gliomas account for more than 70% of all brain tumors , and of which , malignant gliomas , the most common primary brain tumor in adults , are generally associated with poor survival relative to other types of brain tumors .
many environmental and lifestyle factors , including several occupations , ionizing radiation , cellular phones , smoking , and diet , have been considered to be associated with an increased glioma risk .
recently , accumulating evidence suggests that inherited risks may play an important role in glioma .
genetic studies , including genome - wide association studies ( gwas ) , demonstrated that several genetic factors might be associated with glioma , such as ccdc26 , egfr , rtel , gstp1 , tert , and phldb1 genes .
usually , dna damage can be induced by exogenous carcinogens , such as ultraviolet rays and ionizing radiation , and contributes to genomic instability .
dna repair , playing an important role in the maintaining genomic integrity , involves several dna repair pathways , including base excision repair ( ber ) , mismatch repair ( mmr ) , and nucleotide excision repair ( ner ) .
previous studies indicated that variants in dna repair genes might impair the dna repair capacity and contribute to cancer risk .
excision repair cross complementation group 1 ( ercc1 ) , ercc2 , and ercc5 genes are dna repair genes , whose products are important in ner .
recently , several studies have focused on the association between polymorphisms in ercc1 gene ( rs3212986 , rs11615 ) , ercc2 gene ( rs1799793 , rs13181 , and rs238406 ) , or ercc5 rs17655 polymorphism and glioma risk . however , the results were inconclusive , which might be due to studies with limited sample sizes or ethnic differences . to date , several meta - analyses reported the association between ercc1 or ercc2 polymorphisms and glioma risk , whereas these studies only focused on the 2 polymorphisms ( rs3212986 in ercc1 gene and rs13181 in ercc2 gene ) .
thus , we conducted a comprehensive meta - analysis to investigate whether 6 polymorphisms in ercc1 ( rs3212986 and rs11615 ) , ercc2 ( rs13181 , rs1799793 and rs238406 ) , and ercc5 ( rs17655 ) genes are risk factors to the glioma susceptibility .
we performed this meta - analysis according to the guidelines of preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement .
a comprehensive literature search was performed through the pubmed , embase , and web of science up to september 6 , 2016 .
search strategies were as follows :  glioma  or  brain tumor ,   polymorphism ,  and  ercc1 ,  
in addition , the reference lists of all selected articles were checked by hand - search for additional potential studies .
studies were included in the meta - analysis if they met the following criteria : case  control or cohort studies ; association between ercc1 ( rs3212986and rs11615 ) , ercc2 ( rs13181 , rs1799793 , and rs238406 ) , or ercc5 ( rs17655 ) polymorphism and glioma risk ; available allele and genotype frequencies .
major reasons for exclusion of studies were as follows : articles only with an abstract , review articles , and comments ; articles considered overlapped with other studies ; and studies that had no control group .
the following information from each eligible study was extracted independently by 2 investigators : first author 's name , publication year , ethnicity ( europeans and asians ) , whether cases and controls were matched ( for case  control studies ) , and genotype distribution in cases and controls .
if the article did not provide sufficient genotype distribution , the corresponding author was contacted for the detailed data .
disagreements were resolved by discussion between the 2 investigators . moreover , our analyses were based on previously published studies ; thus , no ethical approval and patient consent are required the quality of the studies was independently assessed by 2 authors according to the quality scoring criteria , which is modified from previous meta - analyses ( table 1 ) .
quality scores ranged from 0 points ( worst ) to 13 points ( best ) .
studies scoring less than 9 points were classified as low quality , and those scoring 9 points or higher were classified as high quality .
the strength of the association between 6 polymorphisms in ercc1 , ercc2 , and ercc5 genes and glioma risk was estimated by odds ratios ( ors ) with corresponding 95% confidence intervals ( cis ) .
the genetic models evaluated for the pooled or of rs3212986 polymorphism were allele contrast ( a vs c ) , homozygote comparison ( aa vs cc ) , heterozygote comparison ( ac vs cc ) , dominant model ( aa+ac vs cc ) , as well as recessive model ( aa vs ac+cc ) .
the significance of the pooled or was determined by the z - test , and a p value less than .05 was considered as statistically significant .
heterogeneity was considered significant for p  <  .10 , and then the random effect model was selected ; otherwise , a fixed - effects model was used .
in addition , galbraith plot was used to visualize the impact of individual studies on the overall heterogeneity , which spotted the outlier as the possible origin of heterogeneity .
the hardy  weinberg equilibrium ( hwe ) in the control group was also assessed , and a p  <  .05 was considered as significant disequilibrium .
sensitivity analysis was performed by sequential excluding a single study each time in an attempt to identify the potential influence of the individual data to the pooled ors .
cumulative meta - analysis was carried out for each polymorphism in association with glioma to evaluate the trend of the genetic risk effect ( or ) of the allele comparisons as evidence accumulates over time .
if significant publication bias was detected , trim and fill methods was used to adjust ors and 95% cis .
analyses were performed using stata software , version 12 ( statacorp lp , college station , tx ) .
we performed this meta - analysis according to the guidelines of preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement .
a comprehensive literature search was performed through the pubmed , embase , and web of science up to september 6 , 2016 .
search strategies were as follows :  glioma  or  brain tumor ,   polymorphism ,  and  ercc1 ,  
in addition , the reference lists of all selected articles were checked by hand - search for additional potential studies .
studies were included in the meta - analysis if they met the following criteria : case  control or cohort studies ; association between ercc1 ( rs3212986and rs11615 ) , ercc2 ( rs13181 , rs1799793 , and rs238406 ) , or ercc5 ( rs17655 ) polymorphism and glioma risk ; available allele and genotype frequencies .
major reasons for exclusion of studies were as follows : articles only with an abstract , review articles , and comments ; articles considered overlapped with other studies ; and studies that had no control group .
the following information from each eligible study was extracted independently by 2 investigators : first author 's name , publication year , ethnicity ( europeans and asians ) , whether cases and controls were matched ( for case  control studies ) , and genotype distribution in cases and controls .
if the article did not provide sufficient genotype distribution , the corresponding author was contacted for the detailed data .
disagreements were resolved by discussion between the 2 investigators . moreover , our analyses were based on previously published studies ; thus , no ethical approval and patient consent are required
the quality of the studies was independently assessed by 2 authors according to the quality scoring criteria , which is modified from previous meta - analyses ( table 1 ) .
quality scores ranged from 0 points ( worst ) to 13 points ( best ) .
studies scoring less than 9 points were classified as low quality , and those scoring 9 points or higher were classified as high quality .
the strength of the association between 6 polymorphisms in ercc1 , ercc2 , and ercc5 genes and glioma risk was estimated by odds ratios ( ors ) with corresponding 95% confidence intervals ( cis ) .
the genetic models evaluated for the pooled or of rs3212986 polymorphism were allele contrast ( a vs c ) , homozygote comparison ( aa vs cc ) , heterozygote comparison ( ac vs cc ) , dominant model ( aa+ac vs cc ) , as well as recessive model ( aa vs ac+cc ) .
the significance of the pooled or was determined by the z - test , and a p value less than .05 was considered as statistically significant .
heterogeneity was considered significant for p  <  .10 , and then the random effect model was selected ; otherwise , a fixed - effects model was used .
in addition , galbraith plot was used to visualize the impact of individual studies on the overall heterogeneity , which spotted the outlier as the possible origin of heterogeneity .
the hardy  weinberg equilibrium ( hwe ) in the control group was also assessed , and a p  <  .05 was considered as significant disequilibrium .
sensitivity analysis was performed by sequential excluding a single study each time in an attempt to identify the potential influence of the individual data to the pooled ors .
cumulative meta - analysis was carried out for each polymorphism in association with glioma to evaluate the trend of the genetic risk effect ( or ) of the allele comparisons as evidence accumulates over time .
if significant publication bias was detected , trim and fill methods was used to adjust ors and 95% cis .
analyses were performed using stata software , version 12 ( statacorp lp , college station , tx ) .
a total of 166 studies were identified during our premature searches . after a review of titles and abstracts ,
1 article only with an abstract , 8 about other tumors , 3 review articles , and 2 articles reported other polymorphisms . finally , a total of 14 articles met our selection criteria .
1 . among them , 1 article reported data on 2 different series , and we treated them independently . finally , 15 studies comprising 4878 cases and 6748 controls were included in the meta - analysis .
studies were conducted in 2 populations of ethnic descent : 8 europeans and 7 asians .
the distribution of genotypes in the control groups of all studies was in agreement with hwe except one .
the association between the ercc1 rs3212986 polymorphism and susceptibility to glioma was assessed in a total of 3539 cases and 5035 controls . as summarized in table 3 and fig .
2a , a significant association was observed in allele comparison ( a vs c : or  =  1.079 , 95% ci  =  1.0071.157 , p  =  .032 ) , homozygote comparison ( aa vs cc : or  =  1.280 , 95% ci  =  1.0831.514 , p  =  .004 ) , and recessive model ( aa vs ac + cc : or  =  1.263 , 95% ci  =  1.0741.486 , p  =  .005 ) in overall population . in the subgroup analysis by ethnicity
, a significantly increased glioma risk was found in asian population ( a vs c : or  =  1.132 , 95% ci  =  1.0221.254 , p  =  .018 ; aa vs cc : or  =  1.298 , 95% ci  =  1.0431.630 , p  =  .025 ; and aa vs aa + ac : or  =  1.250 , 95% ci  =  1.0041.556 , p  =  .046 ) .
however , in europeans , a significant association between rs3212986 polymorphism and glioma risk was only observed in recessive model ( aa vs aa + ac : or  =  1.280 , 95% ci  =  1.0041.631 , p  =  .046 ) .
moreover , the results did not show significant association between ercc1 rs11615 polymorphism and glioma risk .
forest plots for the association between theercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( a vs c ) ; ( b ) ercc2 rs13181 polymorphism ( c vs a ) .
the sizes of the squares reflect the weighting of included studies ; the center of diamonds reflect summary effect , the left and right extremes of diamonds reflect 95% confidence intervals .
meta - analysis findings of association between rs13181 polymorphism and glioma are summarized in table 4 .
when stratified by ethnicity , a significantly increased glioma risk was found in asians ( c vs a : or  =  1.259 , 95% ci  =  1.0951.466 , p  =  .001 ) ( fig
. 2b ) . for the rs1799793 polymorphism , significantly increased glioma risk was also observed in asians ( a vs g : or  =  1.274 , 95% ci  =  1.1181.451 , p  <  .001 ) . however , nonsignificant correlation was observed between rs238406 polymorphsim and glioma risk .
chi - square based q test showed that significant heterogeneity existed in 3 genetic models for rs13181 polymorphism ( c vs a : p  =  .045 , ca vs aa : p  =  .070 , cc+ca vs aa : p  =  .051 , cc vs ca+aa : p  =  .037 ) .
galbraith plots showed that 1 independent study was the possible origin of heterogeneity , and the heterogeneity was removed when this study was excluded ( c vs a : ph  =  .452 , ca vs aa : ph  =  .242 , cc+ca vs aa : ph  =  .254 ) ( fig .
the 95% confidence interval is between the 2 outer parallel lines at 2 units above and below the regression line .
a total of 1989 patients and 3216 controls were analyzed for ercc5 rs17655 polymorphism and glioma risk .
the results showed that the risk for glioma was not significantly increased in persons carrying a c allele compared with those carrying a g allele ( c vs g : or=1.036 , 95% ci=0.8991.195 ) .
moreover , the chi - square based q test and i test indicated that between - study heterogeneity was not significant in all genetic models .
sensitivity analysis was performed by sequential removal of each study , the results of which showed that the pooled ors were consistently significant by omitting 1 study at a time ( fig .
, pooled ors tended to be significant and stable with the accumulation of more data over time ( fig .
, these results suggested that the results of this meta - analysis were highly stable .
sensitivity analysis on the association between the ercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( a vs c ) ; ( b ) ercc2 rs13181 polymorphism ( c vs a ) .
results were computed by omitting each study ( left column ) in turn . a cumulative meta - analysis on the association between the ercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( a vs c ) ; ( b ) ercc2 rs13181 polymorphism ( c vs a ) . pooled or estimates with the 95% ci as information accumulates at the end of each year ( left column ) .
the shapes of the funnel plots did not reveal evidence of obvious asymmetry in all comparison models ( fig .
moreover , the results of egger test confirmed this finding ( p  =  .566 for aa vs cc in rs3212986 polymorphism , p  =  .163 for tt vs cc in rs11615 polymorphism , p  =  .311 for cc vs aa in rs13181 polymorphism , p  =  .973 for aa vs gg in rs1799793 polymorphism , p  =  .076 for aa vs cc in rs238406 polymorphism , and p  =  .735 for cc vs gg in rs17655 polymorphism ) .
funnel plots of the association between the ercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( aa vs ac+cc ) ; ( b ) ercc2 rs13181 polymorphism ( cc vs ca+aa ) .
the vertical line in the funnel plot indicates the summary estimate , while the sloping lines indicate the expected 95% ci for a given standard error , assuming no heterogeneity between studies .
a total of 166 studies were identified during our premature searches . after a review of titles and abstracts ,
1 article only with an abstract , 8 about other tumors , 3 review articles , and 2 articles reported other polymorphisms . finally , a total of 14 articles met our selection criteria .
1 . among them , 1 article reported data on 2 different series , and we treated them independently . finally , 15 studies comprising 4878 cases and 6748 controls were included in the meta - analysis .
studies were conducted in 2 populations of ethnic descent : 8 europeans and 7 asians .
the distribution of genotypes in the control groups of all studies was in agreement with hwe except one .
the association between the ercc1 rs3212986 polymorphism and susceptibility to glioma was assessed in a total of 3539 cases and 5035 controls . as summarized in table 3 and fig .
2a , a significant association was observed in allele comparison ( a vs c : or  =  1.079 , 95% ci  =  1.0071.157 , p  =  .032 ) , homozygote comparison ( aa vs cc : or  =  1.280 , 95% ci  =  1.0831.514 , p  =  .004 ) , and recessive model ( aa vs ac + cc : or  =  1.263 , 95% ci  =  1.0741.486 , p  =  .005 ) in overall population . in the subgroup analysis by ethnicity , a significantly increased glioma risk was found in asian population ( a vs c : or  =  1.132 , 95% ci  =  1.0221.254 , p  =  .018 ; aa vs cc : or  =  1.298 , 95% ci  =  1.0431.630 , p  =  .025 ; and aa vs aa + ac : or  =  1.250 , 95% ci  =  1.0041.556 , p  =  .046 ) .
however , in europeans , a significant association between rs3212986 polymorphism and glioma risk was only observed in recessive model ( aa vs aa + ac : or  =  1.280 , 95% ci  =  1.0041.631 , p  =  .046 ) .
moreover , the results did not show significant association between ercc1 rs11615 polymorphism and glioma risk .
forest plots for the association between theercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( a vs c ) ; ( b ) ercc2 rs13181 polymorphism ( c vs a ) .
the sizes of the squares reflect the weighting of included studies ; the center of diamonds reflect summary effect , the left and right extremes of diamonds reflect 95% confidence intervals .
meta - analysis findings of association between rs13181 polymorphism and glioma are summarized in table 4 .
there was no significant association observed in the overall population . when stratified by ethnicity , a significantly increased glioma risk was found in asians ( c vs a : or  =  1.259 , 95% ci  =  1.0951.466 , p  =  .001 ) ( fig .
for the rs1799793 polymorphism , significantly increased glioma risk was also observed in asians ( a vs g : or  =  1.274 , 95% ci  =  1.1181.451 , p  <  .001 ) .
chi - square based q test showed that significant heterogeneity existed in 3 genetic models for rs13181 polymorphism ( c vs a : p  =  .045 , ca vs aa : p  =  .070 , cc+ca vs aa : p  =  .051 , cc vs ca+aa : p  =  .037 ) .
galbraith plots showed that 1 independent study was the possible origin of heterogeneity , and the heterogeneity was removed when this study was excluded ( c vs a : ph  =  .452 , ca vs aa : ph  =  .242 , cc+ca vs aa : ph  =  .254 ) ( fig .
the 95% confidence interval is between the 2 outer parallel lines at 2 units above and below the regression line .
a total of 1989 patients and 3216 controls were analyzed for ercc5 rs17655 polymorphism and glioma risk .
the results showed that the risk for glioma was not significantly increased in persons carrying a c allele compared with those carrying a g allele ( c vs g : or=1.036 , 95% ci=0.8991.195 ) .
moreover , the chi - square based q test and i test indicated that between - study heterogeneity was not significant in all genetic models .
sensitivity analysis was performed by sequential removal of each study , the results of which showed that the pooled ors were consistently significant by omitting 1 study at a time ( fig .
, pooled ors tended to be significant and stable with the accumulation of more data over time ( fig .
, these results suggested that the results of this meta - analysis were highly stable .
sensitivity analysis on the association between the ercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( a vs c ) ; ( b ) ercc2 rs13181 polymorphism ( c vs a ) .
results were computed by omitting each study ( left column ) in turn . a cumulative meta - analysis on the association between the ercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( a vs c ) ; ( b ) ercc2 rs13181 polymorphism ( c vs a ) . pooled or estimates with the 95% ci as information accumulates at the end of each year ( left column ) .
the shapes of the funnel plots did not reveal evidence of obvious asymmetry in all comparison models ( fig .
6 ) . moreover , the results of egger test confirmed this finding ( p  =  .566 for aa vs cc in rs3212986 polymorphism , p  =  .163 for tt vs cc in rs11615 polymorphism , p  =  .311 for cc vs aa in rs13181 polymorphism , p  =  .973 for aa vs gg in rs1799793 polymorphism , p  =  .076 for aa vs cc in rs238406 polymorphism , and p  =  .735 for cc vs gg in rs17655 polymorphism ) .
funnel plots of the association between the ercc1 rs3212986 and ercc2 rs13181 polymorphisms and glioma risk .
( a ) ercc1 rs3212986 polymorphism ( aa vs ac+cc ) ; ( b ) ercc2 rs13181 polymorphism ( cc vs ca+aa ) .
the vertical line in the funnel plot indicates the summary estimate , while the sloping lines indicate the expected 95% ci for a given standard error , assuming no heterogeneity between studies .
logor natural logarithm of the or , s.e . of logor standard error of the logor .
dna repair plays an important role in the maintaining genomic integrity , which consists of several pathways .
recent studies showed that ner was one of the most important pathways during dna repair .
ercc1 , ercc2 , and ercc5 were core factors that participated in the ner pathway . during ner , the ercc1 gene codes for a protein that makes the 5 incision by forming a complex with xpf .
moreover , melton et al showed that mutant cells from ercc1-deficient mice showed ner deficiency and had an increased mutation frequency as well as an elevated level of genomic instability .
moreover , accumulated genetic epidemiological studies have been conducted to explore the association between ercc1 , ercc2 , and ercc5 polymorphisms and glioma risk ; however , the results were inconclusive .
therefore , we performed a comprehensive meta - analysis with published studies to clarify the role of these polymorphisms in glioma .
this meta - analysis demonstrated that ercc1 rs3212986 polymorphism was significantly associated with glioma risk under the following genetic models ( aa vs cc : or  =  1.280 , 95% ci=1.0831.514 , p  =  .004 and aa vs ac + cc : or  =  1.263 , 95% ci  =  1.0741.486 , p  =  .005 ) .
when stratified by ethnicity , the significant association was still observed in asians ( aa vs cc : or  =  1.298 , 95% ci  =  1.0431.630 , p  =  .025 ) , but not among europeans in major genetic models , suggesting that the contribution of ercc1 rs3212986 polymorphism might vary across different populations . generally , europeans more frequently suffered from glioma than people of african or asian descent , which was also observed in children .
in addition , the pooled or did not change in the sensitivity analysis by excluding 1 study each time , indicating that the results of this meta - analysis were highly stable . finally , cumulative meta - analysis indicated that pooled ors tended to be significant and stable with the accumulation of more data over time .
the ercc2 rs13181 polymorphism showed significant association with glioma susceptibility ( cc vs aa : or  =  1.539 , 95% ci  =  1.1222.109 , p  =  .007 ) in asians .
( aa vs gg : or  =  1.474 , 95% ci  =  1.0901.994 , p  =  .012 ) . in the analysis of rs11381 polymorphism ,
significant heterogeneity existed in major genetic models when all eligible studies were pooled into analysis .
however , the results of galbraith plots analyses indicated that 1 independent study was the main potential origin of heterogeneity ; when excluding , the heterogeneity was removed .
moreover , a sensitivity analysis showed that no single study qualitatively changed the pooled ors .
however , there was no significant association observed between rs11615 , rs238406 , or rs17655 polymorphism and glioma susceptibility .
our analyses demonstrated that the ercc1 rs3212986 and ercc2 gene ( rs13181 and rs1799793 ) polymorphisms had a moderate increase in glioma susceptibility .
second , it is clear that genetic susceptibility to cancer is complex because of interactions between genes and environmental factors .
however , we could not assess gene  environment interactions due to insufficient data in most studies .
recently , pan et al investigated the association between language biases and selective reporting in human genome epidemiology , which demonstrated that chinese studies showed more prominent genetic effects than non - chinese studies , whereas the sample size of chinese studies was always smaller .
thus , more non - chinese studies in asian populations were needed to confirm the significant association in asians .
in addition , gwas have identified single nucleotide polymorphisms implicating hundreds of replicated loci for common traits and became a powerful tool to detect the susceptibility genes in cancers .
accumulated gwas have provided strong evidences for the association between glioma risk and numerous genes , including tert , terc , egfr , ccdc26 , and rtel .. however , to date , association of polymorphisms in ercc genes with susceptibility to glioma has not been investigated in gwas .
thus , further genetics studies , especially gwas studies , are required to confirm the possible role of ercc polymorphisms in glioma .
future studies with larger sample size in different ethnic groups ( e.g. , asians and africans ) are needed to clarify the possible roles of ercc1 , ercc2 , and ercc5 genes in the etiology and progression of glioma .
in addition , studies investigating gene  environment may lead to a better understanding of the role of the ercc gene polymorphisms in glioma .
 abstractbackground : a number of studies have investigated the roles of excision repair cross complementation group 1 ( ercc1 ) , ercc2 , and ercc5 genes polymorphisms in the development of glioma ; however , the results were inconsistent . here , we performed a meta - analysis to investigate the association between 6 polymorphisms in the ercc genes ( rs3212986 , rs11615 , rs13181 , rs1799793 , rs238406 , rs17655 ) and glioma risk.methods:the pubmed , embase , and web of science were searched up to september 6 , 2016 , for studies on the association between ercc polymorphisms and glioma risk . 
 a fixed - effects or random - effects model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests . 
 sensitivity and cumulative meta - analyses were also performed.results:a total of 15 studies were eligible for the pooled analysis , conducted in 2 populations of ethnic descent : 8 europeans and 7 asians . 
 the results showed that ercc1 rs3212986 polymorphism was positively associated with glioma [ aa vs cc : odds ratio ( or ) = 1.298 , 95% confidence interval ( 95% ci ) = 1.0431.230 , p  =  .025 ] . 
 association of the ercc2 rs13181 and rs1799793 polymorphisms was only observed in asians ( cc vs aa for rs13181 : or  =  1.539 , 95% ci  =  1.1222.109 , p  =  .007 ; aa vs gg for rs1799793 : or  =  1.474 , 95% ci  =  1.0901.994 , p  =  .012 ) . 
 however , no association was observed between glioma risk and ercc1 rs11615 , ercc2 rs238406 , and ercc5 rs17655 polymorphisms . 
 moreover , sensitivity and cumulative meta - analyses confirmed the stability of the results.conclusions:our meta - analysis indicated that the ercc1 rs3212986 polymorphism and 2 polymorphisms in ercc2 gene ( rs13181 and rs1799793 ) contributed to the susceptibility of glioma . 