Single nucleotide polymorphisms (SNPs) located in the vascular endothelial growth factor (VEGF) gene may be correlated with the susceptibility to coronary artery disease (CAD) – although results have been controversial. The aim of this meta–analysis is to clarify the effects of VEGF –2578A/C (rs699947), −1154G/A (rs1570360), +405C/G (rs2010963), and + 936C/T (rs3025039) polymorphisms on CAD risk.Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the association between VEGF gene polymorphisms and CAD risk. Fixed- or random-effects model was used depending on the heterogeneity between studies.In total, 13 eligible articles containing 29 studies were analysed. The pooled analysis indicated that the VEGF gene polymorphisms of rs699947, rs2010963, and rs3025039 were associated with an increased risk of CAD, whereas no significant associations were observed with the rs1570360 polymorphism. A subgroup analysis stratified by ethnicity revealed that the rs699947 and rs3025039 polymorphisms were associated with CAD risk in Asian populations. In addition, stratification by control source indicated an increased risk of CAD susceptibility with the rs699947 polymorphism for population–based studies of reduced heterogeneity.In summary, we concluded that the VEGF gene polymorphisms rs699947, rs2010963, and rs3025039 are correlated with an elevated CAD risk.The online version of this article (10.1186/s12881-018-0628-3) contains supplementary material, which is available to authorized users. Coronary artery disease (CAD) is and will remain the main cause of morbidity and mortality worldwide . CAD is Vascular endothelial growth factor (VEGF), an essential component of angiogenesis, has been reported to induce endothelial cell migration and proliferation, enhance vascular permeability, and modulate thrombogenicity –9. The VSome of these polymorphisms, including VEGF –2578A/C (rs699947), −1154G/A (rs1570360), +405C/G (rs2010963), and + 936C/T (rs3025039), which arise from the vascular expression of different VEGF proteins, have been associated with CAD susceptibility; however, these findings are controversial. For example, Han et al.  indicateThe existence of a correlation between VEGF gene SNPs and CAD susceptibility remains controversial and inconclusive. Moreover, no relevant meta–analyses have been published. Consequently, we performed a meta–analysis to investigate the association between VEGF gene polymorphisms and CAD risk.The literature search was conducted by two authors (Ma and Han). PubMed, EMBASE, Web of Science, ScienceDirect, and Cochrane Library were systematically searched. The keywords and terms used for the searches included the following: “vascular endothelial growth factor” OR “VEGF” OR “–2578 A/C” OR “+405C/G” OR “+936C/T” OR “–1154G/A” OR “rs699947” OR “rs3025039” OR “rs2010963” OR “rs1570360”; “genetic polymorphism” OR “mutation” OR “variant” OR “genotype”; and “angina” OR “myocardial infarction” OR “atherosclerosis” OR “acute coronary syndrome” OR “coronary artery disease” OR “coronary heart disease”. Hand–searching of reference lists in relevant articles was also performed. The last search was conducted on October 24, 2017.Eligible studies in our meta–analysis complied with the following criteria: 1) case–control studies evaluating VEGF gene polymorphisms  and CAD susceptibility; 2) all CAD cases were documented by angiographic evidence showing at least 50% stenosis of one major coronary artery, myocardial infarction (MI), or coronary artery bypass surgery; 3) sufficient published data, such as the total number of cases and controls, distribution of genotypes, and other relevant information; and 4) language was restricted to English. Studies were excluded if they met the following criteria: 1) letters to the editor, abstracts, animal studies, or reviews; 2) data overlapping with previous publications; and 3) studies with unusable or insufficient data.Following the Meta–analysis of Observational Studies in Epidemiology (MOOSE) guidelines for reporting meta–analyses of observational studies  quality score was applied to assess the quality of each eligible study. Validated quality assessment consisted of three parameters, including selection, comparability, and exposure. NOS scores ranged from 0 and 9 stars. Studies with an NOS score of five or greater were deemed moderate to high quality, whereas studies with an NOS score of less than five were considered low quality.2) were used to assess the heterogeneity within studies. A Q–test with P < 0.10 indicated significant heterogeneity. I2 values of 0–25, 25–50%, and > 50% represented mild, moderate, and high–level heterogeneity, respectively. A fixed– or random–effects model was used to calculate OR and 95% CIs based on the study heterogeneity strength. Subsequently, a subgroup analysis was performed to search for potential sources of heterogeneity. If there was an appropriate number of included studies, subgroup analyses based on ethnicity (Asian and Caucasian populations), control source , and sample size , and the type of CAD were performed to detect the sources of the heterogeneity. A sensitivity analysis was performed to assess the stability of the individual studies. Possible publication bias was assessed using funnel plots and Egger’s linear regression test.All calculations and graphs were performed by Review Manager v5.2  and Stata 12.0 . Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were selected to estimate the strength of the association. For the VEGF rs6699947 polymorphism, pooled ORs were obtained for dominant (CC + AC vs. AA), recessive (CC vs. AA + AC), homozygous (CC vs. AA), heterozygous (AC vs. AA), and allele (C vs. A) genetic models. Similar genetic models were also used to assess the rs2010963, rs3025039, and rs1570360 polymorphisms. The Cochrane Q–test and index  with a low between–study heterogeneity. No significant associations were observed in the dominant , recessive , homozygous , and allele  genetic models   with a low between–study heterogeneity. No significant associations were observed in the remaining genetic models  .We performed funnel plots and Egger’s test to assess the publication bias of the included studies. A funnel plot was not constructed for the 3 rs1570360 studies. The funnel plot distribution of distinct studies appeared nearly symmetrical  and susceptibility to CAD, especially in Asian populations. Although a subgroup analysis was used to investigate the source of the heterogeneity, the results should be interpreted with caution.Additional file 1:Table S1. MOOSE checklist for meta-analysis. Table S2. Methodological quality of the included studies according to the Newcastle-Ottawa Scale. Figure S1. Forest plot for the association between the VEGF rs699947 polymorphism and CAD risk in dominant genetic models. Figure S2. Forest plot for the association between the VEGF rs699947 polymorphism and CAD risk in recessive genetic models. Figure S3. Forest plot for the association between the VEGF rs699947 polymorphism and CAD risk in heterozygous genetic models. Figure S4. Forest plot for the association between the VEGF rs699947 polymorphism and CAD risk in homozygous genetic models. Figure S5. Forest plot for the association between the VEGF rs699947 polymorphism and CAD risk in allele genetic models. Figure S6. Forest plot for the association between the VEGF rs2010963 polymorphism and CAD risk in dominant genetic models. Figure S7. Forest plot for the association between the VEGF rs2010963 polymorphism and CAD risk in recessive genetic models. Figure S8. Forest plot for the association between the VEGF rs2010963 polymorphism and CAD risk in heterozygous genetic models. Figure S9. Forest plot for the association between the VEGF rs2010963 polymorphism and CAD risk in homozygous genetic models. Figure S10. Forest plot for the association between the VEGF rs2010963 polymorphism and CAD risk in allele genetic models. Figure S11. Forest plot for the association between the VEGF rs3025039 polymorphism and CAD risk in dominant genetic models. Figure S12. Forest plot for the association between the VEGF rs3025039 polymorphism and CAD risk in recessive genetic models. Figure S13. Forest plot for the association between the VEGF rs3025039 polymorphism and CAD risk in heterozygous genetic models. Figure S14. Forest plot for the association between the VEGF rs3025039 polymorphism and CAD risk in homozygous genetic models. Figure S15. Forest plot for the association between the VEGF rs3025039 polymorphism and CAD risk in allele genetic models. (DOC 3267 kb)


Objective: Chronic periodontitis (CP) is a growing problem that affects the worldwide population, having significant impacts on people's daily lives and economic development. Genetics is an important component in the determination of individual susceptibility to periodontal diseases. Numerous studies have been performed to investigate the association between beta defensin 1 (DEFB1) rs11362 polymorphism and risk of CP, but the results are still inconclusive. Therefore, we conducted this meta-analysis to ascertain whether this variation in DEFB1 is associated with CP susceptibility.Methods: The relevant studies were searched in PubMed and Chinese National Knowledge Infrastructure (CNKI) databases up to January 9, 2018. Two independent authors selected citations and extracted the data from eligible studies. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were used to assess the strength of the association.Results: Seven case-control studies were included in this meta-analysis. Based on unadjusted data, there was no obvious association between DEFB1 rs11362 polymorphism and CP risk in all genetic models ; the results of adjusted data also showed no significant relationship. Subgroup analyses based on ethnicity, participants' smoking status, HWE in controls and severity of CP all revealed similar results to that of the overall analysis. Sensitivity analysis indicated the results were robust and no evidence of publication bias was found.Conclusions: Our meta-analysis suggests that DEFB1 rs11362 polymorphism may not have an important effect on the risk of CP. Further large-scale and well-designed studies are necessary to validate our conclusion in the future. Periodontal disease mainly contains two types, namely, chronic periodontitis (CP) and aggressive periodontitis (AgP). According to the global burden of disease (GBD) in the world  have been identified, some of which are expressed in the gingival tissue , which forms an important nuclear factor kappa B (NF-kB) transcription-binding site  statement  study patients were diagnosed with CP, and control group consisted of either healthy individuals or those without periodontitis; (2) CP was identified as mid CP, moderate CP, severe CP, or two or all of these three types; (3) studies reported the frequencies of genotype distribution and/or crude odds ratios (ORs) and their 95% confidence intervals (95%CIs), adjusted ORs and their 95% CIs, or the data for calculate them; (4) if two or more studies covered the same population, we included the one containing the most comprehensive information; (5) the published language was English or Chinese, and full-texts were obtainable.Cohort studies or case-control studies evaluating the risk of CP in relation to We searched PubMed and Chinese National Knowledge Infrastructure (CNKI) up to January 9, 2018 using the following search terms: “DEFB1 protein, human,” “DEFB1,” “beta-defensin-1,” “hBD-1 protein,” “hBD-1,” “beta defensin 1,” “beta-defensin 1,” “beta defensin-1”, “β-defensin 1,” “ genetic,” “polymorphism,” “polymorphisms,” “variants,” “SNP,” “mutation,” “genetic variants,” “periodontal disease,” and “periodontitis.” We also screened reference lists of all relevant reviews, studies, and published meta-analyses for additional eligible studies.p-value for Hardy-Weinberg Equilibrium (HWE) in controls .The following data were extracted from all eligible studies by two authors independently and disagreements were resolved by discussion: last name of the first author, year of publication, country and ethnicity, genotyping method, source of control, numbers, and genotyping distributions of cases and controls or crude OR and its 95%CI, adjusted OR and its 95%CI, adjusted variables, and Quality assessment was performed according to the Newcastle-Ottawa Scale, which is a validated scale for non-randomized studies in meta-analyses Stang, . A ‘starQ and I2 statistic , homozygote comparison (AA vs. GG), heterozygote comparison (AG vs. GG), dominant model (AG+AA vs. GG), and recessive model (AA vs. AG+GG). For adjusted data, we directly combined the relevant ORs and their 95%CIs according to the reported genetic models. Since allele frequencies were different in various ethnicities  and symmetric funnel plots (el plots .Aggregatibacteractinomycetemcomitans, a periopathogenic bacterium, was found to increase DEFB1 levels in gingival epithelium (Kurland et al., With an increasing prevalence of CP in the developing world (Albandar and Rams, DEFB1 may not play an important role in DEFB1 gene regulation (Sun et al., DEFB1 rs11362 polymorphism and risk of severe CP in Caucasians (Wohlfahrt et al., DEFB1 genetic markers on periodontal disease (Ozturk et al., DEFB1 rs11362 polymorphism and risk of CP. Our meta-analysis of seven case-control studies also indicated no significant association between this variant and the susceptibility of CP, either based on unadjusted or adjusted data. Unlike the usual method based on unadjusted data (Zeng et al., Previous work on cancer cell lines suggests that promoter methylation of DEFB1 rs11362 polymorphism on CP ranging from mild to severe were different. Thus, we performed stratified analysis based on the severity of CP. However, only data of moderate and severe CP were extracted because the data of mild CP was not reported in the included studies, which limited us to performing the dose-response analysis.The major strength of this meta-analysis was that we considered adjusted data and severity of CP. However, as we know, meta-analysis is a secondary research, the results of which largely depend on the data from original studies (Zeng et al., Fourthly, allele frequencies were different between Caucasians and African Americans as reported by Ozturk et al. The difference in different allele frequencies between populations would suggest a different haplotype linkage disequilibrium and therefore different haplotype structure between ancestral populations. Although ethnicity based subgroup analysis was conducted, our results could also be influenced by undetected population stratification. In the periodontal researches, there is a common issue that different studies use different diagnosis criteria. There is more than one accepted diagnosis criterion of periodontal disease, such as alveolar bone loss, oral health index, periodontal index and clinical attachment loss; moreover, the detailed information of diagnosis was not reported usually in the published studies. Consequently, our results should be interpreted with caution.DEFB1 rs11362 polymorphism and CP. Moreover, the difference between smokers and non-smokers is also needed to be detected, thereby providing evidence to ascertain the real role of DEFB1 rs11362 polymorphism and smoking in the occurrence and development of CP.In consideration of the above-mentioned restrictions in our meta-analysis, large-scale studies with detailed information of smoking, alcohol drinking, diagnosis criteria, disease severity, ethnic background, concomitant diseases, and occupation are required to be conducted, so as to yield more precise results of the association between JS and X-TZ designed this study. MZ and LW searched databases and collected full-text papers. MZ and Y-HJ extracted and analyzed data. JS, X-WJ, and LW wrote the manuscript. X-TZ reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


IL-10 (interleukin-10) gene on the susceptibility to clinical atopic dermatitis.We retrieved different reports containing different genetic effects of − 1082 A/G, − 819 T/C, and − 592 A/C polymorphisms within the Herein, we conducted a meta-analysis to comprehensively assess such a genetic relationship after collecting the available published evidence. STATA 12.0 software was used for the statistical analysis under the allelic, homozygotic, heterozygotic, dominant, recessive and carrier genetic models.IL-10 -1082 A/G polymorphism, we did not detect a significant difference between atopic dermatitis cases and population-based controls in the overall meta-analysis under the genetic models of allele G vs. A (P = 0.540), GG vs. AA (P = 0.853), AG vs AA (P = 0.265), AG + GG vs AA (P = 0.221), GG vs AA+AG (P = 0.540) and carrier G vs. A (P = 0.643). Moreover, a statistically non-significant association was observed in the most subgroup meta-analyses by the factors of ethnicity, country and Hardy-Weinberg equilibrium. Likewise, the negative results were detected for the synthetic analysis of IL-10 -819 T/C and − 592 C/A polymorphisms.By retrieving and screening database literature, a total of 16 eligible case-control studies were finally selected. For the IL-10 -1082 A/G, − 819 T/C and − 592 A/C polymorphisms and the susceptibility to atopic dermatitis.The current evidence does not support a strong genetic relationship between The online version of this article (10.1186/s12881-019-0817-8) contains supplementary material, which is available to authorized users. The pIL-10 gene, three common single nucleotide polymorphisms (SNPs), namely, − 1082 A/G (rs1800896), − 819 T/C (rs1800871) and − 592 A/C (rs1800872), were identified [IL-10 polymorphisms on the risk of atopic dermatitis were reported by individual researchers. For example, the IL-10 -1082 A/G polymorphism was reportedly linked to susceptibility to atopic dermatitis in patients from India [IL-10 -1082 A/G polymorphism was not associated with atopic dermatitis risk in the Korean population [IL-10 -819 T/C polymorphism in atopic dermatitis patients was higher than that in healthy control subjects in India [IL-10 -819 T/C polymorphism was also reported to be associated with an enhanced risk of severe atopic dermatitis in patients from the Czech Republic [IL-10 -819 T/C polymorphism and atopic dermatitis risk was also reported in Saudi Arabia [The IL-10 cytokine participates in the modulation of acquired immune and anti-inflammatory responses . Within entified –14. Diffom India , Italy [om India , and theom India . Neverth82 A/G rs00896, − in India . HoweverRepublic . A negati Arabia  and Taiwi Arabia . This isIL-10 SNPs on several skin-associated clinical diseases. For instance, the IL-10 -819 T/C polymorphism, rather than − 1082 A/G and − 592 A/C, was reported to be associated with a decreased risk of skin cancer [IL-10 -1082 A/G polymorphism on the risk of atopic dermatitis [IL-10 polymorphisms in the risk of atopic dermatitis.Some meta-analyses examined the variable degrees of the effect of n cancer . In 2013rmatitis . Along wOur meta-analysis follows the guide of preferred reporting items for systematic reviews and meta-analyses (PRISMA) . The PRIIL-10 gene; and (d) the allelic or genotypic frequency data of cases and controls.After database retrieval, we designed our inclusion and exclusion criteria to select the eligible case-control studies for synthetic analysis. Exclusion criteria: (a) other diseases; (b) other genes; (c) animal/cell assay; (d) meeting abstract; (e) meta-analysis; (f) review paper; (g) other IL-10 variant; and (h) duplicate study. Inclusion criteria: (a) case and control study; (b) atopic dermatitis; (c) -1082 A/G, − 819 T/C, − 592 A/C polymorphisms within the P value of Hardy-Weinberg equilibrium (HWE). The Newcastle-Ottawa quality assessment Scale (NOS) scores of study quality were also measured.Subsequently, we extracted basic information, including first author, publication time (year), ethnicity, SNPs, genotypic or allelic frequency data in both controls and cases, control source, genotyping method, sample size, and 2 test and Q statistic test , DerSimonian-Laird and Mantel-Haenszel method (for association test), Begg’s test and Egger’s test  [2 was larger than 50% or the P value was less than 0.05. In contrast, the Mantel-Haenszel method under a fixed-effect model was used for the association test. In addition, the data of the odds ratio (OR), 95% confidence interval (CI) and P value were calculated under the allelic, homozygotic, heterozygotic, dominant, recessive and carrier genetic models in the overall meta-analysis as well as the relative subgroup analysis by the factors of ethnicity, country and HWE. Only the pooling results from at least three case-control studies were considered in our study.After referring to several reported meta-analyses –27, we uluation) , 29, andn = 28), Embase (n = 79), WOS (n = 104), CNKI (n = 1) and WANFANG (n = 10), and we removed the 82 duplicates. Additionally, we ruled out another 116 studies by the exclusion criteria shown in Fig. IL-10 variant were excluded. As a result, a total of 16 eligible case-control studies [As shown in Fig.  WOS n = 04, CNKI  studies , 30–38 w WOS n = 04, CNKI  WOS n = 04, CNKI IL-10 -1082 A/G polymorphism (Table P = 0.540), GG vs. AA (P = 0.853), AG vs AA (P = 0.265), AG + GG vs AA (P = 0.221), GG vs AA+AG (P = 0.540) and carrier G vs. A (P = 0.643). Likewise, we observed a statistically non-significant association in the subgroup analysis of “Asian”, “Caucasian”, “Poland”, and “Y, with a P value of HWE >0.05” (Table P > 0.05), only apart from the “Asian” subgroup under the GG vs AA+AG model . However, when we excluded the studies with the P value of HWE < 0.05, the negative results were obtained in the subgroup analysis of “Asian/Y”, “Caucasian/Y” and “Poland/Y” (Table P > 0.05). Forest plot data of overall meta-analysis under the allelic model , CC vs. TT (P = 0.588), TC vs. TT (P = 0.405), TC + CC vs. TT (P = 0.433), CC vs. TT + TC (P = 0.821), and carrier C vs. T (P = 0.801). Likewise, we observed a non-significant association in the subgroup analysis of “Asian”, “Y” and “Asian/Y”, under all genetic models (Table P > 0.05). The relative forest plots are displayed in Fig. IL-10 -819 T/C SNP may not be associated with the risk of atopic dermatitis.In addition, for the NP Table , nine caT P = 0.43, CC vs.C P = 0.81, and caC P = 0.81, and caC P = 0.81, and caIL-10 -592 A/C SNP  and AC + CC vs. AA  as well as in the subgroup analysis of “Asian” under allele C vs. A  and AC + CC vs. AA  but not others . It is worth mentioning that the negative results were observed in the “Asian/Y” subgroup, under all genetic models, when only the studies with the P value of HWE > 0.05 were included in the analysis of “Asian” subgroup. The relative forest plots are displayed in Fig. IL-10 -592 A/C SNP and atopic dermatitis susceptibility.For the NP Table , nine caIL-10 -1082 A/G SNP; allelic, homozygotic, heterozygotic, dominant and recessive models of the − 819 T/C SNP; and allelic, homozygotic, recessive models of the − 592 A/C SNP . In addition, we did not observe a large publication bias in most above analyses , only apart from the Egger’s test under the allelic (P = 0.028) and heterozygotic (P = 0.021) models of the − 819 T/C SNP. Egger’s publication bias plots are displayed in Figs. As shown in Additional file IL-10 -1082 A/G polymorphism and the risk of atopic dermatitis [IL-10 -1082 A/G SNP and the risk of atopic dermatitis, which is in line with the outcomes of the above meta-analyses. Recently, another meta-analysis by Zhao, et al. [IL-10 -1082 A/G SNP and atopic dermatitis susceptibility under the recessive model in the Association population. However, only three case-control studies [P value of HWE < 0.05 in controls of two studies [In 2013, Chen, et al. included seven case-control studies , 34, 35 rmatitis . In the rmatitis , 36, 37 , et al.  reported studies , 37 wereIL-10 -819 T/C SNP, a meta-analysis containing nine case-control studies was performed under the six genetic models. The subgroup analysis by the ethnicity was also performed, when the studies with the P value of HWE < 0.05 were removed. We found that IL-10 -819 T/C SNP may not be strongly linked to the risk of atopic dermatitis. Even though the potential positive conclusion was observed under the recessive model in the Caucasian populations [IL-10 -819 T/C and − 592 C/A polymorphisms exists in some reports [IL-10 -592 C/A SNP and the risk of atopic dermatitis. This is also in line with the conclusion of Zhao, et al. [With regards to ulations , only twulations , 35 were reports , 21. How reports , 35, 37., et al. .Our meta-analysis exhibits several advantages. First, all eligible studies contain population-based negative control subjects. Second, our results of Begg’s and Egger’s tests ruled out the presence of large publication bias. Third, our sensitivity analyses support the stability of pooling results.IL-10 -819 T/C and − 592 C/A polymorphisms and all the stratification analyses. For the IL-10 -819 T/C SNP, only two case-control studies [IL-10 -1082 A/G polymorphism, and less than three studies were for the other subgroup analyses of “Country”, such as “China” or “India”. Second, a high heterogeneity level among studies was observed in some overall meta-analyses. Third, the genotypic distribution of control groups in some studies was not in line with the Hardy-Weinberg equilibrium. Fourth, of the eligible case-control studies, only allelic frequency data were extracted in one study [IL-10 -1082 A/G polymorphism was obtained in another study [IL-10 genes, including “ACC”, “ATA”, and “GCC”, very limited data resulted in the failure of related meta-analysis. Sixth, one meta-analysis reported that the − 590 C/T polymorphism within the IL-4 (interleukin-4) gene may be linked to the risk of atopic dermatitis, especially for Asian children [IL-10 gene, one member in the interleukin gene family, in the susceptibility to atopic dermatitis in this study, based on the limitations of study publications. Given the contextual effects of the polymorphism and the diversity of the heterozygotic response, more interleukin gene variant-associated association investigations by additional adjusted clinical or environmental factors should be conducted when we can obtain access to more association investigation data for years to come.Despite this, some disadvantages still may limit our statistical evaluation. First, as in other meta-analyses, a small sample size was enrolled in some analyses. For example, less than ten case-control studies were included in the overall meta-analysis of the  studies , 35 werene study , and theer study . Fifth, children . Considechildren –45, it iIL-10 -1082 A/G, − 819 T/C and − 592 A/C polymorphisms may not be strongly related to atopic dermatitis susceptibility, which would be greatly strengthened by a larger sample size.Overall, based on the current case-control association data, Additional file 1:Table S1. NOS assessment system. Table S2. Heterogeneity evaluation. Table S3. Publication bias assessment. (DOCX 43 kb)Additional file 2:Figure S1. Subgroup analysis of the IL-10 -1082 A/G polymorphism according to ethnicity under the allele G vs. A model. Figure S2. Subgroup analysis of the IL-10 -1082 A/G polymorphism according to ethnicity under the AG vs. AA model. Figure S3. Subgroup analysis of the IL-10 -1082 A/G polymorphism according to ethnicity under the AG + GG vs. AA model. Figure S4. Subgroup analysis of the IL-10 -819 T/C polymorphism according to ethnicity under the allele C vs. T model. Figure S5. Subgroup analysis of the IL-10 -819 T/C polymorphism according to ethnicity under the TC vs. TT model. Figure S6. Subgroup analysis of the IL-10 -819 T/C polymorphism according to ethnicity under the TC + CC vs. TT model. Figure S7. Subgroup analysis of IL-10 -592 A/C polymorphism according to ethnicity under the allele C vs. A model. Figure S8. Subgroup analysis of IL-10 -592 A/C polymorphism according to ethnicity under the AC vs. AA model. Figure S9. Subgroup analysis of IL-10 -592 A/C polymorphism according to ethnicity under the AC + CC vs. AA model. (ZIP 2797 kb)


This paper presents the current knowledge concerning the role of polymorphisms of IL1A and IL1B genes in periodontitis. Attention has been paid to the role of IL-1 in the pathogenesis of the disease, and to the significance of a genetic test, investigating the presence of composite two polymorphisms of IL-1 gene, as a risk factor for severe periodontitis. The significance of this test for prevention of periodontitis and its therapy has been discussed. IL-1 polymorphisms have been presented and described according to the reference single nucleotide polymorphism (SNP) identification number (rsID), established to eradicate the redundancy of reported polymorphisms in the SNP database processed by the National Center for Biotechnology Information. The prevalence of these genotypes in different populations and ethnic groups and its effect on periodontal health have been discussed. The presented data show inconsistent results. It seems that at least two polymorphisms, rs1800587 and rs1143634, are associated with periodontal inflammation. Therefore, they can be regarded as candidate genes involved in further periodontitis risk assessment. It seems that geographical and ethnical factors can play a great role, as the prevalence of specific polymorphisms varies greatly depending on the population studied. Periodontitis is caused by pathogenic microorganisms that activate an immunoinflammatory response of the host. Mediators released by inflammatory cells stimulate periodontal cells to secrete metalloproteinases, proteolytic enzymes directly responsible for connective tissue destruction and prostaglandins, contributing to the destruction of the alveolar bone (van Dyke and van Winkelhoff Gene polymorphisms encoding interleukin (IL)-1 are the most prominent gene polymorphisms in studies on periodontitis  of chromosome 2 and having common DNA sequences  and the degree of disease severity in the 35 subjects who smoked. It was interpreted by the author as the major overcasting effect of nicotinism, being the main risk factor for periodontal disease, and indicating the necessity of excluding smokers from further studies , also known in Europe as the PRT test, from the German Parodontitis Risiko Test, in its initial version used a sample of blood drawn from a finger, and now is using swabs from the buccal mucosa, which are sent to a laboratory for DNA analysis. Then, the IL-1A−889 and IL-1B+3953 alleles are identified by the polymerase chain reaction followed by reverse hybridization. In the case of simultaneous occurrence of at least one allele 2 in both loci, the result is referred to as PST® positive, presumably indicating an increased risk of severe periodontitis. For 20 years, numerous polymorphisms of a single nucleotide have been linked with increased incidence or severe course of periodontal inflammation. A vast number of scientific centers spread worldwide conducted such studies which resulted in an increasing variety of the polymorphism description, and potentially might lead to confusion. Therefore, Human Genome Variation Society introduced the description nomenclature unifying the previously used one, last updated in 2016 . The phrases used in the search were “IL1A” and “IL1B”. The search yielded 2919 and 2261 results, respectively. Those were filtered to the rsIDs cited in PubMed. That produced 27 and 24 results, respectively. Filtered rsIDs were manually evaluated regarding the papers in PubMed researching their influence on the periodontal inflammation . A manual search of PubMed database was also performed to identify other potentially important studies. Special attention was paid to the credibility of the results: longitudinal studies and meta-analyses were pointed out. The results were presented with reference to the given rsIDs. Below the rsID, the following data were given: alteration of the genome (following the HGVS criteria) and global MAF .The authors looked for rsIDs regarding IL-1 gene cluster through sources available in the NCBI database  , IL1A, IL1B and composite gene variations correlated with the incidence and severity of periodontal inflammation. Basing on the ten studies eligible to be included in the analysis, OR for the association between rs1143634 and chronic periodontitis was 1.54 (1.51 for the composite genotype) (Karimbux et al. A. actinomycetemcomitans in subgingival biofilm. However, a linkage between rs1143634 and severity of chronic periodontitis was not observed. Similarly, a genome-wide association study did not show a significant correlation between rs1143634 polymorphism and occurrence of moderate or severe chronic periodontitis (Divaris et al. rs1143634 is a polymorphism of IL-1B gene described by Kornman et al. . NumerouA summary of the meta-analyses on the described SNPs is presented in Table The paper by Kornman et al. , though As presented in Table The presented scientific research brings inconsistent results. It is possible that ethnical heterogeneity may be the reason contributing to the diversity of the results. Also, geographical and racial distribution of the specific genes may make it difficult—or even impossible—to globally assess single nucleotide polymorphisms. New evaluation techniques, like standardization of the methodology allowing data meta-analysis, or genome-wide association studies, may shed more light on the linkage between genotype and the onset or progress of periodontitis. Meta-analyses show that at least two single nucleotide polymorphisms: rs1800587 and rs1143634, are associated with periodontal inflammation. Therefore, they can be regarded as candidate genes involved in further periodontitis risk assessment.


Both MTHFR C677T (rs 1801133) and A1298C (rs 1801131) gene polymorphisms were risks for CHD in children with transgenerational effects from their parents. Countries with greater risks of CHD with a pooled risk ratio (RR) > 2 from MTHFR 677 polymorphisms included Germany, Portugal, China, and Egypt for children; and Brazil, Puerto Rico, Mexico, China, and Egypt for mothers. Whereas, countries with greater risk of CHD with RR > 2 from MTHFR 1298 polymorphisms included Taiwan, Turkey, and Egypt for children; and Brazil, China, and Egypt for mothers. Additionally, meta-prediction analysis revealed that the percentages of MTHFR 677TT and TT plus CT polymorphisms together were increased in countries with higher levels of air pollution, with a trend of increased CHD risks with higher levels of air pollution for children (p = 0.07). Our findings may have significant implications for inflammatory pathways in association with MTHFR polymorphisms and future intervention studies to correct for folate-related enzyme deficits resulted from MTHFR polymorphisms to prevent CHDs for future generations.Congenital heart disease (CHD) is the leading cause of death in children, and is affected by genetic and environmental factors. To investigate the association of air pollution with  Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms have been associated with many congenital anomalies including neural tube defects, deformed organs and body structures, and CHD [MTHFR polymorphisms affects folate metabolism in the one carbon metabolism (OCM) and methylation pathways, with MTHFR enzymes involved in the homocysteine metabolism to prevent the accumulation of homocysteine [MTHFR are C677T (rs 1801133) and A1298C (rs 1801131). The MTHFR 677 TT homozygous and CT heterozygous polymorphisms result in 65% to 70% and 25% to 35% loss of the MTHFR enzyme function, respectively [MTHFR 1298CC homozygous and AC heterozygous polymorphisms lead to a 20% and 10% loss of enzyme function, respectively, with an increased homocysteine level [MTHFR 677TT polymorphism have presented the greatest hyperhonocysteinemia and lower plasma folate levels as compared to those with other MTHFR polymorphisms, thus supplementation of folate has been suggested to individuals with MTHFR 677 TT genotype [Congenital heart disease (CHD) is the most common congenital abnormity and causes most mortality in children worldwide ,2. With  and CHD . MTHFR pcysteine ,8. Homoccysteine . Two of ectively ,11, wherMTHFR C677T [MTHFR polymorphism and the risk of CHD for their children [MTHFR polymorphisms and CHD, presenting MTHFR TT homozygous polymorphism as a risk genotype for CHD [MTHFR polymorphisms and the risk of CHD, there are still no conclusive results. Hence, a more comprehensive meta-analysis is necessary.Previous meta-analyses presented that FR C677T ,14,15,16FR C677T  were assFR C677T ,19,20,21children ,14,18,22Previous studies demonstrated that air pollution deterred health outcomes for both generations of parents and children, affecting fetal development ,23,24. AMTHFR polymorphisms and CHD risk presented inconsistent results [MTHFR polymorphisms and the risks of CHD. Hence, we conducted meta-analysis and meta-prediction to examine the impact of air pollution on the MTHFR polymorphisms and the risk of CHD.In summary, previous meta-analyses published on  results ,20,21,22MTHFR”, and “methylenetetrahydrofolate reductase” and limited the results to human studies. Reference lists of previous meta-analysis were reviewed to identify additional articles. We entered the resulting articles into a database organized by key words. The entries were checked between two raters to ensure the accuracy of the data entries.Following the guidelines of meta-analysis of observational studies in epidemiology (MOOSE)  and prefMTHFR C677T or A1298C polymorphisms and CHD; (2) were conducted by case-control and/or cross-sectional designs for children, mothers, or fathers; (3) and were written in English or in Chinese but provided an abstract in English and tables that clearly listed the genotype allele frequencies for both case and control groups. All seven non-English articles were written in Chinese language. And, the authors are proficient in Chinese. Therefore, there was no obstacle to extract the content of these articles. The exclusion criteria were the studies that: (1) Included the subjects with other congenital abnormality such as Down syndrome; (2) and did not offer MTHFR genotype allele counts or no appropriate genotype allele counts.The inclusion criteria were the studies that: (1) examined the association between MTHFR gene polymorphisms and CHD for screening . A total of 74 articles were excluded for not being the original studies, with 10 being meta-analyses [MTHFR genotype allele counts per groups. Additionally, we carefully examined potential duplicate use of data from related publications using the same data and three articles were excluded. Finally, we included 42 articles for pooled analysis  and StatsDirect, version 2.4.7  to pool the results of data analyses. We checked the Hardy-Weinberg Equilibrium (HWE) analysis, which was developed to assess the distribution equilibrium of the evolutionary mechanisms in population genetics ,41,42. Dociation . BecauseMTHFR polymorphism subtypes between cases and controls, and found 95% confidence intervals (CIs) for the associations of MTHFR polymorphism genotypes with CHD. The RR of 1 represents “no effect,” <1 indicates a protective effect , and >1 indicates increased risks for CHD. We defined significant findings as those with p-values < 0.05. We performed the Q test and 2I index to test the heterogeneity between studies. Random effects instead of fixed effects models were used for the risk estimates when the heterogeneity tests were significant with p-value < 0.05 in Q test or values of 2I ≥ 50% [p-value < 0.05 in Begg’s and Egger’s test suggested a possible publication bias. No significant publication bias was found on the meta-analysis of the MTHFR polymorphism test . We used the funnel plot of MTHFR TT plus CT as an example to show the symmetric distribution of the data  and risk ratios (RRs) to perform pooled analysis and compared the differences between the two ratios. The results of ORs and RRs were similar, and the RRs were more conservative with less Type-1 errors. Additionally, RR includes all three genotypes for the ratios versus OR, which is only a pair-wise ratio, thus, RR has been used as the standardized ratio per consensus panel for gene-environment interaction analysis ,44,45,46I2 ≥ 50% . The funthe data .Because different racial-ethnic groups presented different polymorphism patterns, we performed subgroup analysis per racial-ethnic group. The categories of these racial-ethnic groups were presented in the included studies with subgroups of Caucasian, East Asian, South Asian, Mixed, Middle Eastern, Hispanic, and African. The data further revealed heterogeneity with regional differences on the percentage of polymorphisms and risks of CHD, thus, we used geographic information system (GIS) maps in JMP Pro  to visualize the distributions of polymorphisms and risks on the global maps. Analyses were performed by both racial-ethnic group and geographical location because migration is common today and thus one can no longer equate a country or region to only one race or ethnic group. By doing so, a comprehensive picture that takes both genetic and environmental factors into account can be revealed. These GIS maps were drawn by country distribution and were helpful for visually identifying geographic patterns. In addition, we applied recursive partition trees in the JMP Pro program to examine how an independent variable  can make a decisive split of the data by partitioning the groups (such as air pollution levels) into subgroups with reference to the dependent variable (the percentage of polymorphisms and CHD risks). The recursive partition tree does this by exhaustively searching all possible groupings . The gooFor triangulation purpose, we also employed a conventional multiple comparison procedure (Tukey test) to examine whether partition trees and Tukey tests concurred with each other. Furthermore, we used nonlinear curve fit to examine the associations between air pollution and the outcome variables. The aim of meta-predictive analysis was to generate more precise predictions while integrating data from diverse sources. The main purpose for using both conventional statistical and machine learning  methods is to verify the results by cross-validation with AICc . We enteMTHFR C677T genotype, 23 articles included data of children; eight articles of mothers; seven articles for each of children and mothers, yielding seven additional study groups; three articles for each of mothers and fathers but not children yielding three additional study groups; and one article for each of children, mothers, and fathers yielding two additional study groups [For the y groups . Additioy groups  includedMTHFR A1298C genotypes, eight articles included data of children; two articles of mothers; four articles for each of children and mothers yielding four additional study groups; and one article for each of children, mothers, and fathers, yielding two additional study groups. In summary, there were 15 articles containing 21 study groups (2754 cases and 3419 controls). These 21 study groups included 13 studies of children (1835 cases and 2003 controls), seven studies of mothers (691 cases and 1165 controls), and one study of fathers (228 cases and 251 controls) (For ontrols) .Study populations were drawn from countries across the globe, including Europe, North America, South America, East Asia, South Asia, Middle East Asia and Africa. We checked the racial-ethnic compositions of each study to ensure that we properly accounted for data from distinct versus mixed racial-ethnic groups per studies. The most investigated racial-ethnic populations in those studies were Asian , followed by Caucasian (14 studies), then African (8 studies), mixed race (7 studies), Hispanics (5 studies), and Middle-East Asian (3 studies) .MTHFR C677T polymorphisms and CHD risks     ; and for04–1.11) , parents04–1.11) , and mot04–1.11) , while M02–1.91) . Contrar87–0.96) ; childre87–0.96) ; parents87–0.96) ; and mot87–0.96) .MTHFR 677TT in the case group than the control group in East Asian (24.1% versus 17.6%) and Hispanic (19.2% versus 15.6%) than other ethnic groups. MTHFR 677TT was the risk genotype for CHD in Caucasian and East Asian; and a potential risk genotype for African  than mixed (14.0%) and acyanotic CHDs (6.2%), and a risk type for mixed CHD (RR = 1.25) and cyanotic CHD , China (19.5%) and Brazil (15.8%) in the control group , Germany (RR = 2.00), Mexico (RR = 1.77), Egypt (RR = 1.69), China (RR = 1.33), Netherlands (RR = 1.39), US and Turkey (RR = 0.95), and Brazil (RR = 0.76)  .MTHFR 677TT as a risk genotype. For all groups combined, countries with RR > 1 included Russia, Germany, Italy, Netherlands, Portugal, Puerto Rico, Mexico, Brazil, Taiwan, China, and Egypt. Conversely, countries with TT as a protective genotype (RR < 1) included US and Turkey . An RR > 2 inferred causality for health outcomes in biologic studies as a strong evidence by the consensus panels [Additionally, we pooled countries per RR > 1, <1, or varied with d Turkey . For chid Turkey . It is ns panels ,45. CounMTHFR A1298C polymorphisms, we summarized significant findings in MTHFR 1298CC and CC plus AC polymorphisms together were risk genotypes for CHD    and for 02–1.31) .MTHFR 1298CC homozygous polymorphism in the case group than in the control group in South Asian (38.5% versus 22.0%), Middle Eastern (18.0% versus 9.9%), and African (54.5% versus 22.7%) than other ethnic groups. MTHFR 1298CC was a risk genotype for CHD in East Asian, Middle Eastern, and African (MTHFR 1298CC were much higher in the case group than in the control group in South Asian (38.5% versus 22.0%), Middle Eastern (18.0% versus 9.9%), and African (55.5% versus 23.6%) than other ethnic groups. MTHFR 1298CC was a risk type for CHD in Middle Eastern (MTHFR 1298CC was much higher in the case group than in the control group in African (53.6% versus 21.8%) than other ethnic groups. MTHFR 1298CC was a protective genotype for CHD in Caucasian while MTHFR 1298AA was a protective genotype for CHD in African , India (22.0%), and Netherlands (10.0%) in the control group; and Egypt (55.58%), India (38.5%), and Turkey (18.0%) in the case group  in Brazilian children  in Russia and Netherlands  approach [MTHFR 677 TT polymorphisms   for the control group  than the Levels 2 and 3 combined (RR = 1.30), with smaller AICc (ranged from 56 to 62) for the partition tree tests . There were no significant findings on the parental subgroup for the association of air pollution with MTHFR polymorphisms and CHD, and on the association of air pollution with MTHFR A1298C polymorphism and CHD risk for any groups.We then analyzed the association of air pollution with CHD risk  using bo to 300) . Specifiol group . On the MTHFR polymorphisms of C677T and A1298C in association with the development of CHD, involving children and parents. With meta-predictive analysis, we demonstrated that air pollution was associated with the increased percentage of MTHFR 677 TT homozygous and MTHFR 677 TT plus CT polymorphisms together, and the trends of increased risks of CHD with TT polymorphisms in children. MTHFR 677 TT homozygous polymorphism was a risk genotype for CHD across all study groups in both generations combined, and subgroups of children, mothers, and fathers. Additionally, MTHFR 677 TT plus CT polymorphisms together were risk genotypes for all groups combined in both generations and subgroups of children and mothers, whereas, MTHFR 677 CC common allele type played a protective role against CHD. These polymorphisms carried significance in ethnic subgroups of Caucasian, East Asian, and African. Furthermore, we found both generations’ MTHFR 1298 CC and CC plus AC polymorphisms together were risk types for CHD, and also significant for subgroups of children: East Asian, Middle Eastern, and African. These results demonstrated the significance of MTHFR polymorphisms and associated enzyme functions in the development of CHD for future prevention efforts.We presented a comprehensive meta-analysis for transgenerational effects of MTHFR polymorphisms play an essential role in the methylation pathway decreasing folate levels and causing hyper-homocysteinemia. Additionally, air pollution may affect normal differentiation of neural crest cells which are important for heart development [MTHFR 677 polymorphisms, with a more profound impact in countries with higher levels of air pollution, especially in East Asian countries, China particularly. These findings are consistent with prior studies associating increased air pollution levels with increased MTHFR gene polymorphisms in various cancers, Alzheimer’s disease, and hypertensive disorders during pregnancy (HDP) [MTHFR polymorphism-associated HDP risk [Air pollution was associated with CHD ,24,64. Selopment  and are elopment . We democy (HDP) ,38,39,40HDP risk . FurtherFor meta-prediction-associated meta-regression analyses, linear modeling, such as Pearson’s correlation and ordinary least squares regression, have been criticized as overly simplistic. One of the classic examples is presented by Anscombe , who claMTHFR 677 TT and MTHFR 677 TT plus CT and paternal MTHFR 677 TT polymorphisms were significant risk genotypes for CHD, demonstrating a greater and more extensive impact of maternal than paternal polymorphisms on the CHD risk [MTHFR 677 TT polymorphism was also a risk type for East Asian and Hispanic, while paternal MTHFR 677 TT polymorphism was a risk type for Caucasian. Our results demonstrated that MTHFR polymorphisms were associated with all subtypes of CHD for children [MTHFR A1298C polymorphism on CHD risks, while previous meta-analyses demonstrated inconsistent results on such an association [Our results presented that both maternal CHD risk . Maternachildren , versus children ,72. Addiociation ,15,17, aMTHFR polymorphisms of both 677 and 1298, which inferred causality in biologic studies as strong evidence by the consensus panels [MTHFR 677 polymorphisms . Whereas, countries with greater risk of CHD from MTHFR 1298 polymorphisms included Taiwan, Turkey, and Egypt (three studies) for children; and Brazil, China, and Egypt (three studies) for mothers . The number of studies with high risk of disease risk (RR > 2) resulted from MTHFR polymorphisms, which are greater in this meta-analysis of CHD condition than in previous meta-analyses of pregnant women with hypertensive diseases  [MTHFR 677) [MTHFR polymorphisms are worthy of further investigations on the transgenerational effects for epigenetic methylation pathways. Future studies could be conducted to examine the effects of gene-environment interactions between gene polymorphisms and air pollution on the health outcomes across generations and lifespan. The results of heightened disease risks for children with CHD could bring attention to health policy for a clean air environment and interventions to mitigate the enzyme deficiency in the folate metabolism pathways for parents with MTHFR polymorphisms to prevent CHDs for future generations.It is noteworthy that many countries presented CHD risk with RR > 2 from s panels ,45. ThesFR 1298)  and AlzhHFR 677) . The mecSeveral limitations should be considered when interpreting these findings. First, the air pollution measure presented great challenges in the assessment of exposure ,70 and tMTHFR C677T and A1298C gene polymorphisms were risks for CHD, with transgenerational effects. Additionally, meta-prediction analysis revealed the percentage of MTHFR 677TT and TT plus CT polymorphisms together were increased in countries with higher levels of air pollution, with a trend of increased CHD risks with higher levels of air pollution for children. Our findings may have significant implications on advocating for a clean-air environment for public health policy and future intervention studies to mitigate the folate-related enzyme deficits in the folate-related metabolism pathways resulting from MTHFR polymorphisms which prevent CHDs for future generations.We applied a comprehensive meta-analysis and found that both


ADH1B have been frequently studied for its potential effect on carcinogenesis. However, the findings are as yet inconclusive. To gain a more precise estimate of this potential association, we conducted a meta-analysis including 66 studies from 64 articles with 31999 cases and 50964 controls. The pooled results indicated that ADH1B Arg47His polymorphism is significantly associated with the decreased risk of overall cancer  = 0.62, 95% confidence interval (CI) = 0.49–0.77; heterozygous model, OR = 0.71, 95% CI = 0.60–0.84; recessive model, OR = 0.83, 95% CI = 0.76–0.91; dominant model, OR = 0.62, 95% CI = 0.53–0.72; and allele comparison, OR = 0.82, 95% CI = 0.75–0.89). Stratified analysis by cancer type and ethnicity showed that a decreased risk was associated with esophageal cancer and head and neck cancer amongst Asians. In conclusion, our meta-analysis suggested that ADH1B Arg47His polymorphism was significantly associated with decreased overall cancer risk. These findings need further validation in large multicenter investigations.Alcohol consumption has been established to be a major factor in the development and progress of cancer. Genetic polymorphisms of alcohol-metabolism genes result in differences between individuals in exposure to acetaldehyde, leading to possible carcinogenic effects. Arg47His (rs1229984 G > A) in  Cancer is a major public health problem worldwide. According to GLOBOCAN worldwide estimates, an estimated 14.1 million new cancer cases and 8.2 million cancer-related deaths occurred in 2012 .ADH1B have been frequently studied for its potential effect on the carcinogenesis. Compared with the Arg/Arg individuals, the His/His individuals have a 40-fold higher enzyme activity oxidized alcohol to toxic acetaldehyde , dominant model [(Arg/His + His/His) vs. Arg/Arg], as well as allele comparison (His vs. Arg). Stratification analyses were further conducted according to ethnicity, cancer type, control source, and HWE. Chi square-based Q-test was applied to assess between-study heterogeneity. If no heterogeneity (P>0.10) was found, the fixed-effect model (Mantel–Haenszel method) was performed [P-value less than 0.05 was considered statistically significant.The strength of the association between erformed . Otherwierformed . Sensitierformed . All theADH1B Arg47His polymorphism and cancer risk were included in the final meta-analysis [As listed in analysis .Overall, 66 studies from 64 articles with 31999 cases and 50964 controls were finally included in our meta-analysis. As shown in ADH1B Arg47His polymorphism and cancer risk are shown in ADH1B Arg47His polymorphism significantly associated with the decreased risk of overall cancer under all the five genetic models: homozygous model, OR = 0.62, 95% CI = 0.49–0.77; heterozygous model, OR = 0.71, 95% CI = 0.60–0.84; recessive model, OR = 0.83, 95% CI = 0.76–0.91; dominant model, OR = 0.62, 95% CI = 0.53–0.72; and allele comparison, OR = 0.82, 95% CI = 0.75–0.89.The main results for the association between Regarding the stratified analysis by ethnicity, a decreased cancer risk was also detected amongst Asians under all the genetic models: homozygous model, OR = 0.60, 95% CI = 0.48–0.76; heterozygous model, OR = 0.66, 95% CI = 0.53–0.81; recessive model, OR = 0.82, 95% CI = 0.75–0.91; dominant model, OR = 0.58, 95% CI = 0.47–0.72; and allele comparison, OR = 0.80, 95% CI = 0.72–0.88, and amongst mixed ethnic group: homozygous model, OR = 0.35, 95% CI = 0.13–0.93; heterozygous model, OR = 0.53, 95% CI = 0.37–0.75; recessive model, OR = 0.37, 95% CI = 0.14–0.98; dominant model, OR = 0.46, 95% CI = 0.36–0.60; and allele comparison, OR = 0.50, 95% CI = 0.36–0.68. However, an increased risk of cancer was detected amongst Caucasians under homozygous model  and recessive model .ADH1B Arg47His polymorphism significantly decreased the risk of esophageal cancer: homozygous model, OR = 0.39, 95% CI = 0.28–0.55; heterozygous model, OR = 0.47, 95% CI = 0.34–0.66; recessive model, OR = 0.72, 95% CI = 0.62–0.83; dominant model, OR = 0.41, 95% CI = 0.31–0.54; and allele comparison, OR = 0.67, 95% CI = 0.57–0.78; upper aerodigestive tract cancer: homozygous model, OR = 0.31, 95% CI = 0.23–0.42; heterozygous model, OR = 0.33, 95% CI = 0.21–0.53; recessive model, OR = 0.70, 95% CI = 0.57–0.86; dominant model, OR = 0.39, 95% CI = 0.26–0.58; and allele comparison, OR = 0.62, 95% CI = 0.54–0.71; and head and neck cancer: homozygous model, OR = 0.55, 95% CI = 0.31–0.97; recessive model, OR = 0.78, 95% CI = 0.66–0.93; dominant model, OR = 0.64, 95% CI = 0.47–0.87; and allele comparison, OR = 0.80, 95% CI = 0.66–0.96.Regarding the stratified analysis by cancer type, the Regarding the stratified analysis by control source and HWE, a decreased cancer risk was detected in hospital-based studies: homozygous model, OR = 0.53, 95% CI = 0.40–0.71; heterozygous model, OR = 0.64, 95% CI = 0.51–0.81; recessive model, OR = 0.79, 95% CI = 0.69–0.90; dominant model, OR = 0.56, 95% CI = 0.44–0.72; and allele comparison, OR = 0.77, 95% CI = 0.68–0.87; population-based studies: dominant model, OR = 0.68, 95% CI = 0.54–0.85; and allele comparison, OR = 0.87, 95% CI = 0.76–0.99; and also the studies in agreement with HWE: homozygous model, OR = 0.60, 95% CI = 0.48–0.76; heterozygous model, OR = 0.71, 95% CI = 0.60–0.84; recessive model, OR = 0.81, 95% CI = 0.74–0.89; dominant model, OR = 0.67, 95% CI = 0.56–0.81; and allele comparison, OR = 0.81, 95% CI = 0.74–0.88.P<0.001). Therefore, the random-effect model was adopted to assess the ORs and 95% CIs. Furthermore, the leave-one-out sensitivity analyses indicated that no single study could change the pooled ORs. The results of the Begg’s funnel plot and Egger’s linear regression test showed no evidence of publication bias  for histidine (His) at codon 47. Compared with the Arg/Arg individuals, the His/His individuals have a 40-fold higher enzyme activity oxidized alcohol to toxic acetaldehyde, thereby inducing tumorigenesis [Alcohol consumption has been established to be a major factor in the development and progress of cancer . Alcoholfunction . Arg47Hiigenesis ,85.ADH1B Arg47His polymorphism and the overall cancer risk. A total of 66 studies from 64 articles with 31999 cases and 50964 controls were included, and the large sample size provided adequate power to detect this association. Overall, ADH1B Arg47His polymorphism was associated with a decreased risk of overall cancer under all the five genetic models. Stratified analysis by ethnicity revealed that ADH1B Arg47His polymorphism reduced cancer risk amongst Asians and mixed ethnicity group but increased risk amongst Caucasians. Stratified analysis by cancer type revealed that ADH1B Arg47His polymorphism reduced risk in esophageal cancer, upper aerodigestive tract cancer, and head and neck cancer, while no effect was found on colorectal, hepatocellular, gastric and pancreatic cancer. In stratified analysis by control source and HWE, a decreased cancer risk was detected in hospital-based studies, population-based studies, and also the studies in agreement with HWE.To the best of our knowledge, this is the first meta-analysis investigating the association between ADH1B Arg47His polymorphism and only one particular type of cancer risk, such as esophageal, head and neck, gastric and colorectal cancer [ADH1B Arg47His polymorphism was associated with decreased risk of colorectal cancer supported by four studies. However, this decreased risk was not present in the current one including six more studies. It was noteworthy that we found that ADH1B Arg47His polymorphism was associated with decreased cancer risk amongst Asians while increased cancer risk amongst Caucasians. In Caucasian population, the A allele was found to associate with an increased risk of colorectal cancer [There were several meta-analyses focussed on l cancer . For esol cancer  found thl cancer . Howeverl cancer  found thl cancer . The oppSeveral limitations in the current meta-analysis should be addressed. First, a number of studies adopted in our meta-analysis had relatively small sample size for each cancer type, like bladder and breast cancer. Second, because of the absence of original data, our analyses were based on unadjusted estimates of ORs without adjustment for other confounding factors. Third, there were substantial heterogeneities in all the five genetic models, hence the random-effect model was adopted and might present unstable results. Overall, due to these limitations, the findings in the current meta-analysis should be interpreted with caution.ADH1B Arg47His polymorphism was significantly associated with the decreased overall cancer risk, especially for esophageal cancer and head and neck cancer amongst Asians.In conclusion, our meta-analysis suggested that


Several studies have investigated the potential relationship between IL-1β polymorphism (rs16944) and susceptibility to chronic periodontitis; inflammatory process is involved, but conclusions is still controversial.  Interleukin-1β polymorphism (rs16944) is associated with susceptibility to chronic periodontitis.  The aim of this study was to determine whether the IL-1P values; logistic regression models were used. And to perform meta-analysis, studies about IL-1β polymorphism (rs16944) and chronic periodontitis were searched in PubMed, Embase, Google Scholar, and Korean Studies Information Service System (KISS) electronic databases until July 2017.  For the case-control study, 51 patients with chronic periodontitis and 33 healthy control patients were recruited in the study. Genotyping was conducted by direct sequencing. SNPStats and SPSS 18.0 were used for the analysis of genetic data and to evaluate odds ratios, 95% confidence intervals, and β polymorphism (rs16944) and chronic periodontitis (P > 0.05 in each model). When combined with the previous studies in the meta-analysis, the result was not associated with chronic periodontitis in any of the models . The subgroup analysis stratified by ethnicity showed a weak association between the IL-1β polymorphism (rs16944) and chronic periodontitis in the Caucasian population .  In our case-control study, no significant relationship was revealed between IL-1β polymorphism (rs16944) is not associated with susceptibility to chronic periodontitis. Evidences from a case-control study and the meta-analysis suggest that IL-1 Periodontitis, one of the most common infectious diseases, is the major cause of tooth extraction in the elderly population . Accordiβ) gene located at 2q14 encodes the IL-1β protein which plays an important role as a mediator in a variety of inflammatory response as well as in bone metabolism [β mRNA expression is much higher in a group affected by chronic periodontitis than in the control group [β transcription site, three polymorphisms at base pair positions +3954/3953 , −511 , and −31  caused transitions between C and T [β polymorphism (rs16944) is one of the most commonly investigated polymorphism regarding susceptibility to chronic periodontitis. Kornman et al. reported on the relationship between the IL-1β polymorphism (rs16944) and periodontal diseases in a population of European descent for the first time in 1997 [β polymorphism (rs16944) and chronic periodontitis, with many results that do not coincide and remain debatable. The discrepancy in results may be due to heterogeneity between studies, as well as small sample sizes. To overcome issues due to small sample sizes and error from inadequate statistical power, meta-analysis is performed. To obtain more reliable results on the relationship between the IL-1β polymorphism (rs16944) and the susceptibility to chronic periodontitis, we performed a case-control study and meta-analysis with all eligible studies.The interleukin-1 beta  and the susceptibility to chronic periodontitis from a new case-control study and then to further perform an updated meta-analysis to derive a more precise conclusion.The purpose of this study was to evaluate the association of IL-1β gene polymorphism (rs16944) and the susceptibility to chronic periodontitis, 51 patients with chronic periodontitis and 33 nonperiodontitis controls were recruited. The criteria for diagnosis for chronic periodontitis and control groups are described in Kang et al. [To investigate the relationship between IL-1g et al. . This stA previous study reported that oral epithelial cells near teeth in patients with gingivitis and periodontitis underwent changes such as proliferation, DNA damage, or apoptosis . Collecthttp://bioinfo.iconcologia.net/SNPstats) in the control group. Genotype models  were applied to determine relationship between differences in genotype frequencies between the chronic periodontitis group and the control group. Logistic regression was used for the analysis. SNPStats and SPSS 18.0  were used for the statistical analysis. Logistic regression was conducted to evaluate the odds ratio (OR), 95% confidence intervals (CI), and P value. For statistical tests, the level of significant P value was set at 0.05.The Hardy–Weinberg equilibrium (HWE) was estimated using SNPStats (β polymorphism (rs16944) with chronic periodontitis, a meta-analysis combining published literature and our current study was performed. Studies about IL-1β polymorphism (rs16944) and chronic periodontitis were searched in electronic databases including PubMed, Embase, Google of Scholar, and Korean Studies Information Service System (KISS) up to July 2017 using the keywords “Interleukin-1β”, “IL1B”, “rs16944”, or “IL1B-511”, AND “polymorphism”, “polymorphisms”, or “variant” AND “alveolar bone loss”, “periodontitis”, or “periodontal disease”. First, we screened the titles and abstracts, and then examined the full text of screened articles. Some studies were included by manual search from references in related original studies or review articles.To further investigate the association of IL-1β polymorphism (rs16944) and chronic periodontitis, (2) a case-control study, and (3) sufficient genotype and allele distribution data of the IL-1β polymorphism (rs16944) in the control group and the chronic periodontitis group to calculate an odds ratio (OR) with a 95% confidence interval (CI). The data of the first author's name, published year, country, ethnicity, sample size of the control and chronic periodontitis, and genotype frequencies of IL-1β polymorphism (rs16944) in the control and chronic periodontitis groups were extracted from the included studies.Inclusion criteria were the following: (1) the study about the association between IL-1I2 statistic for inconsistency and the χ2 distribution of Cochran Q statistic were used to assess heterogeneity across studies. A χ2 test-based Q statistic test and a I2 test were performed to assess heterogeneity of the study. The P value less than 0.05 of Q was considered to be statistically significant. The fixed effects model was adopted if the result of the Q test was P > 0.05 or I2 statistic was <50%, which indicated the statistically no significant heterogeneity in the meta-analysis. The random effects model was used when significant heterogeneity was detected among the included studies. Publication bias was evaluated by a funnel plot and Egger's test.Statistical analysis was performed by meta-analysis software . The random effects model or the fixed effects model was selected according to the degree of heterogeneity. The β gene with susceptibility to chronic periodontitis was investigated. β polymorphism (rs16944) with chronic periodontitis. In the control group, genotype distributions for IL-1β polymorphism (rs16944) were in HWE (P = 0.178). Frequencies of C/C, C/T, and T/T genotypes were 37.5%, 37.5%, and 25% in the control group, and 22%, 64%, and 14% in the chronic periodontitis group, respectively  and chronic periodontitis was not observed. In the genotype analysis of the IL-1β polymorphism, all models  showed no significant association with chronic periodontitis (P > 0.05).Any association between IL-1A total of 457 studies were screened using the mentioned search strategy. After deleting duplicates, a record screen was performed and 16 case-control studies were finally selected –31. The P > 0.05).The characteristics of selected studies in meta-analysis, including our case-control study, are showed in β polymorphism (rs16944) (β polymorphism (rs16944) in the allele, dominant, and recessive models  . There wβ polymorphism (rs16944) in the allele, dominant, and recessive models  showed a weak association with chronic periodontitis in the Caucasian population . However, association between IL-1β polymorphism (rs16944) and chronic periodontitis was not observed in the allele  and dominant  models (β polymorphism (rs16944) and chronic periodontitis.IL-1) models . ConsequP > 0.05), and Egger's linear regression test showed that there was no publication bias (P > 0.05).It is not too much to emphasize the importance of existence of teeth in one's life. The presence of teeth is closely connected with one's daily activities and quality of life (QoL) . Tooth lβ is expressed most abundantly in blood mononuclear cells and mediates host response [β plays an important role in inflammation, regulating inflammatory pain hypersensitivity by modulating COX2 expression [β can also participate in this process [β in these inflammations, there have been many studies on inflammatory diseases and polymorphisms of the IL-1β gene. IL-1β polymorphism may be associated with an increased risk of hypochlorhydria and gastric cancer by altering the level of IL-1β expression due to Helicobacter pylori infection [β gene mutations in the patient group than in the control group [β polymorphism (rs16944), one of the single nucleotide polymorphisms of IL-1β, has been reported to be associated with various diseases, such as diabetic nephropathy in Korean type 2 diabetic patients [IL-1response . IL-1β ppression . CD4+ T  process . Becausenfection . Studiesol group . The IL-patients , Parkinspatients , and Behism rs169, one of β polymorphism (rs16944) and chronic periodontitis in a population of European descent [β polymorphism (rs16944) as a risk indicator for chronic periodontitis in Brazilians [β polymorphism (rs16944) and reduced risk of periodontitis [β polymorphism (rs16944) variants and the risk of periodontitis [Therefore, there have been many studies on periodontitis as one of the inflammatory diseases. Ever since the first reported study on the association between the IL-1 descent , many stazilians . In contdontitis . A recendontitis .β polymorphism (rs16944) and chronic periodontitis. Our study included 1540 patients with chronic periodontitis and 2472 healthy control subjects in 16 articles. The result shows that the development of chronic periodontitis is not associated with IL-1β polymorphism (rs16944), except in the case of Caucasian population, where a weak statistical significance in the recessive model was detected (P = 0.037). Our present result for host response might partially explain this difference.In the present study, we have collected the previous studies conducted on the association between IL-1β polymorphism (rs16944) and the chronic periodontitis, but our results failed to show the association. These findings should be interpreted with caution and have some limitations. We could not investigate various ethnic distributions because all studies included only Caucasian and Asian populations. Though environmental or habitual elements are key factors in the risk of chronic periodontitis and the pathophysiological processes are very complex, we cannot but consider only one genetic factor in this meta-analysis. With this regard, we have added a new original case-control study to the meta-analysis and have found some more accurate results by removing some papers outside of the HWE. The ethnic-specific genotypes CC, CT, and TT of rs16944 are known as 0.416, 0.451, and 0.133 in Caucasian, 0.279, 0.535, and 0.186 in Chinese, and 0.290, 0.465, 0.244 in the Japanese population, respectively. The genotype in our case-control study in the Korean population was 0.375, 0.375, and 0.250. These differences among genotypes are likely to be the reason for the different results between ethnicities.The purpose of our study was to find a significant relationship between IL-1β polymorphism (rs16944) and chronic periodontitis in the present case and control study. We observed that IL-1β polymorphism (rs16944) was not associated with chronic periodontitis in the Korean population. We also evaluated the relationship between IL-1β polymorphism (rs16944) and chronic periodontitis using meta-analysis. A statistically meaningful association was detected with IL-1β polymorphism (rs16944) in the Caucasian population, but it is difficult to describe a strong association with chronic periodontitis due to insufficient statistical power. If more results in various populations would be accumulated in further studies, the relation between IL-1β polymorphism (rs16944) and chronic periodontitis would be clarified and that would help improving clinical prognosis.We evaluated the association between IL-1