the incidence rate of community - acquired pneumonia ( cap ) is estimated to be 5.2 to 6.1 cases per 1000 adults , and the mortality rate may reach 23% .
several independent risk factors for pneumonia have been identified , such as increasing age , comorbidities , swallowing dysfunction , and nutritional status .
host genetic susceptibility has also been reported to be an important risk factor for pneumonia .
toll - like receptors ( tlrs ) are transmembrane proteins that recognize infection with various pathogens and damaged host cells , which lead to the subsequent inflammation responses .
tlr4 can distinguish between lipopolysaccharide and gram - negative bacteria , and can initiate intracellular signal cascades .
standiford et al . showed that tlr4 played a protective role in lung epithelium during gram - negative bacterial pneumonia .
tang et al . found that decreased tlr4 expression occurred in deceased patients compared with survivors .
furthermore , tanaka et al . found that tlr4 agonistic monoclonal antibody ut12 could improve the prognosis of secondary pneumococcal pneumonia .
previous studies have found 2 single - nucleotide polymorphisms ( snps ) of tlr4 : tlr4 a299 g and tlr4 t399i .
figueroa et al . suggested that tlr4 a299 g polymorphism impaired lps - induced phosphorylation of p38 and tank - binding kinase 1 , activation of nf-b and ifn regulatory factor 3 , and induction of il-8 and ifn- mrna . in addition , long et al .
found that the tlr4 a299 g variant , but not the t399i variant , was responsible for impaired responsiveness of tlr4 to lps and corresponding activation of nf-b .
recently , studies assessed the association between tlr4 a299 g polymorphism and the risk of pneumonia [ 1219 ] , but the results were inconclusive and mixed .
we thus conducted this meta - analysis to investigate the association between tlr4 a299 g polymorphism and the risk of pneumonia .
relevant studies were systematically searched for by using the ncbi , medline , web of science , and embase databases ( he last retrieval date was august 29 , 2014 , using the search terms :  pneumonia  and   toll like receptor 4  or
all discovered studies were retrieved and only published studies with full - text articles were included . for publications with duplicates ,
the inclusion criteria was : ( 1 ) the diagnosis of pneumonia was confirmed by x - ray or ct ; ( 2 ) the research was a case - control study or a cohort study ; ( 3 ) the study focused on the association between the tlr4 a299 g polymorphism and the risk of pneumonia ; and ( 4 ) the tlr4 a299 g genotype of individual groups were provided , the exclusion criteria were : ( 1 ) pneumonia was not confirmed by x - ray or ct ; ( 2 ) animal studies ; and ( 3 ) reviews or abstracts .
based on the selection criteria , 2 reviewers ( xingjun cai and yihui fu ) extracted and sorted the data independently ( including author , year , ethnicity , age , type , and sample size ) . authors were contacted by email if further study details are needed .
statistical analysis was conducted using stata software 11.0 ( statacorp , college station , texas , usa ) .
odds ratio ( or ) with a 95% confidence interval ( ci ) was presented for dichotomous data , and significant level was 0.05 .
q statistic and i statistic were used to measure statistical heterogeneity and significant level was 0.10 .
a fixed - effects model was selected when no significant heterogeneity , otherwise we used a random - effects model .
we performed a cumulative meta - analysis by sequential random - effects pooling , starting with the earliest studies .
results were presented as a series of mini meta - analyses , which were ordered chronologically in a forest plot to show the consequence of adding studies on the effect size . to evaluate the effect of individual studies on overall risk of pneumonia , we conducted sensitivity analyses by excluding each study individually and recalculating the ors and 95% ci .
funnel plots were performed to estimate potential publication bias , with an asymmetrical plot suggesting possible publication bias .
the asymmetry was assessed using the egger s linear regression test and p<0.05 was considered to represent statistically significant publication bias .
relevant studies were systematically searched for by using the ncbi , medline , web of science , and embase databases ( he last retrieval date was august 29 , 2014 , using the search terms :  pneumonia  and   toll like receptor 4  or
all discovered studies were retrieved and only published studies with full - text articles were included . for publications with duplicates ,
the inclusion criteria was : ( 1 ) the diagnosis of pneumonia was confirmed by x - ray or ct ; ( 2 ) the research was a case - control study or a cohort study ; ( 3 ) the study focused on the association between the tlr4 a299 g polymorphism and the risk of pneumonia ; and ( 4 ) the tlr4 a299 g genotype of individual groups were provided , the exclusion criteria were : ( 1 ) pneumonia was not confirmed by x - ray or ct ; ( 2 ) animal studies ; and ( 3 ) reviews or abstracts .
based on the selection criteria , 2 reviewers ( xingjun cai and yihui fu ) extracted and sorted the data independently ( including author , year , ethnicity , age , type , and sample size )
statistical analysis was conducted using stata software 11.0 ( statacorp , college station , texas , usa ) . hwe test in the healthy control group was conducted using  test .
odds ratio ( or ) with a 95% confidence interval ( ci ) was presented for dichotomous data , and significant level was 0.05 .
q statistic and i statistic were used to measure statistical heterogeneity and significant level was 0.10 .
a fixed - effects model was selected when no significant heterogeneity , otherwise we used a random - effects model .
we performed a cumulative meta - analysis by sequential random - effects pooling , starting with the earliest studies .
results were presented as a series of mini meta - analyses , which were ordered chronologically in a forest plot to show the consequence of adding studies on the effect size . to evaluate the effect of individual studies on overall risk of pneumonia , we conducted sensitivity analyses by excluding each study individually and recalculating the ors and 95% ci .
funnel plots were performed to estimate potential publication bias , with an asymmetrical plot suggesting possible publication bias .
the asymmetry was assessed using the egger s linear regression test and p<0.05 was considered to represent statistically significant publication bias .
only 1 study used pediatric patients , while 7 studies used adult patients . only 1 study assessed ventilator - associated pneumonia ( vap ) patients , while other studies used cap patients .
a total of 658 patients and 1862 controls were included in our meta - analysis .
we investigated the association between tlr4 a299 g polymorphism and pneumonia risk in the recessive models .
result of this meta - analysis showed that tlr4 a299 g polymorphism was significantly associated with pneumonia risk ( or=1.74 ; 95% ci 1.192.53 ; p=0.004 ; figure 2 ) .
when we deleted the pediatric study , the result was not changed ( or=1.81 ; 95% ci 1.222.69 ; p=0.003 ) .
when the vap study was deleted , the result was also not changed ( or=1.67 ; 95% ci 1.062.62 ; p=0.03 ) . to determine the stability of the result , we performed sensitivity analysis by omitting 1 study at a time .
we found that single study did not impact the pooled or , indicating that the results of our research are statistically robust ( figure 3 ) .
cumulative meta - analysis was also conducted by the assortment of studies by publication time ( figure 4 ) .
there was no publication bias in this meta - analysis , because no funnel plot asymmetry was detected ( figure 5 ) .
only 1 study used pediatric patients , while 7 studies used adult patients . only 1 study assessed ventilator - associated pneumonia ( vap ) patients , while other studies used cap patients .
a total of 658 patients and 1862 controls were included in our meta - analysis .
we investigated the association between tlr4 a299 g polymorphism and pneumonia risk in the recessive models .
result of this meta - analysis showed that tlr4 a299 g polymorphism was significantly associated with pneumonia risk ( or=1.74 ; 95% ci 1.192.53 ; p=0.004 ; figure 2 ) .
when we deleted the pediatric study , the result was not changed ( or=1.81 ; 95% ci 1.222.69 ; p=0.003 ) .
when the vap study was deleted , the result was also not changed ( or=1.67 ; 95% ci 1.062.62 ; p=0.03 ) . to determine the stability of the result , we performed sensitivity analysis by omitting 1 study at a time .
we found that single study did not impact the pooled or , indicating that the results of our research are statistically robust ( figure 3 ) .
cumulative meta - analysis was also conducted by the assortment of studies by publication time ( figure 4 ) .
there was no publication bias in this meta - analysis , because no funnel plot asymmetry was detected ( figure 5 ) .
this meta - analysis of 8 case - control studies evaluated the association between tlr4 a299 g polymorphism and the risk of pneumonia .
we found that tlr4 a299 g polymorphism might be a risk factor for developing pneumonia .
this result suggests that tlr4 299aa genotype carriers might have increased pneumonia risk compared to the ag or gg carriers .
in addition , we also found that tlr4 a299 g polymorphism was associated cap risk .
since there was only 1 study each with pediatric patients and vap patients , more studies in these populations are needed to validate the result of this meta - analysis .
did a meta - analysis and showed that tlr4 a299 g polymorphism increased risk for all parasitic infections , malaria , brucellosis , cutaneous leishmaniasis , neurocysticercosis , streptococcus pyogenes tonsillar disease , typhoid fever , and adult urinary tract infections . however , no study evaluated the association between tlr4 a299 g polymorphism and pneumonia .
thus , to the best of our knowledge , this is the first meta - analysis of the association between tlr4 a299 g polymorphism and pneumonia risk .
a recent study suggested that deficient recruitment of signaling adapters myd88 and trif to tlr4 was a mechanistic basis for a299g - mediated impairment of tlr4-elicited , lps - induced activation of myd88-dependent il-8 and tnf- genes , deficient trif - dependent phosphorylation of tbk1 and irf3 , transactivation of irf3 , and expression of ifn- mrna .
thus , it is important to pay more attention to the subjects with tlr4 a299 g polymorphism .
however , results from cumulative meta - analysis and sensitivity analysis suggest that our results are reliable and robust . secondly , pneumonia is a complex process modulated by a series of genetic factors beyond tlr4 .
however , our analysis only tried to explore the effect of tlr4 a299 g polymorphism on pneumonia , and did not link other gene variants that may be involved in pathophysiological pathways .
therefore , larger clinical studies are required to validate the hypothesis and findings obtained in this study .
once validated , they can be very helpful evidence in developing tailored therapeutics for individual patients .
the results of this meta - analysis suggest that susceptibility to pneumonia is associated with tlr4 a299 g polymorphism .
 backgroundseveral genetic studies have evaluated the association between toll - like receptor 4 ( tlr4 ) a299 g polymorphism and the risk of pneumonia . however , the results were not consistent . 
 we thus did this meta-analysis.material/methodsrelevant studies were systematically searched by using the ncbi , medline , web of science , and embase databases . 
 data were extracted independently by 2 investigators . 
 odds ratios ( ors ) and corresponding 95% confidence intervals ( cis ) were estimated.resultseight case - control studies with 658 patients and 1862 controls were included in this meta - analysis . 
 tlr4 a299 g polymorphism was significantly associated with pneumonia risk ( or=1.74 ; 95% ci 1.192.53 ; p=0.004 ) . 
 the result was significant in adults . 
 in addition , 
 tlr4 a299 g polymorphism was also associated with community - acquired pneumonia ( cap ) risk . 
 results from cumulative meta - analysis and sensitivity analysis suggested that the results are reliable and robust.conclusionsthe results of this meta - analysis suggest that susceptibility to pneumonia was associated with tlr4 a299 g polymorphism . 
Background
Material and Methods
Publication search
Inclusion and exclusion criteria
Data extraction
Statistical analysis
Results
Study characteristics
Quantitative data synthesis
Discussion
Conclusions