diabetes is a group of worldwide prevalent , metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion , insulin action , or both . two major etiopathogenetic groups of diabetes mellitus have been defined : type 1 and type 2 . diabetes type 2 is much more prevalent and has a more complicated etiology involving a combination of genetic to environmental factors . diabetes mellitus affects approximately 347 million people worldwide , 90% of which have type 2 diabetes , and accounts for an estimated 3.4 million death in 2004 . the economic costs and burden of diabetes are considerable , given the substantial morbidity and vital multi - organ complications . in recent years many genes have been identified to be associated with type 2 diabetes susceptibility . slc30a8 , as a coding gene of zinc transporter 8 ( znt8 ) , was reported to contribute to type 2 diabetes susceptibility [ 69 ] . znt8 , a novel member of znt family , is predominately expressed in pancreatic islet beta cells and is responsible for cellular efflux of zinc from cytoplasm into intracellular vesicles . it localizes into insulin secretory granules and is indispensable for insulin crystallization , storage , and secretion [ 1012 ] . antibodies against znt8 have been identified as novel biomarkers for autoimmune diabetes [ 1319 ] . the association of slc30a8 variants with type 2 diabetes has also received much attention , with an important polymorphism , rs13266634 , being the most studied [ 1929 ] . this non - synonymous variant ( rs13266634 ) is a c - to - t variant ( arginine to tryptophan at position 325 , r325w ) and had been confirmed to be associated with higher risk of type 2 diabetes in various ethnic populations [ 69,3033 ] . although a number of studies , including some meta - analyses , have been conducted to investigate the association between rs13266634 , the most common variant of slc30a8 , and the risk of type 2 diabetes in diverse populations , the results were mixed and inconclusive , possibly due to the relatively small sample size in the included studies . meta - analysis is a cost - effective method to increase sample size by combining data from different independent studies , and is recognized as a ideal tool for summarizing inconsistent results from multiple studies . there has recently been an increase in the number of these studies , but there is no updated meta - analysis investigating the association between them . to provide the most comprehensive assessment of the relationship between rs13266634 variant and type 2 diabetes risk , we performed an updated meta - analysis of all available studies . the meta - analysis was conducted according to the prisma statement ( preferred reporting items for systematic reviews and meta - analyses , checklist s1 )   and meta - analysis on genetic association studies ( checklist s2 ) . we searched pubmed and cochrane library from 2007 , the year when the association of slc30a8 and diabetes was first reported [ 69 ] , to identify all relevant papers on humans published in english . the following terms were used in searching : ( rs13266634 or zinc transporter protein member 8 or znt8 or znt-8 or slc30a8 ) and ( polymorphism or variant or loci ) and diabetes . all eligible studies were retrieved and their references were checked for other relevant publications in english . the titles and abstracts were scanned to exclude studies that were clearly irrelevant to the current topic . the full text of the remaining articles was read to determine whether they contained information of interest . two independent reviewers ( cheng and zhang ) performed a systematic search in pubmed and cochrane databases , with the last search updated on june 25 , 2014 . studies included in the meta - analysis were required to meet the following criteria : ( 1 ) case - control study or prospective study that evaluated the association between rs13266634 and type 2 diabetes in humans ; and ( 2 ) had an odds ratio ( or ) with 95% confidence interval ( ci ) or detailed genotype data for estimating or ( 95% ci ) . exclusion criteria are : ( 1 ) duplication of previous publications ; ( 2 ) comment , review , or editorial ; and ( 3 ) family - based studies of pedigrees . two investigators ( cheng and zhang ) independently extracted information from all eligible publications . data extracted from each study included the following characteristics : the first author s name , the year of publication , ethnicity of participants , age , age at diagnosis , body mass index ( bmi ) , fasting plasma glucose ( fpg ) , total number , genotype numbers and frequency , and the most completely adjusted estimate ( or and 95% ci , respectively ) of the rs13266634 polymorphism in the cases and controls . if dissent still existed , the third investigator ( zhou ) would be involved to adjudicate the disagreements . for those included articles without all desired wanted data , we emailed the authors , providing contact information , to ask for details . the quality of selected studies was assessed by 3 investigators ( cheng , zhang , and zhou ) independently scoring studies according to a set of predetermined criteria adjusted from previous reports . quality scores ranged from 0 to 10 and studies were scored as  good  if the score was 810 , all statistical tests were conducted with stata software version 11.0 ( stata corp , college station , texas ) . to investigate the association strength between slc30a8 rs13266634 polymorphism and the susceptibility of type 2 diabetes , we used adjusted ors and corresponding 95% cis from all studies , and calculated ors from studies with genotype distribution information to pool ors and corresponding 95% cis . for those studies with raw genotype count , we then obtained pooled ors and corresponding 95% cis from combination of single studies by homozygote and heterozygote comparison ( cc vs. tt , or1 ; ct vs. tt , or2 ; cc vs. ct , or3 ) , overdominant ( cc+ct vs. tt ) an dominant and recessive models ( cc vs. ct+tt and cc+ct vs. tt ) , respectively . we also performed subgroup analysis on ethnicity , hardy - weinberg equilibrium ( hwe ) , genotyping methods , sample size ( large sample 1000 , small sample < 1000 ) , study design ( population - based case - control study , hospital - based case - control study , and prospective study ) , and quality of studies in these comparisons . environmental effects associated with diabetes , such as diet and exercise , were not analyzed due to limited details . z - test was used for assessing the significance of the pooled ors , with p<0.05 considered statistically significant . a biological justification for the choice of the genetic model was estimated according the relationships of or1 , or2 and or3 . cumulative meta - analysis by publication year was conducted to investigate time - based fluctuation and robustness of results . heterogeneity among the studies was evaluated as notable by the chi - square - based q - test ( significance level of p<0.10 ) and/or i index ( greater than 50% as evidence of significant inconsistency )   and the random - effects model ( dersimonian and laird method ) ; otherwise , the fixed - effects model ( mantel and haenszel method ) was employed . the significance of pooled ors was determined by z - test and p<0.05 was considered as statistically significant . for the controls of each study with detailed genotype count , hwe was evaluated using the goodness - of - fit chi - square test and a p<0.05 was considered to deviate from hwe . to identify the effect of any individual study , especially studies deviating from hwe sensitivity analysis was also carried out by deleting a single study each time to examine the influence of individual data sets on the pooled ors . publication bias of literature was examined using begg s funnel plots and egger s test . an asymmetrical plot suggests possible publication bias and the p value of egger s test less than 0.05 was considered the presence of potential publication bias . we searched pubmed and cochrane library from 2007 , the year when the association of slc30a8 and diabetes was first reported [ 69 ] , to identify all relevant papers on humans published in english . the following terms were used in searching : ( rs13266634 or zinc transporter protein member 8 or znt8 or znt-8 or slc30a8 ) and ( polymorphism or variant or loci ) and diabetes . all eligible studies were retrieved and their references were checked for other relevant publications in english . the titles and abstracts were scanned to exclude studies that were clearly irrelevant to the current topic . the full text of the remaining articles was read to determine whether they contained information of interest . two independent reviewers ( cheng and zhang ) performed a systematic search in pubmed and cochrane databases , with the last search updated on june 25 , 2014 . studies included in the meta - analysis were required to meet the following criteria : ( 1 ) case - control study or prospective study that evaluated the association between rs13266634 and type 2 diabetes in humans ; and ( 2 ) had an odds ratio ( or ) with 95% confidence interval ( ci ) or detailed genotype data for estimating or ( 95% ci ) . exclusion criteria are : ( 1 ) duplication of previous publications ; ( 2 ) comment , review , or editorial ; and ( 3 ) family - based studies of pedigrees . data extracted from each study included the following characteristics : the first author s name , the year of publication , ethnicity of participants , age , age at diagnosis , body mass index ( bmi ) , fasting plasma glucose ( fpg ) , total number , genotype numbers and frequency , and the most completely adjusted estimate ( or and 95% ci , respectively ) of the rs13266634 polymorphism in the cases and controls . if dissent still existed , the third investigator ( zhou ) would be involved to adjudicate the disagreements . for those included articles without all desired wanted data , we emailed the authors , providing contact information , to ask for details . the quality of selected studies was assessed by 3 investigators ( cheng , zhang , and zhou ) independently scoring studies according to a set of predetermined criteria adjusted from previous reports . quality scores ranged from 0 to 10 and studies were scored as  good  if the score was 810 , all statistical tests were conducted with stata software version 11.0 ( stata corp , college station , texas ) . to investigate the association strength between slc30a8 rs13266634 polymorphism and the susceptibility of type 2 diabetes , we used adjusted ors and corresponding 95% cis from all studies , and calculated ors from studies with genotype distribution information to pool ors and corresponding 95% cis . for those studies with raw genotype count , we then obtained pooled ors and corresponding 95% cis from combination of single studies by homozygote and heterozygote comparison ( cc vs. tt , or1 ; ct vs. tt , or2 ; cc vs. ct , or3 ) , overdominant ( cc+ct vs. tt ) an dominant and recessive models ( cc vs. ct+tt and cc+ct vs. tt ) , respectively . we also performed subgroup analysis on ethnicity , hardy - weinberg equilibrium ( hwe ) , genotyping methods , sample size ( large sample 1000 , small sample < 1000 ) , study design ( population - based case - control study , hospital - based case - control study , and prospective study ) , and quality of studies in these comparisons . environmental effects associated with diabetes , such as diet and exercise , were not analyzed due to limited details . z - test was used for assessing the significance of the pooled ors , with p<0.05 considered statistically significant . a biological justification for the choice of the genetic model was estimated according the relationships of or1 , or2 and or3 . cumulative meta - analysis by publication year was conducted to investigate time - based fluctuation and robustness of results . heterogeneity among the studies was evaluated as notable by the chi - square - based q - test ( significance level of p<0.10 ) and/or i index ( greater than 50% as evidence of significant inconsistency )   and the random - effects model ( dersimonian and laird method ) ; otherwise , the fixed - effects model ( mantel and haenszel method ) was employed . the significance of pooled ors was determined by z - test and p<0.05 was considered as statistically significant . for the controls of each study with detailed genotype count , hwe was evaluated using the goodness - of - fit chi - square test and a p<0.05 was considered to deviate from hwe . to identify the effect of any individual study , especially studies deviating from hwe sensitivity analysis was also carried out by deleting a single study each time to examine the influence of individual data sets on the pooled ors . publication bias of literature was examined using begg s funnel plots and egger s test . an asymmetrical plot suggests possible publication bias and the p value of egger s test less than 0.05 was considered the presence of potential publication bias . figure 1 is a flow diagram illustrating the strategy used to identify and select studies for inclusion in the meta - analysis . according to the pubmed and cochrane database with associated key words , a total of 156 articles were retrieved and 2 studies from references were included . after excluding 2 duplicates , 156 articles were screened by titles and abstracts and 106 of them were excluded as review articles or irrelevant studies . fifty studies appeared to satisfy our criteria and their full texts were evaluated . in further examination , we excluded 11 studies deviating from inclusion criteria . finally , 39 studies , including 36 case - control studies , 2 prospective studies , and 1 study including both case - control and prospective groups , were eligible and included in our meta - analysis[69,28,30,31,33,4171 ] . a summary of characteristics of each selected study , including first author , year of publication , ethnicity , genotype distribution , hwe , score of studies , and adjusted estimate ( or and 95% ci ) . we pooled overall and ethnic - specific ors for allelic contrast with adjusted or calculated ors , respectively , from the included studies to assess the association between rs13266634 variants and susceptibility to type 2 diabetes ( table 1 and figure 2 ) . a significant association was identified with adjusted ors from all eligible studies in the overall population , asian and european populations , but not in african population ( overall population : or=1.147 , 95% ci 1.1141.181 , p=0.000 ; asian : or=1.186 , 95% ci 1.1501.222 , p=0.000 ; european : or=1.100 , 95% ci 1.0491.153 , p=0.000 ; african : or=1.255 , 95% ci 0.9641.634 , p=0.091 ) using the random - effects model from 55 data sets of 39 independent studies with 65 767 cases and 100 182 controls . similar results were acquired using calculated ors from 38 datasets of 24 studies with detailed genotype distribution under the fixed - effects model ( overall population : or=1.157 , 95% ci 1.1351.180 , p=0.000 ; asian : or=1.165 , 95% ci 1.1321.198 , p=0.000 ; european : or=1.151 , 95% ci 1.1201.183 , p=0.000 ; african : or=1.111 , 95% ci 0.9081.360 , p=0.305 ) . then 38 data sets from 24 studies with detailed genotype distribution the fixed - effects model was conducted in all genetic models except for overdominant model analysis , which showed significant heterogeneity ( p<0.1 ) the pooled analysis of all genetic models yielded significant overall association ( cc+ct vs. tt : or=1.216 , 95% ci : 1.1231.318 , p=0.000 ; cc vs. ct+tt : or=1.197 , 95% ci : 1.1651.229 , p=0.000 ; cc+tt vs. ct : or=1.086 , 95% ci : 1.0501.123 , p=0.000 ; cc vs. tt : or1=1.330 , 95% ci : 1.2741.388 , p=0.000 ; ct vs. tt : or2=1.136 , 95% ci : 1.0891.184 , p=0.000 ; cc vs. ct : or3=1.165 , 95% ci : 1.1321.198 , p=0.000 ) . when stratifying the data by ethnicity , we observed an increased risk among asians in all except the overdominant model ( cc+tt vs. ct , p=0.050 ) . not surprisingly , this polymorphism did not appear to influence risk of african population and type 2 diabetes in all genetic models ( table 1 and figure 3 ) . according to the recommendation of thakkinstian et al . , pairwise differences of or1 , or2 , and or3 were used to indicate the most appropriate genetic model ( or1=or31,or2=1 , recessive model ; or1=or21 , or3=1 , dominant model;or2=1,or31 , or1=1 , overdominant model ; or1>or2>1,or1>or3<1 or or1<or2<1 , or1<or3<1 , codominant model ) . the pooled or1 for cc versus tt , or2 for ct versus tt , or3 for cc versus ct(or1=1.330 , or2=1.136 , or3=1.165 ) suggested that a codominant effect was most likely and that individuals with cc genotype had 33.0% and 16.5% higher risk of type 2 diabetes than those carrying tt and ct genotypes , respectively . we further carried out subgroup analysis under this genetic model based on hwe , genotyping methods , sample size , study design and quality of studies ( conducted by fixed - effects model ) . we observed increased risk of type 2 diabetes regardless of hwe , genotyping methods , and study design . in subgroup analysis stratified by ethnicity , we found that this polymorphism was associated with type 2 diabetes risk both in asians and europeans but not in africans . in subgroup analysis stratified by sample size , we found increased risk in large sample sizes but not small sample sizes . in subgroup analysis stratified by quality of studies , however , fair quality subgroup in cc vs. ct comparison , unlike that in cc vs. tt comparison , indicated no significant association . in allelic comparison using adjusted ors , there was heterogeneity across studies ( p=0.000 and i=62.0% ) ; thus , a random - effects model was finally employed to obtain summary or . the source of heterogeneity was further explored by subgroup analysis based on ethnicity , which indicated that studies of europeans were mainly responsible for the overall heterogeneity ; in allelic comparison using calculated ors from raw data , there was no heterogeneity across the study ( p=0.152 and i=19.2% ) ; thus , a fixed - effects model was finally employed to obtain summary or . for comparisons using studies with raw genotype count , the fixed - effects model was conducted in all contrasts except overdominant model ( cc+ct vs. tt : p=0.182 , i=17.1% ; cc vs. ct+tt : p=0.120 , i=21.7% ; cc vs. tt : p=0.369 , i=5.7% ; ct vs. tt : p=0.126 , i=21.2% ; cc vs. ct : p=0.122 , i=21.6% ; cc+tt vs. ct : p=0.048 , i=29.4% ) due to heterogeneity ( table 1 ) . to evaluate the effect of each individual study , especially studies deviating from hwe , on the pooled estimate , we performed a sensitivity analysis by deleting 1 study each time in turn . it showed that all the results hardly changed after sequential removal of each study from the total analysis , indicating the robustness of these results ( data not shown ) . we also observed that the significance of the overall data for the different genetic models was not statistically altered under either random- or fixed - effects models . cumulative meta - analysis was also performed in allelic contrast with adjusted and calculated ors by gradually including each additional study according to published year . the pooled genetic risk effect of both adjusted and calculated allelic contrasts remained significant in the entire period studied and the 95% ci for pooled ors became progressively narrower after adding 1 more study , indicating that the precision of our estimation was gradually improved after adding more studies ( figure 4 ) . funnel plot and egger s test were performed to assess the publication bias of included studies . as shown in figure 5 , the shapes of the begg s funnel plot did not reveal any evidence of obvious asymmetry in both stages . then , egger s test was used to provide statistical evidence of funnel plot symmetry . the results still did not show any evidence of publication bias ( p=0.496/0.249 , respectively ) . figure 1 is a flow diagram illustrating the strategy used to identify and select studies for inclusion in the meta - analysis . according to the pubmed and cochrane database with associated key words , a total of 156 articles were retrieved and 2 studies from references were included . after excluding 2 duplicates , 156 articles were screened by titles and abstracts and 106 of them were excluded as review articles or irrelevant studies . fifty studies appeared to satisfy our criteria and their full texts were evaluated . in further examination , we excluded 11 studies deviating from inclusion criteria . finally , 39 studies , including 36 case - control studies , 2 prospective studies , and 1 study including both case - control and prospective groups , were eligible and included in our meta - analysis[69,28,30,31,33,4171 ] . a summary of characteristics of each selected study , including first author , year of publication , ethnicity , genotype distribution , hwe , score of studies , and adjusted estimate ( or and 95% ci ) . we pooled overall and ethnic - specific ors for allelic contrast with adjusted or calculated ors , respectively , from the included studies to assess the association between rs13266634 variants and susceptibility to type 2 diabetes ( table 1 and figure 2 ) . a significant association was identified with adjusted ors from all eligible studies in the overall population , asian and european populations , but not in african population ( overall population : or=1.147 , 95% ci 1.1141.181 , p=0.000 ; asian : or=1.186 , 95% ci 1.1501.222 , p=0.000 ; european : or=1.100 , 95% ci 1.0491.153 , p=0.000 ; african : or=1.255 , 95% ci 0.9641.634 , p=0.091 ) using the random - effects model from 55 data sets of 39 independent studies with 65 767 cases and 100 182 controls . similar results were acquired using calculated ors from 38 datasets of 24 studies with detailed genotype distribution under the fixed - effects model ( overall population : or=1.157 , 95% ci 1.1351.180 , p=0.000 ; asian : or=1.165 , 95% ci 1.1321.198 , p=0.000 ; european : or=1.151 , 95% ci 1.1201.183 , p=0.000 ; african : or=1.111 , 95% ci 0.9081.360 , p=0.305 ) . then 38 data sets from 24 studies with detailed genotype distribution the fixed - effects model was conducted in all genetic models except for overdominant model analysis , which showed significant heterogeneity ( p<0.1 ) the pooled analysis of all genetic models yielded significant overall association ( cc+ct vs. tt : or=1.216 , 95% ci : 1.1231.318 , p=0.000 ; cc vs. ct+tt : or=1.197 , 95% ci : 1.1651.229 , p=0.000 ; cc+tt vs. ct : or=1.086 , 95% ci : 1.0501.123 , p=0.000 ; cc vs. tt : or1=1.330 , 95% ci : 1.2741.388 , p=0.000 ; ct vs. tt : or2=1.136 , 95% ci : 1.0891.184 , p=0.000 ; cc vs. ct : or3=1.165 , 95% ci : 1.1321.198 , p=0.000 ) . when stratifying the data by ethnicity , we observed an increased risk among asians in all except the overdominant model ( cc+tt vs. ct , p=0.050 ) . significant associations were also found among europeans . not surprisingly , this polymorphism did not appear to influence risk of african population and type 2 diabetes in all genetic models ( table 1 and figure 3 ) . according to the recommendation of thakkinstian et al . , pairwise differences of or1 , or2 , and or3 were used to indicate the most appropriate genetic model ( or1=or31,or2=1 , recessive model ; or1=or21 , or3=1 , dominant model;or2=1,or31 , or1=1 , overdominant model ; or1>or2>1,or1>or3<1 or or1<or2<1 , or1<or3<1 , codominant model ) . the pooled or1 for cc versus tt , or2 for ct versus tt , or3 for cc versus ct(or1=1.330 , or2=1.136 , or3=1.165 ) suggested that a codominant effect was most likely and that individuals with cc genotype had 33.0% and 16.5% higher risk of type 2 diabetes than those carrying tt and ct genotypes , respectively . we further carried out subgroup analysis under this genetic model based on hwe , genotyping methods , sample size , study design and quality of studies ( conducted by fixed - effects model ) . we observed increased risk of type 2 diabetes regardless of hwe , genotyping methods , and study design . in subgroup analysis stratified by ethnicity , we found that this polymorphism was associated with type 2 diabetes risk both in asians and europeans but not in africans . in subgroup analysis stratified by sample size , we found increased risk in large sample sizes but not small sample sizes . in subgroup analysis stratified by quality of studies , however , fair quality subgroup in cc vs. ct comparison , unlike that in cc vs. tt comparison , indicated no significant association . in allelic comparison using adjusted ors , there was heterogeneity across studies ( p=0.000 and i=62.0% ) ; thus , a random - effects model was finally employed to obtain summary or . the source of heterogeneity was further explored by subgroup analysis based on ethnicity , which indicated that studies of europeans were mainly responsible for the overall heterogeneity ; in allelic comparison using calculated ors from raw data , there was no heterogeneity across the study ( p=0.152 and i=19.2% ) ; thus , a fixed - effects model was finally employed to obtain summary or . for comparisons using studies with raw genotype count , the fixed - effects model was conducted in all contrasts except overdominant model ( cc+ct vs. tt : p=0.182 , i=17.1% ; cc vs. ct+tt : p=0.120 , i=21.7% ; cc vs. tt : p=0.369 , i=5.7% ; ct vs. tt : p=0.126 , i=21.2% ; cc vs. ct : p=0.122 , i=21.6% ; cc+tt vs. ct : p=0.048 , i=29.4% ) due to heterogeneity ( table 1 ) . to evaluate the effect of each individual study , especially studies deviating from hwe , on the pooled estimate , we performed a sensitivity analysis by deleting 1 study each time in turn . it showed that all the results hardly changed after sequential removal of each study from the total analysis , indicating the robustness of these results ( data not shown ) . we also observed that the significance of the overall data for the different genetic models was not statistically altered under either random- or fixed - effects models . cumulative meta - analysis was also performed in allelic contrast with adjusted and calculated ors by gradually including each additional study according to published year . the pooled genetic risk effect of both adjusted and calculated allelic contrasts remained significant in the entire period studied and the 95% ci for pooled ors became progressively narrower after adding 1 more study , indicating that the precision of our estimation was gradually improved after adding more studies ( figure 4 ) . funnel plot and egger s test were performed to assess the publication bias of included studies . as shown in figure 5 , the shapes of the begg s funnel plot did not reveal any evidence of obvious asymmetry in both stages . then , egger s test was used to provide statistical evidence of funnel plot symmetry . the results still did not show any evidence of publication bias ( p=0.496/0.249 , respectively ) . so far , 3 previous meta - analysis have been conducted to explore the function of slc30a8 gene polymorphisms in type 2 diabetes [ 7274 ] . one of them pooled allelic ors but provided no details about selecting criteria , another also conducted allelic contrast with adjusted individual or , and the last one carried out contrasts under different genetic models with calculated individual or . although all 3 articles indicated increased risk of type 2 diabetes with polymorphism rs13266634 , they employed either adjusted or calculated individual or only rather than both , and did not conclude which was the appropriate genetic model . additionally , considering several new original studies on this variant , we therefore decided to perform this updated meta - analysis , with more samples ( including 38 studies , involving 65 767 type 2 diabetes patients and 100 182 controls ) and more comprehensive comparisons ( using both adjusted and calculated individual or , under most likely and overall genetic models ) , to elucidate the relationship between rs13266634 variant and type 2 diabetes . the summary results from adjusted ors demonstrated that c allele carriers of rs13266634 are strongly associated with type 2 diabetes risk in the total population . subgroup analysis by ethnicity showed the same result in asian and european populations but not in african populations . furthermore , meta - analysis with calculated raw ors generated similar results in overall and ethnic populations under different s models . finally , we decided on the most likely genetic model , the codominant model , and performed subgroup analysis based on hwe , genotyping methods , sample size , study design , and quality of studies , and observed increased risk of type 2 diabetes in all populations except africans , small sample size subgroups , and fair subgroup in cc vs. ct comparison . hence , the result of subgroup analysis also confirmed the association between polymorphism rs13266634 and risk of type 2 diabetes . this differences in ethnicity may be due to the different genetic backgrounds of and limited articles on the african population . the difference in sample size subgroup is reasonable and indicates the importance of sample size in research . the difference in study quality subgroup between cc vs. tt and cc vs. ct contrasts may result from gene additive effect besides quality itself . cumulative meta - analysis indicated a consistent and more precise estimation as evidence from published studies accumulated according to year published . to date , 5 genome - wide association studies ( gwas ) involving type 2 diabetes and slc30a8 polymorphism rs13266634 have been published [ 69 , 64 ] , which were all included in this meta - analysis . four of them reported that this common variant is also associated with the risk of type 2 diabetes in europeans ( combined or=1.12 and 95% ci=1.071.16 ) , although data from 1 study were less compelling ( p=0.90 in the genome scan and p=0.01 in replication samples ) . one replication in asians also showed similar results as in europeans ( or=1.16 and 95% ci=1.051.27 ) . therefore , results from gwas were consistent with that of our meta - analysis , which indicated that slc30a8 polymorphism rs13266634 confers risk of type 2 diabetes . potential mechanisms whereby rs13266634 variant of znt8 may modulate insulin biophysiological activities and plasma glucose metabolism have been extensively studied . there are several possible explanations for the association between type 2 diabetes risk and rs13266634 . firstly , given the significant role of znt8 in insulin activities , this mutation may affect the basal function of znt8 and subsequent insulin synthesis . zinc is essential for the correct processing , storage , secretion , and action of insulin in pancreatic  cells [ 7577 ] . the w325 variant displayed higher zinc transport activity than r325 znt8 in a murine -cell line and protective effect against cyclosporin a - induced suppression of insulin secretion . similarly , studies also demonstrated that this polymorphism is strongly associated with abnormal insulin behaviors in humans , including decreased insulin secretion response to glucose stimulations , lower fasting insulin levels , reduced disposition index , and decreased proinsulin - to - insulin conversion [ 56,8082 ] . controversially , the risk c - allele does not affect ex - vivo insulin secretion and slc30a8 expression in isolated human islets . a recent study revealed that humans carrying rs13266634 exhibited increased insulin clearance , as assessed by c - peptide / insulin ratio , and mice with beta cell - specific slc30a8 knockout demonstrated the similar results ; thus , we speculate that the rs13266634 variant may result in the same consequence . the studies cited above suggest that rs13266634 variant can modulate plasma glucose homeostasis via full - scale insulin activities from synthesis to clearance [ 56,8082 ] . first of all , we followed a rigorous protocol of meta - analysis   and meta - analysis of genetic association studies . we performed subgroup analysis , hwe test , sensitivity analysis , and funnel plots to explore the source of heterogeneity , indicating the reliability of our study . next , we included more original studies and more samples than previous studies to enhance the statistical power of the study . moreover , we used adjusted and calculated ors to summarize estimate and raw genotype count , respectively , analyzed under different genetic models with the codominant model deemed to be most likely . all previous meta - analyses used either adjusted or calculated ors and did not specify a most likely genetic model . lastly , we conducted cumulative meta - analysis to investigate the dynamic change trend of the research results and the potential impact of small samples on estimate effect size . the small sample sizes without cumulative analyses may have influenced the strength of results of previous studies . the first limitation comes from multiple and diverse methods for snp detection in different studies . the second limitation is that type 2 diabetes is a complex and multifactorial disorder and potential interactions among gene - gene and gene - environment should be considered ; however , insufficient information , including nutrient , lifestyle behavior , and demographic details , hinder us from performing further adjusted analysis . the third limitation is that although we tried our best to contact the corresponding authors of published articles , we could not get information on gain genotypes data of all studies . the final limitation is that studies of africans and prospective research were limited ; thus , the interpretation of results should be cautious . the present meta - analysis suggests that slc30a8 gene polymorphism rs13266634 may be an important genetic factor in the risk for developing type 2 diabetes among asian and european populations but not african populations .
backgroundaccumulating but inconsistent data about the role of rs13266634 variant of slc30a8 in type 2 diabetes have been reported , partly due to small sample sizes and non - identical ethnicity.material/methodswe searched pubmed and cochrane library to identify eligible studies and extract data of baseline characteristics , genotype count , odds ratio ( or ) , and 95% confidence interval ( ci ) . both adjusted or with 95% ci and genotype counts 
 were employed to assess the association . 
 genotype data were further pooled to provide estimates under different genetic models and the most appropriate model was determined . 
 sensitivity and cumulative analysis were conducted to assure the strength of results.resultsfifty-five datasets of 39 studies ( including 38 of 24 with genotype count ) were included . 
 significant associations were found in allelic contrasts using adjusted ors and raw genotype count , respectively , overall in asian and european populations ( overall : or=1.147/1.157 , 95% ci 1.1141.181/1.1351.180 ; asian : or=1.186/1.165 , 95% ci 1.1501.222/1.1321.198 ; european : or=1.100/1.151 , 95% ci 1.0491.153/1.1201.183 ; all p=0.00 ) , but not in african populations ( african : or=1.255/1.111 , 95% ci 0.9641.634/0.9081.360 , p=0.091/0.305 ) . further analysis with genotype count under different genetic models all showed that individuals with cc genotype had 33.0% and 16.5% higher risk of type 2 diabetes than those carrying tt and ct genotypes , respectively , under the most likely codominant model . cumulative analysis indicated gradually improved precision of estimation after studies accumulated.conclusionsour results suggest that rs13266634 may be an important genetic factor of type 2 diabetes risk among asian and european but not african populations .