minimal change nephrotic syndrome ( mcns ) is one of the most important histopathological characteristics in patients with idiopathic nephrotic syndrome ( ins ) , and long - term outcome of most of the patients with this disease is favorable .
some investigations suggested that genetic factors might play a key role in the pathomechanism of mcns [ 25 ] . the angiotensin - converting enzyme ( ace ) insertion / deletion ( i / d ) gene polymorphism , correlating with circulating and cellular ace concentration , might take part in the etiology of mcns and have been investigated in numerous epidemiologic studies at present .
however , the available evidence reported to date is weak , due to sparseness of data or disagreements among studies .
there is rare meta - analysis to explore the association of ace i / d gene polymorphism with mcns risk .
we performed this meta - analysis to investigate the association between ace i / d gene polymorphism and mcns susceptibility , with the intention to provide a much more reliable finding on the significance of the association .
the relevant studies were screened from the search engines of pubmed , cochrane library , and cbm - disc ( china biological medicine database ) on september 1 , 2010 .
( minimal change nephrotic syndrome or mcns ) and ( angiotensin converting enzyme or ace ) was used in pubmed , cochrane library , and cbm - disc .
we also extended search spectrum to the  related articles  and the bibliographies of all retrieved studies . if multiple publications from the same study group occurred , we only recruited the most complete paper for analysis .
( 1 ) a case - control study , ( 2 ) the outcome had to be mcns , and ( 3 ) there had to be at least two comparison groups ( mcns group versus control group ) . ( 1 ) review articles ; ( 2 ) case reports ; ( 3 ) articles did not provide the detail genotype data ; ( 4 ) investigated the association of other genes with mcns .
the following information was extracted from each study independently by at least 2 investigators : first author 's 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 distribution .
available data was entered into cochrane review manager ( revman , version 5 ) and analyzed .
the pooled statistic was counted using the fixed effects model , but a random effects model was conducted when the p value of heterogeneity test was less than  .1 .
results were expressed with odds ratios ( or ) for dichotomous data , and 95% confidence intervals ( ci ) were also calculated .
the search yielded 46 references , 38 in pubmed , 0 from cochrane library and 7 in cbm - disc , and one study   was included from the  related articles  and the bibliographies of all retrieved studies . according to the inclusion and exclusion criteria , six studies [ 611 ]
were identified for the meta - analysis of the association between ace i / d gene polymorphism and mcns susceptibility in our final review .
four studies [ 811 ] were conducted in asians , one investigation   for caucasians and one   in africans .
the data of our interest were extracted : first author 's surname , year of publication , ethnicity of study population , and the number of cases and controls for ace genotypes ( table 1 ) .
the average distribution frequency of ace d allele in asian patients with mcns was 53.91% , and the frequency in controls was 47.65% .
the average distribution of d allele frequency in caucasians was 64.71% in cases and 52.01% for controls .
furthermore , the average distribution frequency of d allele in africans with mcns was 50.00% , and the frequency in control group was 54.00% .
the ratio of cases / controls for average distribution frequency of d allele in caucasians was slightly elevated when compared with those in asians and africans ( asians : mcns / control = 1.13 ; caucasians : mcns / control = 1.24 ; africans : mcns / control = 0.93 ) . in this meta - analysis , we found there was a significant association between d allele or dd genotype and risk of mcns in overall populations ( p = .007 , p = .04 ; table 2 ) .
the fixed effects or estimated for the mcns susceptibility was 1.39 in d allele patients when compared with patients carrying i allele ( 95% ci : 1.091.76 ) , with evidence of between - study heterogeneity ( p = .64 ; table 2 ) .
furthermore , the fixed effect or estimated for the risk of developing mcns was 1.46 in dd homozygous patients compared with both other genes combined ( 95% ci : 1.012.11 ) , for the reason that the p value of heterogeneity test was  .45 .
we also documented there was notable association between the ii genotype and the risk of mcns relative to both other genotypes combined ( or = 0.65 , 95% ci : 0.440.96 , p = .03 , table 2 ) . in our study , we found that the average frequency of d allele in control group of africans was a little elevation when compared with those in asians and caucasians ( africans : 54.00% ; asians : 47.65% ; caucasians : 52.01% ) .
true race - specific genetic effects might affect the results of our analysis for the association of ace i / d gene polymorphism with the onset of mcns . in order to evaluate the race - specific effect , we divided the population by ethnicity . in asians
, we found that the association of d allele or dd genotype with mcns susceptibility was positively significant ( p = .01 and p = .02 , resp . ) ( table 2 , figures 1 and 2 ) .
however , the ii genotype seemed not to play a protective role against mcns risk for asians ( or = 0.73 , 95% ci : 0.491.09 ; p = .12 ) ( table 2 , figure 3 ) .
interestingly , there was also no significant association between ace i / d gene polymorphism and mcns susceptibility in caucasian population and africans ( caucasian : d : p = .16 ; dd : p = .98 ; ii : p = .09 ; africans : d : p = .81 ; dd : p = .49 ; ii : p = .76 ) ( table 2 ) .
there is increasing evidence suggesting that the rennin - angiotensin system ( ras ) has been a well - documented participation in the pathogenesis of renal disease .
genetic markers , in particular ace i / d gene polymorphism , might offer some benefits to better predict the outcome of renal diseases .
the level of plasma ace , constitutively expressed in several types of somatic cells , is linked to an i / d gene polymorphism of 287  bp in intron 16 of the ace gene [ 7 , 12 ] .
the d allele and dd genotype has been reported to be associated with higher plasma ace level .
ace is a key enzyme of ras that can convert inactive angiotensin i into a vasoactive and aldosterone - stimulating peptide angiotensin ii [ 14 , 15 ] .
the elevation of ace protein expression might be responsible for the elevation of plasma angiotensin ii level . increased angiotensin ii level
makes deleterious actions on renal hemodynamics and induces the protein expression of some other growth factors , leading to glomerulosclerosis [ 17 , 18 ] .
mcns , an important histopathological characteristic of ins , is one of the most common acquired renal diseases .
data on the risk factors for poor prognosis and the pathogenesis of mcns are insufficient .
furthermore , findings on the association of ace i / d gene polymorphism with mcns susceptibility have been controversial since the first investigation was reported . in order to draw a more convincing conclusion ,
this meta - analysis was performed to explore the association between ace i / d gene polymorphism and mcns risk .   in this investigation ,
six studies were recruited into our meta - analysis , four studies in asians , one investigation for caucasian population and one in africans . in order to achieve a satisfactory power , meta - analysis of multiple studies clearly has a role in offering an association with such potentials . in our meta - analysis for overall populations
, we found the association between d allele or dd homozygous and the risk of mcns was statistically significant , and the ii genotype seemed to play a protective factor against mcns risk .
however , the disequilibrium of gene distributions among asians , caucasians , and africans in healthy controls was observed in our study , which might affect the credibility of the conclusion .
the average frequency of d allele in control group for african population was a little elevation when compared with that in asians or caucasians , suggesting a discrepant role of continental differences in gene background and living environment .
the results of overall population might be less powerful and it was difficult to draw a convincing conclusion .
therefore , the subgroup analysis was very important in this meta - analysis . in our subgroup analysis , we found that d allele or dd genotype was associated with mcns susceptibility in asians , but not for caucasians and african population . furthermore , ii genotype seemed not to play a positive role against mcns onset for three races .
we speculated that d allele or dd homozygous might sensitively affect mcns susceptibility in asians , but not other two races . in the included investigations
, some studies found the ace i / d gene polymorphism might not be associated with mcns susceptibility . in asians ,
lee et al .    found that the distribution of ace genotypes in korean patients with mcns was similar to that in control , and the dd genotype was more frequent in focal segmental glomerulosclerosis ( fsgs ) than in mcns .
performed an investigation in javanese - indonesian patients and found the ace genotype frequencies of mcns patients were consistent with those of the controls , and d - allele tended to exist more frequently in fsgs patients than in the mcns patients and controls . in caucasians ,
found there was no significant correlation between ace genotype and histology of fsgs or mcns .
furthermore , in africans , saber - ayad et al .   also performed a study on egyptian children with ins and did not find an association between the ace i / d gene polymorphism and histological findings ( including mcns and fsgs ) .
the results in those studies mentioned above were consistent with ours for caucasians and african population , but our conclusions were inconsistent with those of asians above .
however , in the other studies for asian population , the study of al - eisa et al .   suggested an association of the d - allele of the ace gene i / d polymorphism with the clinical manifestation of ins in kuwaiti arab children , but they had not calculated the associations of ace i / d gene polymorphism with mcns risk between the controls and case group , and serdaroglu et al .  
found that d allele frequency was higher in ins group than control group in turks and the d allele frequency had no statistically significant difference between mcns group and fsgs group .
we speculated that the d allele frequency in mcns group in the investigation of serdaroglu et al .
the sample number of the study from serdaroglu et al . was much larger than that in other investigations .
the conclusion of serdaroglu et al . might be more stable when compared with that of others .  
interestingly , in our investigation , we found the distributions of d allele frequency in control group among four asian studies were disequilibrium , ranged   from 24.26% to 75.00% .
the investigated countries for those studies were from east asian to west asian . in the past years
, some studies found that living environment might influence the gene expression [ 1922 ] .
we speculated that the living environment might affect the d allele frequency in controls . on the other hand ,
the sample sizes for some studies were small , which might affect the result for the d allele frequency in controls . in order to draw a more stable conclusion for asians ,
some investigations following larger sample sizes are needed in the future .   for caucasians , the ratio of cases / controls for average distribution frequency of d allele in caucasians was 1.24 , which is slightly elevated when compared with those in asians and africans .
however , the ace i / d gene polymorphism were not associated with the risk of mcns in caucasians ( the analysis for caucasians only including one study ) .
more investigations are required to investigate this relationship for caucasian population in the future . the same as that , more studies investigating the association between ace i / d gene polymorphism and mcns susceptibility for african population are required in the future study .
there were some meta - analyses to explore the relationship between ace i / d gene polymorphism and the susceptibility of some diseases in the past years .
zhang et al .   conducted a meta - analysis to investigate the association of ace i / d gene polymorphism with asthma risk and found there was an association between d allele or dd homozygote and the onset of asthma in asians but not for caucasian population .
ji et al .   performed a meta - analysis to explore the relation between ace i / d gene polymorphism and risk of hypertension in asian population and found that dd genotype was associated with the onset of hypertension .
, respectively , took a meta - analysis for the association of ace i / d gene polymorphism with susceptibility of immunoglobulin a nephropathy ( igan )   and observed that the dd homozygous was associated with an increased risk of igan in asians , but not for caucasian population .
however , there is rarely a   meta - analysis for african population at present .
the conclusions of our investigation were similar   to those in the meta - analyses mentioned above and also found ace d allele or dd homozygote was more sensitive for asians when compared with other ethnic groups .
first , an important threat to any literature - based review and meta - analysis is that of reporting bias ( we only searched the published literatures in english or chinese ) .
last but not the least , the genotype distributions of the control population in two included studies [ 6 , 11 ] did not conform to hardy - weinberg equilibrium test and it might cause bias in our study
in conclusion , the results in our study supported that dd genotype or d allele was associated with mcns susceptibility in asians and overall populations , but the association was not found in caucasians and africans .
the ii homozygous seemed to play a protective role against mcns risk in overall populations , but the associations in asians , caucasian population and africans were not observed . however , more case - control association investigations on larger , stratified populations are required to further clarify the role of this ace i / d gene polymorphism in mcns susceptibility .
 
 aim . 
 this meta - analysis was performed to evaluate the association between ace i / d gene polymorphism and mcns susceptibility . 
 method . a predefined literature search and selection of eligible relevant studies 
 were performed to collect the data from electronic databases . 
 
 results . 
 six articles were identified for the analysis of association between ace i / d gene polymorphism and mcns risk , including 4 for asians , one in caucasian population and one for africans . 
 there was a markedly positive association between d allele or dd genotype and mcns susceptibility in asians ( d : p = .01 , dd : p = .02 ) , but not for caucasians and africans ( caucasians : d : p = .16 , dd : p = .98 ; 
 africans : d : p = .81 , dd : p = .49 ) . 
 furthermore , the ii genotype seemed not to play a protective role against mcns risk for asians , caucasians and africans ( p = .12 , p = .09 , p = .76 , resp . ) . 
 interestingly , there was also significant association between ace i / d gene polymorphism and mcns susceptibility in overall populations ( d : p = .007 , dd : p = .04 , ii : p = .03 ) . 
 conclusion . 
 d allele or dd genotype might be a significant genetic molecular marker for mcns susceptibility in asians and overall populations , but not for caucasians and africans . 
 more larger and rigorous genetic epidemiological investigations are required to further explore this association . 
 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Limitations
6. Conclusions
 Conflict of Interests