periodontitis is a kind of chronic disease affected by multiple factors such as microorganism , host and environment . periodontitis was identified into 3 types : chronic periodontitis ( cp ) , aggressive periodontitis ( ap ) , and periodontitis as a manifestation of systemic disease . kassebaum et al predicted an increasing global burden of severe periodontitis on account of growing life expectancy resulted in decreased tooth loss and increasing world population during 1990 to 2010 . susin et al summarized the features of epidemiology and demographics in ap which clarified the prevalence of ap varied significantly in different regions and races . thus , periodontitis has became one of the hot research fields all over the world . the traditional method for dealing with periodontitis mainly focused on removing pathogenic bacteria , which resulted in bacteria resistance and disease recurrence . besides , the host inflammatory response plays a critical role in the destruction of periodontal tissue . in the recent decades , the development of sequencing technology enabled us to discuss whether the variations of host 's immune - related deoxyribose nucleic acid molecules affected the occurrence and development of diseases . thus , there is a great significance to discuss the gene variants of immune - related molecules for the prevention and treatment of periodontitis . luigi elucidated host genetic variants may work in the occurrence and development of ap through selectively participating in the dysbiotic process . hajishengallis and sahingur reported a polymorphic site in the tlr9 gene promoter region differentially expressed and tlr9 gene and protein expression increased in cp . toll - like receptor 4 ( tlr4 ) was a pattern - recognition receptor , which played an important part in innate immunity by realizing lipid - based structures of bacteria and mediating intracellular signaling . furthermore , many studies reported the association between tlr4 polymorphism and periodontitis susceptibility , and they mainly focused on tlr4299a > g or tlr4399c > t of caucasian but conducted different conclusions . therefore , this meta - analysis and subgroup analyses were carried out to further illuminate the relationship between tlr4 polymorphism and periodontitis susceptibility based on the currently available studies . this review is not a primary research , so ethical approval and informed consent are not necessary . this meta - analysis was reported following the prisma ( preferred reporting items for systematic reviews and meta - analyses ) statement . all retrieved literatures fit the following criteria should be included : the study tested tlr4 polymorphism and periodontitis susceptibility , participants in studies must be explicitly diagnosed with cp or ap , the numbers of every genotypes were available both in case and control groups . the study met the following criteria should be excluded : the review or meta - analysis about this theme , the article not described in chinese or english , no control subjects or without healthy control group , participants who were pregnant or lactating , mutant type not detected . the authors performed a systematic search in cnki , pubmed , and embase up to january 4 , 2016 using key words :  polymorphism or mutation or variant  and  tlr4 or toll like receptor 4  and  periodontal disease or periodontitis . two authors extracted the useful information independently and any disagreement was solved by discussing until reaching an agreement or consulting a third author if needed . the extracted data were as follows : the first author 's name and the publication date , the country or ethnicity of study participants , polymorphisms under investigation , disease type , the numbers of every genotypes both in case and control groups , genotyping method , the hardy  weinberg equilibrium ( hwe ) of the controls . two of us conducted the quality assessment of included studies according to the newcastle - ottawa scale case control study ( nos ) . this standard assessed 3 sections ( selection , comparability , exposure ) and 8 items . in the selection and exposure categories , a quality research item received 1 star , and a comparable category could receive at most 2 stars . generally , the study which scored at least 5 points was considered to be included in meta - analysis . the authors calculated the odds ratios ( ors ) and corresponding 95% confidence interval ( ci ) to estimate the association between tlr4 polymorphism and periodontitis in 5 genetic models : allele comparison ( 1 vs 2 ) , homozygote comparison ( 11 vs 22 ) , heterozygote comparison ( 12 vs 11 ) , dominant model ( 22  +  12 vs 11 ) , recessive model ( 11  +  12 vs 22 ) . values of p  <  0.1 or i  >  50% indicated obvious heterogeneity and the random effects model was considered to use ; otherwise , use the fixed effects model . publication bias was detected with funnel plot in visual and with quantitative method of begg and egger linear regression . p - values and p  <  0.05 was supposed to have a statistically significance . all retrieved literatures fit the following criteria should be included : the study tested tlr4 polymorphism and periodontitis susceptibility , participants in studies must be explicitly diagnosed with cp or ap , the numbers of every genotypes were available both in case and control groups . the study met the following criteria should be excluded : the review or meta - analysis about this theme , the article not described in chinese or english , no control subjects or without healthy control group , participants who were pregnant or lactating , mutant type not detected . the authors performed a systematic search in cnki , pubmed , and embase up to january 4 , 2016 using key words :  polymorphism or mutation or variant  and  tlr4 or toll like receptor 4  and  periodontal disease or periodontitis . two authors extracted the useful information independently and any disagreement was solved by discussing until reaching an agreement or consulting a third author if needed . the extracted data were as follows : the first author 's name and the publication date , the country or ethnicity of study participants , polymorphisms under investigation , disease type , the numbers of every genotypes both in case and control groups , genotyping method , the hardy  weinberg equilibrium ( hwe ) of the controls . two of us conducted the quality assessment of included studies according to the newcastle - ottawa scale case control study ( nos ) . this standard assessed 3 sections ( selection , comparability , exposure ) and 8 items . in the selection and exposure categories , a quality research item received 1 star , and a comparable category could receive at most 2 stars . generally , the study which scored at least 5 points was considered to be included in meta - analysis . the authors calculated the odds ratios ( ors ) and corresponding 95% confidence interval ( ci ) to estimate the association between tlr4 polymorphism and periodontitis in 5 genetic models : allele comparison ( 1 vs 2 ) , homozygote comparison ( 11 vs 22 ) , heterozygote comparison ( 12 vs 11 ) , dominant model ( 22  +  12 vs 11 ) , recessive model ( 11  +  12 vs 22 ) . values of p  <  0.1 or i  >  50% indicated obvious heterogeneity and the random effects model was considered to use ; otherwise , use the fixed effects model . publication bias was detected with funnel plot in visual and with quantitative method of begg and egger linear regression . all data analyses were conducted by stata software , version 12.0 . using 2-sided p - values and p  <  0.05 was supposed to have a statistically significance . seventy - four studies from database searching and 6 studies from manual retrieval , counting up to 80 studies , were identified in this meta - analysis . after removing 30 duplicates , this meta - analysis ultimately included 18 studies , which included 2453 healthy participants and 2987 patients with cp and 462 patients with ap . the basic characteristics of included studies are shown in table 1 . among the 18 included studies , 4 studies were about asian , 12 studies were about caucasian , 1 study was conducted in brazil ( mixed ) , and 1 in usa ( africa ) . only 2 studies reported the relationship between gene polymorphism and nonsmokers , and the basic characteristics are summarized in table 2 . the controls of 2 studies hwe were not reported , and we could not calculate them in any way . one study had low score of 2 points , which would be considered to conduct the sensitive analysis . the percentage of different star numbers involving in all included studies is revealed in fig . 2 . except for item  non - response rate  which the percentage of 0 star was 100% , the remaining items has low percentage of 0 star . evaluations of the qualities of the included studies based on the newcastle - ottawa scale . quality evaluation of the included studies based on the newcastle - ottawa scale . in the association between tlr4c > g ( rs7873784 ) polymorphism and cp susceptibility , there was a significance between tlr4c > g ( rs7873784 ) allele and cp in asian , and its recessive model was also significant ( for c vs g : or = 0.72 , 95% ci = 0.540.95 , i = 0% ; for cc  +  cg vs gg : or = 0.66 , 95% ci = 0.490.89 , i = 0% ) ( figs . 3 and 4 ) . all the genetic models of other tlr4 gene polymorphism included in this article in overall and subgroup revealed no significance , and the results are listed in table 4 . the result of sensitive analysis was still nonsignificant but the heterogeneity significantly decreased , which was conducted by removing the study of low quality ( table 5 ) . forest plot for tlr4c > g ( rs7873784 ) associated with chronic periodontitis in c versus g comparison ( fixed - effect model ) . forest plot for tlr4c > g ( rs7873784 ) associated with chronic periodontitis in cc  +  cg versus gg comparison ( fixed - effect model ) . the funnel plot method was used when the number of included studies at least 10 at which point it had relatively high test efficiency . the 11 included studies about tlr4299a > g polymorphism with cp had nearly symmetric funnel plot , which indicated no obvious publication bias ( fig . the studies which had small quantity of 2 could not be detected the publication bias . egger and begg test did not indicate obvious publication bias for other studies ( for egger test : for tlr4299a > g with ap : a vs g : p = 0.64 ; ag vs aa : p = 0.95 ; gg  +  ag vs aa : p = 0.90 . for tlr4399c > t with cp : c vs t : p = 0.88 ; cc vs tt : p = 0.41 ; ag vs aa : p = 0.78 ; gg  +  ag vs aa : p = 0.49 ; aa  +  ag vs gg : p = 0.60 . for tlr4399c > t with ap : c vs t : p = 0.38 ; ag vs aa : p = 0.36 . for tlr4c > g ( rs11536889 ) with cp : c vs g : p = 0.19 ; cc vs gg : p = 0.23 ; cg vs cc : p = 0.27 ; gg  +  cg vs cc : p = 0.25 ; cc  +  cg vs gg : p = 0.15 ) . seventy - four studies from database searching and 6 studies from manual retrieval , counting up to 80 studies , were identified in this meta - analysis . after removing 30 duplicates , this meta - analysis ultimately included 18 studies , which included 2453 healthy participants and 2987 patients with cp and 462 patients with ap . the basic characteristics of included studies are shown in table 1 . among the 18 included studies , 4 studies were about asian , 12 studies were about caucasian , 1 study was conducted in brazil ( mixed ) , and 1 in usa ( africa ) . only 2 studies reported the relationship between gene polymorphism and nonsmokers , and the basic characteristics are summarized in table 2 . the controls of 2 studies hwe were not reported , and we could not calculate them in any way . one study had low score of 2 points , which would be considered to conduct the sensitive analysis . the percentage of different star numbers involving in all included studies is revealed in fig . which the percentage of 0 star was 100% , the remaining items has low percentage of 0 star . in general , the quality of included studies was good and fair . evaluations of the qualities of the included studies based on the newcastle - ottawa scale . in the association between tlr4c > g ( rs7873784 ) polymorphism and cp susceptibility , there was a significance between tlr4c > g ( rs7873784 ) allele and cp in asian , and its recessive model was also significant ( for c vs g : or = 0.72 , 95% ci = 0.540.95 , i = 0% ; for cc  +  cg vs gg : or = 0.66 , 95% ci = 0.490.89 , i = 0% ) ( figs . 3 and 4 ) . all the genetic models of other tlr4 gene polymorphism included in this article in overall and subgroup revealed no significance , and the results are listed in table 4 . the result of sensitive analysis was still nonsignificant but the heterogeneity significantly decreased , which was conducted by removing the study of low quality ( table 5 ) . forest plot for tlr4c > g ( rs7873784 ) associated with chronic periodontitis in c versus g comparison ( fixed - effect model ) . forest plot for tlr4c > g ( rs7873784 ) associated with chronic periodontitis in cc  +  cg versus gg comparison ( fixed - effect model ) . the funnel plot method was used when the number of included studies at least 10 at which point it had relatively high test efficiency . the 11 included studies about tlr4299a > g polymorphism with cp had nearly symmetric funnel plot , which indicated no obvious publication bias ( fig . the studies which had small quantity of 2 could not be detected the publication bias . egger and begg test did not indicate obvious publication bias for other studies ( for egger test : for tlr4299a > g with ap : a vs g : p = 0.64 ; ag vs aa : p = 0.95 ; gg  +  ag vs aa : p = 0.90 . for tlr4399c > t with cp : c vs t : p = 0.88 ; cc vs tt : p = 0.41 ; ag vs aa : p = 0.78 ; gg  +  ag vs aa : p = 0.49 ; aa  +  ag vs gg : p = 0.60 . for tlr4399c > t with ap : c vs t : p = 0.38 ; ag vs aa : p = 0.36 . for tlr4c > g ( rs11536889 ) with cp : c vs g : p = 0.19 ; cc vs gg : p = 0.23 ; cg vs cc : p = 0.27 ; gg  +  cg vs cc : p = 0.25 ; cc  +  cg vs gg : p = 0.15 ) . this meta - analysis systematically collected studies about tlr4 gene polymorphism associated with periodontitis from frequently used databases and manual retrieval . we analyzed the existing different tlr4 gene associated with different periodontitis and ultimately found that there was a significance between tlr4c > g ( rs7873784 ) polymorphism and cp about c and g allele and its recessive model was also significant in asian , which indicated that the asian people suffered from cp might due to tlr4c > g ( rs7873784 ) and it possibly passed on to offsprings in the form of recessiveness . on account of only 2 included studies about this gene , the reliability of this conclusion still need more research to demonstrate . previous meta - analyses about tlr4 gene polymorphism mainly focused on tlr4299a > g or tlr4399c > t of caucasian , which made different conclusions . ozturk and vieira included 7 studies and calculated the or value of major allele versus minor allele for both tlr4299a > g and tlr4399c > t polymorphisms , and concluded that the tlr4299a > g may be a risk factor against cp ( or = 1.43 , 95% ci = 1.041.97 ) and the tlr4399c > t appeared to be a protective factor to ap ( or = 0.29 , 95% ci = 0.130.61 ) . song et al and zheng et al used differently 4 genetic models , and their overall results associated with ethnic analysis all failed to reveal any association between tlr4299a > g or tlr4399c > t and periodontitis . besides , zheng et al found a significantly increased risk for periodontitis in recessive models of tlr4299a > g . han et al indicated that both tlr4299a > g and tlr4399c > t showed elevated risk of cp in caucasians . this pooled analysis systematically included 18 studies , excluded studies lack of specific statistics and conducted quality assessment for every included study . based on the current studies , the authors did not detect any association between tlr4 polymorphisms and periodontitis susceptibility except for tlr4c > g ( rs7873784 ) . through removing the low quality studies , the sensitive analysis only decreased heterogeneity , but could not change the results . third , the case  control study about the association between tlr4 polymorphisms and smoking status was few , which made us can not extract data directly . fourth , whether periodontal treatment could influence gene mutation should be seriously considered , but the studies included in this meta - analysis did not make the unified description , which may bring in the bias . finally , many risk factors of periodontitis were not studied in clinical trials that led to the limitation of subgroup analyses . in conclusion , the unified baseline of studies and more well - designed clinical trials were expected . we found that there was a significance between tlr4c > g ( rs7873784 ) polymorphism and cp about c and g allele and its recessive model was also significant in asian , which indicated that the asian people suffered from cp may due to tlr4c > g ( rs7873784 ) and it possibly passed on to offsprings in the form of recessiveness . however , the overall and subgroup analyses in other tlr4 polymorphism included in this study found no significance . large quantity and high quality researches were expected to explore the pathogenesis of periodontitis . # 1 search ( ( ( ( ( ( ( polymorphisms , genetic[title / abstract ] ) or genetic polymorphism[title / abstract ] ) or polymorphism ( genetics)[title / abstract ] ) or genetic polymorphisms[title / abstract ] ) or gene polymorphism[title / abstract ] ) or mutation[title / abstract ] ) or variant[title / abstract ] ) or  polymorphism , genetic[mesh ] # 2 search ( ( ( ( ( toll like receptor 4[title / abstract ] ) or toll4 receptor[title / abstract ] ) or toll 4 receptor[title / abstract ] ) or tlr4 receptor[title / abstract ] ) or receptor , tlr4[title / abstract ] ) or  toll - like receptor4[mesh ] # 3 search ( ( ( ( ( ( ( ( ( disease , periodontal[title / abstract ] ) or diseases , periodontal[title / abstract ] ) or periodontal disease[title / abstract ] ) or parodontosis[title / abstract ] ) or pyorrhea alveolaris[title / abstract ] ) or periodontitides[title / abstract ] ) or pericementitis[title / abstract ] ) or pericementitides[title / abstract ] ) or  periodontal diseases[mesh ] ) or  periodontitis[mesh ] # 4 search # 1 and # 2 and # 3
abstractbackground : many primary and secondary studies reported the association between toll - like receptor 4 ( tlr4 ) polymorphism and periodontitis susceptibility , which mainly focused on tlr4299a > g or tlr4399c > t of caucasian , however , these studies had different conclusions . 
 the aim of this study was to reassess relative studies about tlr4 polymorphism and periodontitis susceptibility , and update meta-analysis.methods:we searched the electronic database including cnki ( chinese national knowledge infrastructure ) , pubmed , embase , and hand searched relative studies until january 4 , 2016 . 
 two authors selected studies according to inclusion and exclusion criteria , assessed studies using newcastle - ottawa scale case control study ( nos ) , and calculated the combined effect size using stata software , version 12.0.results:this meta - analysis included 18 studies , containing 2453 healthy participants and 2987 patients with chronic periodontitis ( cp ) and 462 patients with aggressive periodontitis ( ap ) . 
 there was a significance between tlr4c > g ( rs7873784 ) allele and cp in asian , and its recessive model was also significant ( for c vs g : odds ratio [ or ] = 0.72 , 95% confidence interval [ ci ] = 0.540.95 , i2 = 0% ; for cc  +  cg vs gg : or = 0.66 , 95% ci = 0.490.89 , i2 = 0% ) . 
 however , we did not detect any significant relevance between other tlr4 polymorphism and periodontitis susceptibility in overall and subgroup analyses . 
 the sensitive analysis showed that dropping any single studies did not affect the pooled - analysis results . 
 publication bias was not detected.conclusions:the meta - analysis found association between tlr4c > g ( rs7873784 ) allele and cp in asian and it may passed on to offsprings in the form of recessiveness . 
 however , further studies about the association between tlr4c > g ( rs7873784 ) and cp is warranted to confirm .