cancer is one of the most common malignancies worldwide ; it is the leading cause of death in economically developed countries and the second leading cause of death in developing countries .
approximately 12.7 million new cases of cancer and 7.6 million cancer - related deaths were reported in 2008 . despite the efforts exerted by many researchers to elucidate the mechanism of carcinogenesis ,
environmental factors , diet , lifestyle , and smoking and drinking habits have been implicated in the development of cancer [ 3 , 4 ] .
various epidemiological studies have revealed that inflammation - associated factors , such as interleukin- ( il- ) 1 , il-6 , il-10 , and tumor necrosis factor- , are associated with cancer tumorigenesis .
interleukin-17 ( il-17 ) is a proinflammatory cytokine that serves important functions in inflammation , autoimmune disorders , and cancer .
the il-17 cytokine family consists of six members ( il-17a to il-17f ) and five receptors ( il-17ra to il-17rd and sef ) [ 7 , 8 ] . these cytokines are primarily produced from a subset of cd4 + effector cells known as th17 cells [ 9 , 10 ] .
clinical studies have shown increased il-17 expression in malignant tumors [ 1114 ] . single nucleotide polymorphisms ( snps )
can alter gene functions and protein expression , which influence cell proliferation and increase cancer risk .
the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms are the most common loci associated with il-17 activity and cancer risk . in 2009 , shibata et al .  
conducted the first study and reported a positive relationship between gastric cancer and the il-17a rs2275913g > a polymorphism in a japanese population . but
no significant association was found between gastric cancer and polymorphisms of il-17f rs763780 t > c .
many epidemiological studies have focused on the association of the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms with cancer risk
therefore , we performed a meta - analysis to clarify the possible association of the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms with cancer risk .
the pubmed , embase , and chinese national knowledge infrastructure databases were searched using the terms  cancer ,   tumor ,  
the  related articles  option was also used in each research article to find potential relevant studies on the same topic . only studies published in english or chinese
the inclusion criteria in this meta - analysis were as follows : ( a ) researches that focused on population , ( b ) studies that evaluated the association of the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms with cancer risk , ( c ) case - controls studies , and ( d ) studies that contain available genotype frequency to estimate the odds ratio ( or ) and 95% confidence intervals ( cis ) .
the largest or the most recent publication was selected when some data were the same or overlapped .
two investigators ( yu - ming niu and hua yuan ) independently extracted the following information from each eligible publication : first author 's name , publication year , country of origin , ethnicity of the individuals involved ( categorized as asian or caucasian ) , source of controls , number of cases and controls , number of genotypes cases and controls , hardy - weinberg equilibrium ( hwe ) and minor allele frequency ( maf ) , and cancer category .
the strength of the association of the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms with cancer risk was assessed by calculating crude ors with 95% cis .
heterogeneity was calculated based on the i statistic with low , moderate , and high i values of 25% , 50% , and 75% , respectively [ 16 , 17 ] .
when i  50% ( which indicated a lack of heterogeneity ) , the or estimation of each model was calculated by using the fixed - effects model ( mantel - haenszel method ) ; otherwise , the random - effects model ( dersimonian and laird method ) was used .
sensitivity analyses were assessed by deleting each study to reflect the influence of individual datasets on the pooled ors .
statistical analysis was performed using stata version 11.0 ( stata corporation , college station , tx , usa ) with two - sided p values .
a total of 185 relevant studies were found with the research words and manual research . after careful review ,
10 published case - control studies involving 4,516 cases and 5,645 controls met our inclusion criteria [ 15 , 2028 ] .
we found 10 and 7 eligible studies with adequate genotype and research subjects according to il-17a rs2275913g > a and il-17frs763780t > c polymorphism .
nine studies involved asian populations ( seven involved the chinese population ) , and one study involved a caucasian population . diverse genotyping methods were used , including polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) [ 23 , 27 ] , taqman [ 21 , 24 , 28 ] , polymerase chain reaction - sequence specific primers ( pcr - sscp ) [ 15 , 25 ] , massarray [ 20 , 22 ] , and snapshot snp assay   methods in eligible publications .
the genotypic distribution of controls in only two and three studies deviated from hwe in the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms , respectively . 

the il-17a rs2275913g > a polymorphism showed significant associations with cancer risk in all populations ( for a versus g : or = 1.28 , 95% ci : 1.161.41 , p < 0.001 , i = 61.1% ; for ga versus gg : or = 1.12 , 95% ci : 1.021.23 , p = 0.015 , i = 27.8% ; for aa versus gg : or = 1.71 , 95% ci : 1.382.41 , p < 0.001 , i = 69.6% ; for ga + aa versus gg : or = 1.23 , 95% ci : 1.131.34 , p < 0.001 , i = 6.4% ( figure 2 ) ; and for aa versus gg + ga : or = 1.62 , 95% ci : 1.272.07 , p < 0.001 , i = 81.4% ) .
the succeeding stratified analysis according to hwe , ethnicity , and study design subgroup also presented that the il-17a rs2275913g > a polymorphism may be a strong risk factor in the development of cancer , especially gastric cancer , in the chinese population .
statistical analysis also indicated that the il-17f rs763780t > c polymorphisms were significantly associated with cancer risk , particularly gastric cancer ( for c versus t : or = 1.29 , 95% ci : 1.141.46 , p < 0.001 , i = 0% ; for tc versus tt : or = 1.33 , 95% ci : 1.131.55 , p < 0.001 , i = 21.6% ; for cc versus tt : or = 1.40 , 95% ci : 1.041.88 , p = 0.026 , i = 0% ; for tc + cc versus tt : or = 1.34 , 95% ci : 1.161.55 , p < 0.001 , i = 16% ( figure 3 ) ) . a single study involved in the meta - analysis was deleted each time to reflect the influence of the individual data set on the pooled ors , and the corresponding pooled ors were not qualitatively altered .
this indicated that the results about the association between il-17 gene polymorphisms and cancer risk were statistically robust ( figures 4 and 5 ) .
funnel plot and egger 's test were performed to estimate the publication bias of literature .
publication bias was detected in the meta - analyses on the allele contrast , homozygote ( aa versus gg ) , dominant , and recessive models of the il-17a rs2275913g > a polymorphism ( figure 6 for ga + aa versus gg model ) , except for the ga versus gg model ( p = 0.652 ) .
stratified analyses were conducted only with the hwe and chinese population , but the results were not substantially different . for the il-17f rs763780t
> c polymorphism , the funnel plots did not show any asymmetrical evidence in all genetic models ( figure 7 ) .
the result was further supported by analysis using egger 's tests ( p = 0.102 for c versus t ; p = 0.185 for tc versus tt ; p = 0.382 for cc versus tt ; p = 0.114 for tc + cc versus tt ( figure 7 ) ; p = 0.792 for cc versus tt + tc ) .
carcinogenesis is a multistep process that involves numerous factors , such as smoking , drinking , xenobiotics infections , nutrition deficiency , and host genetic factor .
cancer - related inflammation factors have been recently confirmed to increase the risk of developing malignant tumors .
il-17 is a relatively novel cytokine family that is connected with adaptive and innate immune systems . il-17a and il-17f are members of the il-17 cytokine family that are responsible for the pathogenic activity of il-17 cells , the lineage of cd4 effector cells , and multiple proinflammatory mediators .
genetic polymorphisms of the il-17a and il-17f cytokines could change the function and expression of cytokines , which influence the activity of ils [ 12 , 30 , 31 ] .
several studies have revealed that il-17a and il-17f polymorphisms are associated with gastric cancer , breast cancer , and so on
. however , the results of these studies are inconsistent . in 2009 , shibata et al .  
were the first to report that the aa homozygote was significantly correlated with the development of gastric cancer compared with the common homozygous genotype ( gg ) in a japanese population ( or = 3.02 , 95% ci : 1.864.91 ) .
one year later , chen et al .   also found a positive relationship between gastric cancer and the il-17a rs2275913g > a polymorphism in a chinese han population with a drinking habit ( for a versus g : or = 1.37 , 95% ci : 1.071.76 ) .
, rafiei et al . , zhang et al . , and zhuet al .   in gastric cancer .
furthermore , the mutation of il-17a rs2275913g > a locus was also demonstrated as tumorigenic for bladder cancer , breast cancer , and cervical cancer . however , another article detected no significant association between the il-17a rs2275913g > a polymorphism and gastric cancer risk . regarding the il-17f rs763780t > c polymorphism , wu et al
.   found that the ct and cc genotypes are associated with an increased risk of gastric cancer compared with the tt genotype ( or = 1.51 , 95% ci : 1.221.87 for ct ; or = 1.61 , 95% ci : 1.032.51 for cc ) .
by contrast , zhou et al .   showed that bladder cancer patients have significantly higher frequencies of t allele than controls .
this result indicates that this t allele is significantly associated with bladder cancer ( or = 1.46 , 95% ci : 1.072.00 ) .
furthermore , other researches did not find any significant association between the il-17f rs763780t > c polymorphism and cancer risk [ 15 , 20 , 22 , 24 , 26 ] . to the best of our knowledge , this meta - analysis is the first to determine the association of il-17 polymorphisms with cancer risk .
this study focused on two common il-17 polymorphisms , namely , il-17a rs2275913g > a ( 10 studies with 4,516 cases and 5,645 controls ) and il-17f rs763780t > c ( 7 studies with 2,863 cases and 3,773 controls ) .
significant associations were found between the il-17a rs2275913g > a polymorphism and cancer risk in all five genotype models of total populations .
besides , we also detected some association between the il-17f rs763780t > c polymorphism and the risk of asians ( chinese ) , population - based and hospital - based controls , and gastric cancer or other cancers in the subgroup analysis by hwe publications , ethnicity , control design , and cancer category .
interestingly , nine researches focused on asian population ; the results of our meta - analysis demonstrated that the il-17a rs2275913g > a polymorphism may be a stranger canner risk for asian ethnicity ( including chinese ) .
moreover , the category of control design did not influence the results ; not only the population - based but also the hospital - based controls all showed that significant association existed between il-17a rs2275913g > a polymorphism and cancer risk . in all selected publications , seven studies focused on gastric cancer and
the results also indicated that il-17a rs2275913g > a polymorphism plays an important role during the development of gastric cancer . for il-17f rs763780t >
c polymorphism , all selected studies were conducted in asian population and significant association only was found in codominant model ( cc versus tt ) in total population .
furthermore , subgroup analyses revealed a significantly increased risk of gastric cancer with il-17f rs763780t > c polymorphism in four models .
a combination of relative genotypes may be a higher risk factor than a single locus genotype .
linkage disequilibrium and haplotype analyses of the two polymorphisms were not conducted because of the lack of original data on the individual genotypes from the included studies .
third , these results were based on unadjusted estimates , and the evaluations were limited without the effects of gene - gene and gene - environment interactions .
finally , most of the included studies had been conducted on asians but not on caucasians and africans , and the association between ethnicity variation and cancer risk could not be explored deeply . in conclusion , despite these limitations , the present meta - analysis demonstrates that the il-17a rs2275913g > a polymorphism is associated with cancer development .
furthermore , the il-17f rs763780t > c polymorphism may be a potential risk factor in the development of gastric cancer . in the future ,
large - scale , case - control , and well - designed studies must be conducted to validate the findings of our meta - analysis and to comprehensively understand the potential gene - gene and gene - environment interactions between il-17 polymorphisms and cancer risk .
 epidemiological studies have suggested that interleukin-17 ( il-17 ) polymorphisms are associated with cancer risk . however , the results of these studies are inconsistent . 
 therefore , we performed a meta - analysis to obtain a precise conclusion . 
 odds ratios ( ors ) with 95% confidence intervals ( cis ) were used to assess the association of the il-17a rs2275913g > a and il-17f rs763780t > c polymorphisms with cancer risk . 
 publication bias and sensitivity analyses were performed to ensure the statistical power . 
 overall , 10 relevant case - control studies involving 4,516 cases and 5,645 controls were included . 
 the pooled ors with 95% cis indicated that the il-17a rs2275913g > a polymorphism was significantly associated with increased cancer risk ( for a versus g : or  =  1.28 , 95% ci : 1.161.41 , p < 0.001 , i2 = 61.1% ; for ga versus gg : or  =  1.12 , 95% ci : 1.021.23 , p  =  0.015 , i2 = 27.8% ; for aa versus gg : or  =  1.71 , 95% ci : 1.382.41 , p < 0.001 , i2 = 69.6% ; for ga + aa versus gg : or  =  1.23 , 95% ci : 1.131.34 , p < 0.001 , i2 = 6.4% ; for aa versus gg + ga : or  =  1.62 , 95% ci : 1.272.07 , p < 0.001 , i2 = 81.4% ) . 
 succeeding analysis of hwe and stratified analysis of gastric cancer and the asian ( and chinese ) population revealed similar results . 
 the il-17f rs763780t > c polymorphism was also significantly associated with gastric cancer development . 
 overall , the present meta - analysis suggests that il-17 polymorphisms increase the risk of developing cancer , particularly gastric cancer , in the asian ( and chinese ) population . 
1. Introduction
2. Materials and Methods 
3. Results
4. Discussion