.59).Conclusions: D allele and DD homozygous might become significant genetic molecular markers for INS susceptibility in Asian children, but the association was not observed in Caucasians or Africans. However, the conclusion from our study cannot be sustained and more investigations on larger sample in different populations are required to further clarify the role of D allele or DD homozygous in the onset of INS in difference races.

Keywordsangiotensin-converting enzyme (ACE), idiopathic nephrotic syndrome (INS), insertion/deletion (I/D) gene polymorphism, meta-analysis

Introduction

Nephrotic syndrome (NS) is characterized by substantial loss of protein in the urine (primarily albuminuria), leading to hypoproteinaemia (hypoalbuminaemia) and its result, oedema.1,2 Hyperlipidaemia, hypercholesterolaemia and increased lipiduria are usually associated.1,2 Although not commonly thought of as part of the syndrome, hypertension, haematuria, and azotaemia may also occur.1 NS is usually due to a glomerular disease and is currently categorized into primary and secondary forms.1,3 Idiopathic

by guest on October 2, 2015jra.sagepub.comDownloaded from

602 Journal of the Renin-Angiotensin-Aldosterone System 12(4)

nephrotic syndrome (INS) is not associated with any underlying disease. The syndrome manifests with varied clinical and pathologial states.1 The term secondary NS relates to various clinical diseases affecting the kidneys, such as anaphylactic purpura, systemic lupus erythematosus, diabetes mellitus, sickle cell disease, syphilis, and others.1 About 90% of the NS is INS and most of these have a favourable prognosis.4 However, INS is also the most common renal disease that leads to endstage renal disease in children. Early diagnosis for patient is very import for improving the prognosis in clinic. There was rare measure for the early diagnosis of INS. Some investigations suggested that genetic factor might play a key role in the onset of INS.57

Angiotensinconverting enzyme (ACE) is a zinc metallopeptidase that converts angiotensin I to angiotensin II (Ang II).8 The ACE gene consists of either an insertion (I) allele or a deletion (D) allele forming three possible genotypes: II, ID and DD.9 As far as we known, the D allele and DD genotype are associated with higher plasma ACE levels and thus increased angiotensin II levels.10,11 The increased angiotensin II level plays deleterious effects on renal haemodynamics and increases the expression of some growth factors, which take part in the onset of INS. Fahmy et al.12 showed that INS was associated with a higher incidence of DD genotype. AlEisa et al.13 found that the Dallele frequency in the INS group was much higher when compared with that in the controls. The DD genotype or D allele might be implicated in the aetiology of INS and has been investigated in numerous epidemiological studies. However, the available evidence reported to date is weak, due to the sparseness of data or disagreements among the reported investigations. We hypothesized that the DD genotype or D allele might be associated with the onset of INS. There was not any metaanalysis to explore the association of ACE I/D gene polymorphism with the onset of INS. As far as we know, the conclusion from metaanalysis might be more sustainable than that drawn from a separate investigation. This metaanalysis was performed to investigate the relation between ACE I/D gene polymorphism and INS risk, with the intention of providing a much more reliable finding on the significance of the association and to explore whether the ACE DD genotype or D allele could become an early diagnostic indicator to predict the onset of INS in children.

Materials and methods

Search strategy

The relevant studies were searched from the electronic databases of PubMed, Cochrane Library and CBMdisc (China Biological Medicine Database) on 1 September 2010 (nephrotic syndrome OR NS) AND (angiotensin converting enzyme OR ACE) AND (gene OR polymorphism OR genetic variant) was used in PubMed, and (nephrotic

syndrome OR NS) AND (angiotensin converting enzyme OR ACE) was entered into the databases of Cochrane Library and CBMdisc for search. The search in PubMed was limited to humans and the English language. As far as we know, PubMed also indexes some articles published in Chinese, but all the articles published in Chinese were index by CBMdisc. In order to avoid the repetition of included reports, the search in Pubmed did not include the search for Chinese studies. We also extended the search spectrum to the related articles and the bibliographies of all recruited studies. If multiple publications from the same study group occurred, we only recruited the most complete paper for our analysis.

Definition of idiopathic nephrotic syndrome

INS was diagnosed by oedema, hyperlipidaemia, serum albumin below 2.5 g/dl, and urinary protein excretion greater than 40 mg/m2/h. Patients did not suffer from any other renal diseases which could induce the NS symptom, such as HenochSchonlein purpura nephritis (HSPN).

Inclusion and exclusion criteria

Inclusion criteria. Inclusion critera were: (i) a casecontrol study; (ii) the outcome had to be INS; (iii) there had to be at least two comparison groups (INS group vs. control group); and (iv) the investigation was performed in children.

Exclusion criteria. Articles were excluded if: (i) they were review articles or editorials; or (ii) they were case reports; or (iii) they did not provide the detail genotype data; or (iv) they investigated the role ACE inhibitor to disease; or (v) they showed an association of ACE genotypes with histopathological changes of kidney which were not related to INS.

Data extraction and synthesis

The following information was extracted from each investigation independently by at least two investigators: first authors surname, year of publication, ethnicity of study population, and the number of cases and controls for ACE genotypes. Frequencies of alleles were calculated for case group and control group, from the corresponding genotype distributions. The results were compared and disagreements were resolved by discussion.

Statistical analysis

Available data was entered into Cochrane Review Manager Version 5 (Cochrane Library, UK) and analysed. The pooled statistic was calculated using the fixed effects model, but a random effects model was performed when the p value of heterogeneity test was less than 0.1. Results were expressed with odds ratios (OR) for dichotomous data, and 95%


Zhou et al. 603

confidence intervals (CIs) was also counted. A value of p < 0.05 was required for the overall OR to be statistically significant. I2 was used to test the heterogeneity between the recruited studies. We classified the investigations into studies in Caucasians, for Asians and in Africans because genotype frequencies and prevalence of INS were different among ethnic groups. A chisquare test using a webbased program was applied to determine if genotype distribution of the control population reported conformed to HardyWeinberg equilibrium (HWE; p < 0.05 was considered significant). All descriptive data were expressed as mean SD.

Results

Study characteristics

The search yielded 169 references, 78 in Pubmed, one from Cochrane Library and 90 in CBMdisc. Those studies which did not report the association of ACE I/D gene polymorphism with the risk of NS were excluded from our

study: 18 studies for case reports, 24 for editorials/reviews, 17 reports which preliminary results not on ACE I/D gene polymorphism and outcome, 47 studies investigating the role ACE inhibitor to disease, eight investigations studying the association of ACE genotype with histopathological changes of kidney which were not related to INS, 39 studies reporting the association of ACE genotypes with other kidney diseases, such as IgA nephropathy. Finally, 16 articles reported the association of ACE I/D gene polymorphism with the risk of NS or INS. However, two studies14,15 were excluded because the distributions of ACE genotypes were not detailed. One study16 was performed in patients including secondary NS. Patients in four investigations1720 suffered from NS but those studies did not mention whether the patients were suffering from INS or NS, and those investigations were excluded from our metaanalysis. Nine studies12,13,2127 were identified for the analysis of the association between ACE I/D gene polymorphism and INS susceptibility in our final review (Figure 1) and all the studies were performed in children. In those nine reports, three21,26,27

Figure 1. Flow chart for our study.



presented the diagnostic criteria for INS in their studies, which was consistent with the definition of INS in our study, and other six reports only mentioned that the patients recruited into their studies were suffering from INS but did not show the definition of INS in their reports. Six studies13,2124,27 were conducted in Asians, one investigation25 was performed in Caucasian children and two studies12,26 were conducted in Africans. Eight studies were published in English and one investigation21 was published in Chinese. The data of our interest was extracted and frequency of D allele was calculated (Table 1). These nine studies contained 798 case series and 1076 controls. The average distribution frequency of D allele in Asian patients with INS was 67.94%, and the average frequency in controls was 53.49%. Furthermore, the average distribution of D allele frequency in Caucasians was 59.38% in cases and it was 52.01% for controls. In Africans, the average gene frequency for D allele was 55.05% in INS group or 42.00% in control group (Table 1). The ratio of INS/control for the average distribution frequency of D allele in Asians or Africans was a little higher than that of Caucasians (Asians: INS/control = 1.27, Africans: INS/control = 1.31, Caucasians: INS/control = 1.14).

Association of the ACE I/D gene polymorphism with risk of idiopathic nephrotic syndrome

In this metaanalysis, a significant association between DD homozygous or D allele and the risk of INS was observed in overall populations (Table 2). The random effects OR estimated for the INS susceptibility was 1.56 in D allele patients when compared with patients carrying I allele (95% CI: 1.042.36; Table 2), with evidence of betweenstudy heterogeneity (p < 0.00001; Table 2). Furthermore, the random effects OR estimated for the risk of developing INS was 1.74 in DD homozygous patients when compared with both other genes combined (95% CI: 1.042.90; Table 2), because the pvalue of heterogeneity test was 0.0001. Interestingly, we also documented that there was a significant association between II genotype and the risk of INS relative to both other genotypes combined (OR = 0.56, 95% CI: 0.350.89, p = 0.01; Table 2).

True racespecific genetic effects might affect the results of our analysis for the association of ACE I/D gene polymorphism with INS susceptibility. In order to evaluate the racespecific effect, we divided the population by ethnicity. In Asians, we found that the association of D allele or DD

Table 1. Characteristics of the studies evaluating the effects of ACE I/D gene polymorphism on INS risk

First author, year Ethnicity Cases Controls D allele (%)

DD ID II DD ID II Cases Controls

AI-Eisa 2000 Asian 38 11 5 25 22 1 80.56 75.00Wan 2002 Asian 23 20 39 11 9 18 40.24 40.78Serdaroglu 2005 Asian 109 87 31 99 124 64 67.18 56.10Sasongko 2005 Asian 7 33 45 6 21 41 27.65 24.26Tabel 2005 Asian 72 66 20 99 124 64 66.46 56.10Tsai 2006 Asian 31 6 22 2 20 57 57.63 15.19Sasse 2006 Caucasian 9 20 3 58 91 50 59.38 52.01Fahmy 2008 African 21 23 6 2 8 10 65.00 30.00Saber-Ayad 2010 African 5 36 10 10 34 6 45.10 54.00

Figure 2. Association between D allele and INS risk in Asians.


Zhou et al. 605

homozygous with INS risk was positively significant (p = 0.01 and p = 0.02, respectively) (Figures 2 and 3). Furthermore, the II homozygous seemed to play a protective role against INS risk in Asians (OR = 0.59, 95% CI: 0.370.93; p = 0.02) (Figure 4). For Caucasian children, there was no a significant association between D allele or DD homozygous and INS susceptibility (p = 0.27 and p = 0.91, respectively; Table 2), and the II genotype seemed not to play a protective role against the INS onset (OR = 0.31, 95% CI: 0.091.06; p = 0.06; Table 2). Furthermore, we also found that there was not any association between ACE I/D gene polymorphism and the onset of INS for Africans (D: OR = 1.70, p = 0.56; DD: OR = 1.60, p = 0.73; II: OR = 0.50, p = 0.59; Table 2).

Sensitivity analysis

The gene distribution of control group in the included study was not in HWE, which might be an important reason to cause heterogeneity. In this metaanalysis, sensitivity analysis was performed. The genotype distribution of the control populations in four studies, three21,22,27 in Asians and one26 for Africans, did not conform to HWE and those investigations were excluded from our sensitivity analysis. Finally, five studies were recruited into our analysis, three13,23,24 in Asians, one25 for Caucasian children and

one12 in Africans. We found that the results in our sensitivity analysis were inconsistent with those in Table 2, besides II gene for overall populations and all the results for Caucasian children (Table 3). The results in our nonsensitivity analysis (Table 2) might be less powerful.

In our study, not all included studies strictly stated their INS definition for participant recruitment. This was another source of heterogeneity and we conducted a sensitivity analysis according to whether the included study strictly stated their INS definition for participant recruitment. In those nine reports, three21,26,27 presented the diagnostic criteria for INS in their studies, which was consistent with the definition of INS in our study. Another six reports only mentioned that the patients recruited into their studies were suffering from INS but did not show the definition of INS in their reports, and were excluded from this sensitivity analysis. There were two studies21,27 in Asians and one investigation26 for Africans, but no study for Caucasians. We found that the results (Table 3) were consistent with those in nonsensitivity analysis (Table 2) for Asians and Africans, but the results for overall populations (Table 3) were inconsistent with those in nonsensitivity analysis (Table 2). However, the number of included studies for this sensitivity analysis was small (only two for Asians and one for Africans). The results in this sensitivity analysis were less powerful.

Figure 3. Association of DD genotype with INS risk in Asians.

Figure 4. Association between II homozygous and INS risk in Asians.



Discussion

There is welldocumented evidence suggesting that the reninangiotensin aldosterone system (RAAS) takes part in the pathogenesis of some renal diseases.2830 The level of plasma ACE, constitutively expressed in several types of

somatic cells, is linked to an I/D polymorphism of 287 bp in intron 16 of the ACE gene.31,32 The D allele and DD genotype have been reported to be associated with higher plasma ACE levels.33,34 ACE is a key enzyme of RAAS

Table 2. Meta-analysis of association of ACE I/D gene polymorphism with INS risk

Genetic contrasts

Groups and subgroups

Studies Q test p-value

Model selected

OR (95% CI) p-value

D vs. I Overall 9

Zhou et al. 607

which can convert inactive angiotensin I into a vasoactive and aldosteronestimulating peptide angiotensin II.35,36 The elevated expression of ACE protein might be responsible for the elevation of plasma angiotensin II level.37 The increased angiotensin II level makes deleterious actions on renal haemodynamics and induces the protein expression of some growth factors.38,39 Genetic factors, such as ACE I/D gene polymorphism, have been suggested to be important in determining the onset of INS.27 Findings on the association of ACE I/D gene polymorphism with INS susceptibility have been controversial since the first investigation was reported. In order to draw a more convincing conclusion, this metaanalysis was performed to explore the association between ACE I/D gene polymorphism and INS susceptibility and tried to explore whether or not D allele or DD homozygous could become a significant genetic molecular marker for INS susceptibility.

In this investigation, nine studies performed in INS patients were recruited for analysis, six studies for Asians, one investigation in Caucasian children and two for Africans. In our study, we found that the results from overall populations were similar with those in Asians. Most of the included studies for our metaanalysis were from Asian population and the overall pooled results might be mainly contributed by Asians. The geographic and race difference is an important factor to effect the association of gene polymorphism with the susceptibility of renal disease. The results from overall populations might be instable. We conducted the subgroup analysis according to different races.

In Asians, AlEisa et al.13 found that the frequency of the D allele in an INS group was higher when compared with that in healthy children from Kuwaiti Arab. Tsai et al.24 performed an investigation in children from Taiwan and reported that the difference of D allele distribution between the INS patient group and the control group was statistically significant. Serdaroglu et al.22 investigated the distribution of ACE I/D gene polymorphism in children coming from Turkey and found that the distribution of D allele in the patient group was significantly different from that in the control groups. Tabel et al.27 reported that the frequency of the D allele in Turkish children with INS was much higher than that in the healthy controls. However, Wan et al.21 conducted a study in Chinese children and found that the distribution of ACE I/D gene polymorphism in the patient group was not different from that in the control group. Most of the investigations, conducted in Asian countries, found that D allele or DD genotype was associated with the susceptibility of INS and the results were similar to ours. In our study, we found that D allele or DD genotype was a risk factor to INS (D: OR = 1.75, p = 0.01; DD: OR = 2.01, p = 0.02). In our sensitive analysis according to whether the genotype distribution of the control population in the included study was conformed to HWE, we observed that the distribution frequency of D allele or DD homozygous was a significantly favourable to the INS group (D: OR = 2.33, DD:

OR = 4.11, respectively), although the difference was not statistically significant (D: p = 0.17, DD: p = 0.15, respectively). When we conducted a sensitive analysis according to according to whether the included study strictly stated their INS definition for participant recruitment, we found that D allele and DD genotype were associated with the risk of INS. Many studies found that D allele or DD genotype was associated with the onset of some diseases in Asian population.4045 We speculated that D allele or DD genotype might be a risk factor leading INS in Asian children.

In Caucasian participants, an investigation on the association between ACE I/D gene polymorphism and the onset of INS was also performed. Sasse et al.25 found that the distributions of ACE genotypes in Swiss children with INS were not significantly different from those in the normal Swiss population. Our metaanalysis only included this investigation for the analysis in Caucasians. So, the results in our study (including sensitive analysis) were the same as those in Sasse et al. Because the number of included investigation was small (only one article), it was difficult to draw a stable conclusion. However, in recent years, some researchers have found that ACE I/D gene polymorphism is associated with some diseases in Caucasian population.4649 It is necessary to pay more attention to investigating the relation between ACE I/D gene polymorphism and INS susceptibility in Caucasian children in the future.

In Africans, Fahmy et al.12 investigated the difference of ACE I/D gene distribution between Egyptian children with INS and normal controls and found that INS susceptibility was associated with a higher percentage of DD genotype. However, SaberAyad et al.26 reported that the difference of ACE I/D gene distribution between controls and the Egyptian INS patients was not statistically significant. Our pooled results from those two studies mentioned above showed that D allele or DD homozygous was not associated with the onset of INS in African children. It was consistent with that in SaberAyad et al., but was not consistent with that of Fahmy et al. In our sensitivity analysis, we only included the study from Fahmy et al. and the results were the same as theirs. D allele or DD genotype was a risk factor to induce the onset of INS in African children. The gene distribution of ACE in Fahmy et al. was in equilibrium to HWE, and the result coming from Fahmy et al. might be more convincing. When we performed a sensitive analysis according to whether the included study strictly stated their INS definition for participant recruitment, we found that D allele and DD genotype were not associated with the risk of INS. D allele and DD genotype might not be associated with the INS risk in Africans. However, the frequency of D allele in African children with INS was much higher than that in controls (1.31fold). The increased D allele frequency in African children was more notable when compared with that in Asians or Caucasians. Some studies found gene polymorphisms might be associated with the onset of some renal diseases.5052 Whether ACE I/D gene



polymorphism is associated with the INS susceptibility, more investigations paying attention to this association are needed in the future.

People with II genotype can show a lower level of ACE level when compared with those suffering from the DD homozygous. The II genotype might play a protective role against the onset of INS. In our study, we found that the II genotype played a protective role in overall populations and Asians, but this association was not found in Caucasian children and Africans. In the sensitivity analysis according to whether genotype distribution of the control population in the included study was conformed to HWE, the gene frequency of II homozygous was a significantly favourable to the control group in Asians (OR = 0.66), although the difference was not statistically significant (D: p = 0.51). Furthermore, in the sensitivity analysis for Asians according to whether the included study strictly stated their INS definition for participant recruitment, we found that the II genotype might play a protective role against INS risk. In conclusion, II homozygous might play a protective role against INS onset in Asians but the result was not stable. Furthermore, we found that the II genotype could reduce the onset of INS in Africans in the sensitive analysis according to whether genotype distribution of the control population in the included study was conformed to HWE, and the result for Africans was not consistent with that in the nonsensitive analysis and that in the sensitive analysis according to whether the included study strictly stated their INS definition for participant recruitment. The result from Africans was not stable. There was only one included study for our metaanalysis and for sensitive analysis in Caucasian children, so the result that II genotype was not play a protective role against INS risk was less powerful. In the sensitive analysis according to whether genotype distribution of the control population in the included study was conformed to HWE for overall populations, the result was consistent with that in nonsensitive analysis. But in the sensitive analysis according to whether the included study strictly stated their INS definition for participant recruitment for overall populations, the result was inconsistent with that in nonsensitive analysis. Racespecific might affect the result in our analysis and the result for II genotype from overall populations might be less powerful. More investigations in different races should be conducted to investigate this association.

In our investigation, we found that DD genotype or D allele was associated with INS susceptibility in Asians, but not for Caucasian children and Africans. We speculated that ACE DD homozygous or D allele might affect more sensitively for INS susceptibility in Asians than in Caucasians and Africans. Furthermore, II genotype seemed to play a positive role against the onset of INS for Asians; however, the link for Caucasian children and Africans was not found. These findings should be regarded cautiously because many other ingredients, such as heterogeneity of included

cases, limited statistical power and variable study designs, were closely related to affect the results. Furthermore, whether ACE I/D gene polymorphism is just linked with other discrete loci involved in the occurrence of INS is not clear at the moment.

Limitations

Some limitations should be discussed in this metaanalysis. First, heterogeneities may be present, affecting the results of our metaanalysis, although a random effects model has been performed. Second, an important threat to any literaturebased review and metaanalysis is that of reporting bias (only recruit published literatures in English and Chinese). Last but not least, the sample sizes in some studies are relatively small. Undoubtedly, the limitations mentioned above might affect our final conclusions.

Conclusions

In conclusion, the results in our study supported that DD homozygous or D allele was associated with INS susceptibility for Asians, and DD genotype or D allele might become a valuable indicator to predict the onset of INS in Asian children, but not for Caucasians and African children. The results for Asians were slightly stable when compared with those in Caucasian children and for Africans. Furthermore, II genotype seemed to play a positive role against INS onset for Asians, but not for Caucasians and African children. However, the conclusion from this metaanalysis fails in persuasiveness and more casecontrol association investigations on larger sample in different populations are required to further clarify the association of DD genotype or D allele with the onset of INS in difference races.

FundingThis research received no specific grant from any funding agency in the public, commercial, or notforprofit sectors.

Conflict of interestThe authors declare that they have no conflicts of interest.

References 1. Safaei A and Maleknejad S. Spectrum of childhood nephrotic

syndrome in Iran: a single center study. Indian J Nephrol 2009; 19: 8790.

2. Safaei AA and Maleknejad S. Clinical and laboratory findings and therapeutic responses in children with nephrotic syndrome. Indian J Nephrol 2010; 20: 6871.

3. Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician 2009; 80: 11291134.

4. Mishra OP, Gupta AK, Prasad R, et al. Antioxidant status of children with idiopathic nephrotic syndrome. Pediatr Nephrol 2011; 26: 251256.


Zhou et al. 609

5. Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005; 72: 777783.

6. Shono A, Tsukaguchi H, Kitamura A, et al. Predisposition to relapsing nephrotic syndrome by a nephrin mutation that interferes with assembly of functioning microdomains. Hum Mol Genet 2009; 18: 29432956.

7. Vivarelli M, DUrbano LE, Stringini G, et al. Association of the macrophage migration inhibitory factor 173*C allele with childhood nephrotic syndrome. Pediatr Nephrol 2008; 23: 743748.

8. Yaren A, Oztop I, Turgut S, Turgut G, Degirmencioglu S and Demirpence M. Angiotensinconverting enzyme gene polymorphism is associated with anemia in non smallcell lung cancer. Exp Biol Med (Maywood) 2008; 233: 3237.

9. Tronvik E, Stovner LJ, Bovim G, et al. Angiotensinconverting enzyme gene insertion/deletion polymorphism in migraine patients. BMC Neurol 2008; 8: 4.

10. RodriguezRomo G, Ruiz JR, Santiago C, et al. Does the ACE I/D polymorphism, alone or in combination with the ACTN3 R577X polymorphism, influence muscle power phenotypes in young, nonathletic adults? Eur J Appl Physiol 2010; 110: 10991106.

11. Nikzamir A, Nakhjavani M, Golmohamadi T and Dibai L. Association of angiotensinconverting enzyme gene insertion/ deletion polymorphism with metabolic syndrome in Iranians with type 2 diabetes mellitus. Arch Iran Med 2008; 11: 39.

12. Fahmy ME, Fattouh AM, Hegazy RA and Essawi ML. ACE gene polymorphism in Egyptian children with idiopathic nephrotic syndrome. Bratisl Lek Listy 2008; 109: 298301.

13. AlEisa A, Haider MZ and Srivastva BS. Angiotensin converting enzyme gene insertion/deletion polymorphism in idiopathic nephrotic syndrome in Kuwaiti Arab children. Scand J Urol Nephrol 2001; 35: 239242.

14. Luther Y, Bantis C, Ivens K, Fehsel K, KolbBachhofen V and Heering P. Effects of the genetic polymorphisms of the reninangiotensin system on focal segmental glomerulosclerosis. Kidney Blood Press Res 2003; 26: 333337.

15. Patil SJ, Gulati S, Khan F, Tripathi M, Ahmed M and Agrawal S. Angiotensin converting enzyme gene polymorphism in Indian children with steroid sensitive nephrotic syndrome. Indian J Med Sci 2005; 59: 431435.

16. Chen ZH, Liu ZH, Wang QW, Ji SM, Ji DX, Li LS. Angiotensin converting enzyme gene polymorphism inpatients with end stage renal failure. Chin J Nephrol 1997; 13: 2224.

17. Lee DY, Kim W, Kang SK, Koh GY and Park SK. Angiotensinconverting enzyme gene polymorphism in patients with minimalchange nephrotic syndrome and focal segmental glomerulosclerosis. Nephron 1997; 77: 471473.

18. Yang F, Liu WJ, Liu PP, He GL, Guo ZQ and Liu PL. Study on gene polymorphism of renin angiotensin system in children with nephritic syndrome. Journal of Jinan University (Medicine Edition) 2005; 26: 246250.

19. Celik US, Noyan A, Bayazit AK, et al. ACE gene polymorphism in Turkish children with nephrotic syndrome. Ren Fail 2006; 28: 401403.

20. Oktem F, Sirin A, Bilge I, Emre S, Agachan B and Ispir T. ACE I/D gene polymorphism in primary FSGS and steroidsensitive nephrotic syndrome. Pediatr Nephrol 2004; 19: 384389.

21. Wan GP, Gu XQ, Zhu B, Chen HH, Gao Y and He CJ. Angiotensin I converting enzyme gene polymorphism in children with nephritic syndrome. J Mod Clin Med Bioengin 2002; 8: 12.

22. Serdaroglu E, Mir S, Berdeli A, Aksu N and Bak M. ACE gene insertion/deletion polymorphism in childhood idiopathic nephrotic syndrome. Pediatr Nephrol 2005; 20: 17381743.

23. Sasongko TH, Sadewa AH, Kusuma PA, et al. ACE gene polymorphism in children with nephrotic syndrome in the Indonesian population. Kobe J Med Sci 2005; 51: 4147.

24. Tsai IJ, Yang YH, Lin YH, Wu VC, Tsau YK and Hsieh FJ. Angiotensinconverting enzyme gene polymorphism in children with idiopathic nephrotic syndrome. Am J Nephrol 2006; 26: 157162.

25. Sasse B, Hailemariam S, Wuthrich RP, Kemper MJ and Neuhaus TJ. Angiotensin converting enzyme gene polymorphisms do not predict the course of idiopathic nephrotic syndrome in Swiss children. Nephrology (Carlton) 2006; 11: 538541.

26. SaberAyad M, Sabry S, AbdelLatif I, Nabil H, ElAzm SA and AbdelShafy S. Effect of angiotensinconverting enzyme gene insertion/deletion polymorphism on steroid resistance in Egyptian children with idiopathic nephrotic syndrome. J Renin Angiotensin Aldosterone Syst 2010; 11: 111118.

27. Tabel Y, Berdeli A, Mir S, Serdaroglu E and Yilmaz E. Effects of genetic polymorphisms of the reninangiotensin system in children with nephrotic syndrome. J Renin Angiotensin Aldosterone Syst 2005; 6: 138144.

28. Colucci JA, Arita DY, Cunha TS, et al. Reninangiotensin system may trigger kidney damage in NOD mice. J Renin Angiotensin Aldosterone Syst 2011; 12: 1522.

29. Huang HD, Lin FJ, Li XJ, Wang LR and Jiang GR. Genetic polymorphisms of the reninangiotensinaldosterone system in Chinese patients with endstage renal disease secondary to IgA nephropathy. Chin Med J (Engl) 2010; 123: 32383242.

30. Balakumar P and Jagadeesh G. Cardiovascular and renal pathologic implications of prorenin, renin, and the (pro)renin receptor: promising young players from the old renin angiotensinaldosterone system. J Cardiovasc Pharmacol 2010; 56: 570579.

31. Bukreeva L, Grigorov A, Kiesewetter H and Hoppe B. Association of angiotensinconverting enzyme intron 16 insertion/deletion polymorphism with history of foetal loss. J Renin Angiotensin Aldosterone Syst 2009; 10: 237240.

32. Mahjoub S, Mehri S, Bousaada R, et al. Association of ACE I/D polymorphism in Tunisian patients with dilated cardiomyopathy. J Renin Angiotensin Aldosterone Syst 2010; 11: 187191.

33. Yildiz M, Karkucak M, Yakut T, Gorukmez O and Ozmen A. Lack of association of genetic polymorphisms of angiotensinconverting enzyme gene I/D and glutathioneStransferase



enzyme T1 and M1 with retinopathy of prematures. Genet Mol Res 2010; 9: 21312139.

34. Rahimi Z, Felehgari V, Rahimi M, et al. The frequency of factor V Leiden mutation, ACE gene polymorphism, serum ACE activity and response to ACE inhibitor and angiotensin II receptor antagonist drugs in Iranians type II diabetic patients with microalbuminuria. Mol Biol Rep 2011; 38: 21172123.

35. Lambert DW, Clarke NE and Turner AJ. Not just angiotensinases: new roles for the angiotensinconverting enzymes. Cell Mol Life Sci 2010; 67: 8998.

36. Lubel JS, Herath CB, Burrell LM and Angus PW. Liver disease and the reninangiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol 2008; 23: 13271338.

37. RibeiroOliveira Jr A, Nogueira AI, Pereira RM, Boas WW, Dos SR and Simoes ESA. The reninangiotensin system and diabetes: an update. Vasc Health Risk Manag 2008; 4: 787803.

38. Kaneshiro Y, Ichihara A, Sakoda M, et al. Slowly progressive, angiotensin IIindependent glomerulosclerosis in human (pro)renin receptortransgenic rats. J Am Soc Nephrol 2007; 18: 17891795.

39. Huby AC, Rastaldi MP, Caron K, Smithies O, Dussaule JC and Chatziantoniou C. Restoration of podocyte structure and improvement of chronic renal disease in transgenic mice overexpressing renin. PLoS One 2009; 4: e6721.

40. Xiao P, Ling Z, Woo K, et al. Reninangiotensin systemrelated gene polymorphisms are associated with risk of atrial fibrillation. Am Heart J 2010; 160: 496505.

41. Ganesan M, Bhaskar S, Mani R, et al. The relationship of ACE and CETP gene polymorphisms with cardiovascular disease in a cohort of Asian Indian patients with and those without type 2 diabetes. J Diabetes Complications 2010. [In process]

42. Bawazier LA, Sjabani M, Haryana SM, Soesatyo MH and Sadewa AH. Relationship of Angiotensin converting enzyme gene polymorphism and hypertension in yogyakarta, indonesia. Acta Med Indones 2010; 42: 192198.

43. Bayram B, Sayin E, Gunes HV, et al. DD genotype of ace gene I/D polymorphism is associated in a Turkish study population with osteoarthritis. Mol Biol Rep 2011; 38: 17131716.

44. Pulla RB, Srikanth BB, Venkata KK, et al. Angiotensinconverting enzyme gene variant and its levels: risk factors for myocardial infarction in a South Indian population. Singapore Med J 2010; 51: 576581.

45. Li X, An J, Guo R, et al. Association of the genetic polymorphisms of the ACE gene and the eNOS gene with lupus nephropathy in northern Chinese population. BMC Med Genet 2010; 11: 94.

46. Zintzaras E, Raman G, Kitsios G and Lau J. Angiotensinconverting enzyme insertion/deletion gene polymorphic variant as a marker of coronary artery disease: a metaanalysis. Arch Intern Med 2008; 168: 10771089.

47. Zhou JB, Yang JK, Lu JK and An YH. Angiotensinconverting enzyme gene polymorphism is associated with type 2 diabetes: a metaanalysis. Mol Biol Rep 2010; 37: 6773.

48. Niu W, Qi Y, Gao P and Zhu D. Angiotensin converting enzyme D allele is associated with an increased risk of type 2 diabetes: evidence from a metaanalysis. Endocr J 2010; 57: 431438.

49. Liu T, Korantzopoulos P, Xu G, et al. Association between angiotensinconverting enzyme insertion/deletion gene polymorphism and atrial fibrillation: a metaanalysis. Europace 2011; 13: 346354.

50. Gaillard MC, Mahadeva R and Lomas DA. Identification of DNA polymorphisms associated with the V type alpha1antitrypsin gene. Biochim Biophys Acta 1999; 1444: 166170.

51. Dusel JA, Burdon KP, Hicks PJ, Hawkins GA, Bowden DW and Freedman BI. Identification of podocin (NPHS2) gene mutations in African Americans with nondiabetic endstage renal disease. Kidney Int 2005; 68: 256262.

52. ReevesDaniel AM, Iskandar SS, Bowden DW, et al. Is collapsing C1q nephropathy another MYH9associated kidney disease? A case report. Am J Kidney Dis 2010; 55: e2124.


journal of renin angiotensin aldosterone system 2011 zhou 601 10

Documents