Published data revealed that host genetic variants have a substantial influence on sepsis susceptibility. However, the results have been inconsistent. We aimed to systematically review the published studies and quantitatively evaluate the effects of these variants on the risk of sepsis.We searched the PubMed, EMBASE, Medline, Web of Knowledge, and HuGE databases to identify studies that investigated the associations between genetic variants and sepsis risk. Then, we conducted meta-analyses of the associations for genetic variants with at least three study populations and applied the Venice criteria to assess the association result credibility.A literature search identified 349 eligible articles that investigated 405 variants of 172 distinct genes. We performed 204 primary and 185 subgroup meta-analyses for 76 variants of 44 genes. The results showed that 29 variants of 23 genes were significantly associated with the risk of sepsis, including 8 variants of pattern recognition receptors (PRRs), 14 variants of cytokines, one variant of an immune-related gene and 6 variants of other genes. Furthermore, the cumulative epidemiological evidence of a significant association between each variant and the risk of sepsis was classified as strong or moderate for 18 variants. For the 329 variants with fewer than three study populations, 63 variants of 48 genes have been reported to be significantly associated with the risk of sepsis in a systematic review.We identified several genetic variants that could influence the susceptibility to sepsis by systematic review and meta-analysis. This study provides a comprehensive overview of the genetic architecture of variants involved in sepsis susceptibility and novel insight that may affect personalized targeted treatment in the future clinical management of sepsis.The online version of this article (10.1186/s13054-019-2313-0) contains supplementary material, which is available to authorized users. Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection, and it is a major, underrecognized health-care problem worldwide . DespiteRecently, many investigators have reported associations between host genetic variants containing SNPs, insertion/deletions (Ins/Del), and variable numbers of tandem repeats (VNTRs) in genes that regulate the host’s immune response and sepsis susceptibility , 7. HoweThe present study applied a systematic review and meta-analysis approach with a predefined protocol to clarify the potential associations between host genetic variants and the risk of sepsis.This search was conducted according to the PRISMA criteria . A writtWe used a two-stage search strategy to identify relevant publications Fig. . In stagWe included full-length studies that evaluated the associations between sepsis and genetic variants. The following inclusion criteria were applied: (1) the study was an independent case-control or cohort design and evaluated the association between genetic polymorphisms and sepsis susceptibility; (2) the study had sufficient data for calculating an odds ratio (OR) with 95%confidence intervals (CIs); and (3) the study was published in English. The exclusion criteria were as follows: (1) the study was a case report, abstract, comment, letter, or review; (2) the study lacked sufficient data and the relative risk could not be calculated after contacting the authors; and (3) the genotype data overlapped with that of other studies.To minimize bias and improve reliability, two researchers (Lu HX and Zhang AQ) independently screened the titles and abstracts with the same inclusion and exclusion criteria. The final inclusion of studies was determined by consensus between the researchers.Data were independently extracted and evaluated by two researchers (Zeng L and Wen DL) who used standardized data extraction forms. One third of the extracted data were also evaluated by another researcher (Sun JH), with any disagreements being resolved by consensus. For each study, information such as the name of the first author, publication year, country/region origin, ethnicity of the study population, study design , genotyping method, source of controls, genotyped data of cases and controls, and frequencies of the genotypes were collected. When studies included subjects of different ethnicities, the data pertaining to different populations were treated as separate studies. When required, supplemental data were obtained by contacting the authors. Whenever possible, we also evaluated Hardy-Weinberg equilibrium (HWE) based on the genotype distribution among control subjects.P < 0.05 was considered significant, which was not adjusted due to insufficient data and the lack of a uniform population). We did not use adjusted ORs to estimate the pooled ORs since inconsistent covariates were used for adjustment in the original studies included in this meta-analysis. Strong associations with sepsis risk were defined as ORs ≥ 1.5 or ≤ 0.67. Moderate associations were defined as ORs = 1.5–1.15 or 0.67–0.87, according to the recommendations in Ma’s study [p value < 0.001. Heterogeneity between studies was assessed using a χ2-based Q-test [P > 0.05 indicated a lack of heterogeneity across studies, allowing us to use the fixed effects model (the Mantel-Haenszel method). Otherwise, the random effects model was used (the DerSimonianand Laird method) [P < 0.10 being considered clear bias [P values presented are nominal P values and are not corrected for multiple comparisons. All statistical tests were performed with STATA, version 11.0 . To ensure the accuracy and reliability of the results, two researchers (Lu HX and Zhang AQ) entered the data into the software independently and reached a consensus.In the meta-analysis, we only included genetic variants for which at least three studies provided data due to the limited validity of pooled results with a small number of studies. The strength of the association between a given polymorphism and the risk of sepsis was represented by the OR and 95% CI. The pooled ORs were calculated based on the dominant (BB+AB versus AA), recessive (BB versus AB+AA), and allelic genetic models (B versus A) . The significance of the pooled ORs was examined by the Z test (d Q-test . P > 0.0 method) . If the ear bias . The Venear bias , 14. AccFigure n = 379, 94%), followed by insertion/deletions (n = 17) and VNTRs (n = 9). These genetic variants were located upstream of the gene (including the promoter region) (n = 83), in the 5′UTR (n = 15), in exons (n = 113), in introns (n = 149), in the 3′UTR (n = 34), and downstream of the gene (n = 11). Among the exonic SNPs, the functional effects were generally missense (n = 96) and synonymous coding changes (n = 12), with the remaining being frameshift, stop-gain, or splicing variants (n = 5). The distribution of these variants across chromosomes is depicted in Additional file n = 48), none were on chromosome 21 and Y, and only 2 variants were in mitochondrial DNA.The types of variants were mainly SNPs , cytokines , and other immune-related genes. Based on the number of different independent studies of each variant (ranging from 1 to 41), the 5 most commonly studied variants were the following: TNFA rs1800629 (n = 41), LTA rs909253 (n = 32), TLR4rs4986790 (n = 28), IL6 rs1800795 (n = 25), and IL10 rs1800896 (n = 24). Based on the country/region of origin, most studies were performed in China (n = 82), the USA (n = 40), Germany (n = 33), and Spain (n = 22). Based on the number of subjects (cases plus controls) enrolled , the 5 most commonly studied variants were as follows: F5 rs6025 , TNFA rs1800629 , LTA rs909253 , MBL2 A/O haplotype , and IL6 rs1800795 . TaqMan probes, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), allele-specific amplification, and sequencing were the most common methods used to determine the genotype distribution.The majority of candidate genes were PPRs (n = 64) vs. Asian (n = 28)) and age (adult (n = 61) vs. pediatric (n = 32)).In total, 389 meta-analyses were performed for 76 variants of 44 genes, with at least 3 independent studies for each variant. The major results of the meta-analysis under three different genetic models are listed in Table P < 0.05) with the risk of sepsis were found with 26 (34%) variants of 21 genes for at least one genetic model containing TLR1 rs5743551-7202A/G; LBP rs2232618 Phe436Leu; the MBL2 A/O haplotype; RAGE rs1800625-429 T/C and rs1800624-374 T/A; NOD2 rs2066844 Arg702Trp and rs2066847 Leu1007Pro; TNFA rs1799724-857C/T, rs1800629-308G/A, and rs361525-238G/A; LTA rs909253+252 T/C; IL1B rs143634+3594C/T; IL6 rs1800795-174G/C; IL8 rs4073-251 T/A; IFNG rs2430561+874A/T; CXCL1 rs1429638A/C; CXCL12 rs266087A/G and rs2297630A/G; MIF rs755622-173G/C; FCGR2A rs1801274 His131Arg; PAI-1 rs1799768-6755G/4G; ACE rs4646994ins/del; LCE4A rs4845320A/C; TAGAP rs3127214C/T; VDR rs2228570 Met1Thr; and miR-608 rs4919510G/C. The 185 subgroup meta-analyses by ethnicity and age revealed three additive polymorphisms  that were significantly associated with the risk of sepsis. Strong associations with sepsis (ORs ≥ 1.5 or ≤ 0.67) were detected in 14 variants. Moderate associations with sepsis (ORs 1.5–1.15 or 0.67–0.87) were found for the remaining 15 variants. Ten of the 29 positive variants showed a highly significant association with sepsis risk, with p < 0.001; 11 showed an association with sepsis risk with p = 0.001–0.01, and the remaining 8 had p < 0.05.Of the 204 primary meta-analyses performed, nominally significant associations (I2 < 25%), 92 (23.7%) had a moderate level of heterogeneity (25% < I2 < 50%), and 143 (36.7%) had a high degree of heterogeneity (I2 > 50%). The proportion of studies with a high degree of heterogeneity was significantly lower for the 29 positive variants than the remaining 47variants .Of the 389 meta-analyses of all available data, 154 (39.6%) had no or little heterogeneity , 14, and 11 variants, respectively. The details of the nominally significant associations found in the meta-analysis are discussed below.P = 0.002) and allelic models . When subgroups were considered, data from three white populations revealed more significant associations . However, the level of evidence was intermediate due to the study sample size. For rs5743708 Arg753Gln in the TLR2 gene, there was no significant association found in the overall analysis of 14 studies. However, the association between Arg753Gln and the risk of sepsis was significant in the adult population . In contrast, there was a marginally significantly decreased risk of sepsis associated with Arg753Gln in pediatric studies , which may be due to differences between the adult and pediatric populations.Toll-like receptors (TLRs) are a crucial family of pathogen-recognition receptors (PRRs) that provide a major mechanism for innate immune cells to recognize and respond to pathogens . TLR1/2 P < 0.0001). Furthermore, through the subgroup analysis, strong associations were found in three adult populations .The lipopolysaccharide-binding protein (LBP) is an enhancer of the host response to lipopolysaccharides that acts by facilitating the transfer of lipopolysaccharides to CD14 membrane-bound TLRs that ultimately activate signaling transduction pathways and the production of cytokines . The priP < 0.001 for the dominant model, OR = 0.47, 95%CI = 0.24–0.96, P = 0.04 for the recessive model, and OR = 0.61, 95%CI = 0.51–0.74, P < 0.0001 for the allelic model) with a high level of evidence. Moreover, in vitro LPS-induced RAGE expression and TNF-α production were significantly lower in the variant C allele patients than in those with the wild-type T allele [P = 0.02) in three studies.The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin protein family of cell surface molecules and has been shown to bind a diverse set of ligands, and this binding leads to the activation of several pro-inflammatory signaling pathways . Two varT allele . With reP = 0.001). For an additional variant, rs2066847 Leu1007Pro, five studies (326 cases and 1629controls) were included in our meta-analysis. A significant association between rs2066847 Leu1007Pro and the risk of sepsis was confirmed in the dominant model . Mannose-binding lectin (MBL) is a soluble pattern recognition molecule that binds microorganisms, thereby activating the lectin or additional complement pathways [P = 0.01 for the dominant model; OR = 1.19, 95% CI = 1.04–1.36, P = 0.01 for the allelic model). The significant association was stronger when the meta-analysis was restricted to pediatric sepsis .NOD2/CARD15 is a member of a superfamily of genes, the NBS-LRR proteins (for nucleotide-binding sites and leucine-rich repeats), which are involved in the intracellular recognition of microbes and their products . Three spathways . Three pCytokines released from immune cells are major players in the inflammatory response to infection. Primary pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1), induce secondary pro- and anti-inflammatory mediators such as IL-6 and IL-10 . GeneticP = 0.04) with a low level of evidence. Associations between a third TNFA variant (rs361525-238G/A) and the risk of sepsis were investigated in nine studies. The primary meta-analysis indicated a highly significant association between the TNFA rs361525-238G/A variant and the risk of sepsis under the recessive model . Furthermore, in the analysis stratified by ethnicity, only Asian individuals with this variant had a higher risk of sepsis than individuals with the wild-type allele under the dominant and allelic genetic models. The LTA rs909253+252 T/C variant was analyzed in 32 studies with 4762 cases and 7588 controls and was significantly associated with the risk of sepsis under the dominant and allelic models; however, there was a low level of evidence due to between-study heterogeneity. The associations were also significant in the analyses stratified by ethnicity and age.Forty-one studies investigated the association between TNFA rs1800629-308G/A and the risk of sepsis (5540 cases and 9709 controls). In the primary meta-analysis, significant associations between the -308G/A polymorphism and the risk of sepsis were found under all three genetic models. Furthermore, through stratified analysis according to ethnicity and age, the associations were more significant in the adult and Asian populations than in the overall populations, suggesting that this SNP might be specifically linked to the adult and Asian populations. In our study, data on the second TNFA variant (rs1799724-857C/T) from three studies (502 cases and 1373 controls) were meta-analyzed. The overall results showed that there was a significant association between this variant and the risk of sepsis under the dominant model . Meanwhile, the stratified analysis showed that there was a significant association between this variant and the risk of sepsis in the white population  and the adult population . With regard to rs1800796-572G/C, which is located in the IL-6 promoter region, there was no significant association with the risk of sepsis in the primary meta-analysis. However, three studies in Asian populations indicated a significant association between -572G/C and the risk of sepsis . In the adult population, the association between this variant and the risk of sepsis was also confirmed under the dominant model. A significantly increased risk of sepsis was found to be associated with another variant, rs1800795-174G/C, in the allelic model  through the primary meta-analysis of 17 studies and the subgroup analysis of adults . For IL-8rs4073-251 T/A, the association between the variant and the risk of sepsis were confirmed under all genetic models in the primary analysis and the subgroup analysis according to ethnicity. For the IL10 rs1800871-819C/T variant, a significant association with the susceptibility to sepsis was only confirmed in the Asian population .Seven studies investigated the IL1B rs143634+3594C/T variant. The result of the overall comparison suggested that the association of this variant with sepsis susceptibility was significant under the recessive genetic model . The rs1429638A/C variant of the CXCL1 gene and the rs2297630A/G and rs266087A/G polymorphisms of the CXCL12 gene were found to be associated with altered susceptibility to traumatic sepsis in Wang’s study . Four studies of MIF-173G/C were included in the meta-analysis. A significant association between this variant and the susceptibility to sepsis was found under the recessive model .Five studies of the IFNG rs2430561-874A/T variant were included in the meta-analysis. The results of the overall comparison suggested that the association of this variant with the risk of sepsis was significant under the dominant genetic model .FcγRIIA (CD32A) is a tyrosine-based activation motif-bearing immunoreceptor that binds immunoglobulin G and C-reactive protein, which are important opsonins in the host defense response . In totaP = 0.01) and the allelic model . Furthermore, in the subgroup analysis stratified by age, a significant association was also found in the pediatric population . The rs4646994ins/del polymorphism in the ACE gene was significantly associated with the risk of sepsis in the recessive model  according to a primary meta-analysis of nine studies; this association was stronger in the adult population than in the pediatric population. Three studies evaluated the association between the LCE4A rs4845320 polymorphism and the risk of sepsis. There were significant associations between this variant and an increased risk of sepsis under the dominant  and allelic models . For the TAGAP rs3127214C/T variant, there was a significantly increased risk of sepsis under the dominant  and allelic models . For the VDR rs2228570 Met1Thr variant, a statistically significant association with an increased risk of sepsis was found under the dominant model  according to the primary meta-analysis of four studies; this association was also identified in the white and adult populations in the subgroup analyses. Finally, three studies evaluated the association between the miR-608 rs4919510G/C variant and the risk of sepsis, and the meta-analysis results showed that the association was significant under all three genetic models.Eleven studies determined the association between PAI-1-675 5G/4G and the risk of sepsis in white populations. There was a significantly increased risk of sepsis associated with this variant in the recessive model  performed in this study (47 variants of 33 genes) did not yield any evidence of a significant association. These meta-analyses included a median of 4 studies (range 3–28) and 1750 participants .p < 0.05) , signaling molecules (n = 5), transcription factors (n = 3), cytokines (n = 11), and other molecules (n = 19). Furthermore, most of these genetic variants were located in the promoter region (n = 16), introns (n = 23), and 3′UTR (n = 7); 13 variants were missense. Furthermore, some genetic variants (n = 10) were also confirmed to be functional variants. For example, the TLR4 rs10116253-2242C allele enhances the transcriptional activities and expression of TLR4, and trauma patients with the variant C allele have a greater capacity to produce the pro-inflammatory cytokines TNF-α and IL-6 than those with other alleles [In this study, 329 polymorphisms could not be meta-analyzed because fewer than three studies investigated them. We systematically reviewed the associations between these polymorphisms and the risk of sepsis, and nominally statistically significant associations with the susceptibility to sepsis were found for 63 polymorphisms in 48 genes  and age (adult vs. pediatric). Furthermore, an additional 63 variants of 48 genes were found to be significantly associated with the risk of sepsis by systematic review. These findings provide investigators with a robust platform of genetic variant information that may be useful in the attempts to elucidate the molecular mechanisms underlying the pathogenesis of sepsis.n = 14), signaling molecules (n = 5), transcription factors (n = 3), cytokines (n = 18), and other immune-related molecules (n = 24). The elicited inflammatory response depends on the type of antigenic site on the pathogens that are generating the stimulus. Intracellular events are triggered by the binding of pathogens to the PPRs of immune cells, which further leads to the production of large amounts of inflammatory mediators [Variants are alterations in nucleotide base pairs located within a gene or noncoding portion of the genome . In sepsediators , 31. A hediators . This phediators , 34. IdeIn this meta-analysis, using the Venice criteria results, we identified four variants with strong  and 14 variants with moderate levels of cumulative epidemiological evidence of associations with the risk of sepsis. The remaining 11 variants had weak evidence; many of these were identified through meta-analyses using dominant/recessive models or ethnicity/age-specific subgroup analyses. In summary, we provide an updated and more systematic summary of the available evidence compared with the existing studies in this field . Well-deOur meta-analysis also provides no evidence of an association with the risk of sepsis for 313 of the 405 variants evaluated in our study, supporting the idea that the vast majority of genetic variants evaluated in candidate genetic association studies may not be truly related to sepsis. Methodological limitations in previous candidate genetic studies, such as small sample sizes or inappropriate controls, may explain some of the null associations. However, of the 313 nonsignificant variants, 15 variants showed null associations with the risk of sepsis in meta-analyses including a minimum of 1000 cases and 1000 controls, which provides approximately 80% power to detect an OR of 1.15 under the additive model for a variant with MAF 0.10 and type 1 error 0.05. Thus, future epidemiological studies with similar sample sizes are unlikely to be helpful in assessing the effects of these variants.To the best of our knowledge, this study is the largest and most comprehensive assessment of the literature regarding genetic association studies investigating the risk of sepsis that has been conducted to date. However, this study still had some limitations. First, some non-English articles, unpublished reports, and studies without sufficient data were not included in the study, which may have biased the results. Second, the number of eligible studies included in this meta-analysis was small, and the sample size of each study was relatively small, especially in the subgroup analyses, which might have influenced the statistical power. Moreover, we did not have precise information about the ethnicities of all the included populations; our classifications were broad and prone to the effects of population stratification. Third, as none of the studies included in this analysis considered the effect of gene-gene/environment interactions on the pathogenesis of sepsis, this issue could not be addressed in our study. Fourth, the overall outcome was based on unadjusted data; a more precise analysis stratified by variables such as gender, age, and type of infection could not be performed due to the limitations of the data, which also restricted our ability to detect possible sources of heterogeneity. Finally, despite the systematically internationally recognized approaches applied in this study, there is still room for future improvement in assessing the credibility of these associations. The Venice criteria improve the consistency and objectiveness of the interpretation and reporting of genetic associations, but this evidence does not determine causality. Additional sources of evidence, such as gene knockout experiments, gene expression microarray experiments, or other mechanistic data, are necessary to understand the precise functions of variants or genes. In general, associations with strong credibility deserve in-depth evaluations including biological investigations; moderately credible associations warrant more genetic and biological studies; and weak genetic associations may be not worthy of further investigation unless strong mechanistic evidence has been demonstrated.In summary, we performed the first systematic review and meta-analysis of the evidence linking genetic variants to the susceptibility to sepsis. Several genetic variants were confirmed to be significantly associated with the risk of sepsis. We hope that this unprecedented collection of data might represent a useful platform for investigators involved in this research field.Additional file 1:Search strategy. Venice criteria. The list of included articles. (DOCX 70 kb)Additional file 2:Table S1. Main characteristics of the studies included. (XLS 354 kb)Additional file 3:Table S2. Characteristics of the genetic variants investigated for associations with the risk of sepsis. (DOCX 70 kb)Additional file 4:Figure S1. Number of publications (Y-axis) per year (X-axis) addressing the association of genetic variants with the risk of sepsis. In 2018 (diamond), the literature search was performed until December. (TIF 5633 kb)Additional file 5:Figure S2. Chromosome distribution of the genetic variants tested for their association with the risk of sepsis. mtRNA: mitochondrial DNA. (TIF 5967 kb)Additional file 6:Table S3. Genetic variants associated with the risk of sepsis in the meta-analyses of all available data. (XLS 125 kb)Additional file 7:Table S4. Genetic associations with sepsis risk investigated in fewer than three studies. (DOCX 39 kb)


ACMSD-) transmembrane protein 163 (TMEM163) rs6430538, methylcrotonyl-CoA carboxylase 1 (MCCC1) rs12637471, and branched-chain ketoacid dehydrogenase kinase- (BCKDK-) syntaxin 1B (STX1B) rs14235, by genotyping 599 Taiwanese patients with PD and 598 age-matched control subjects. PD patients demonstrate similar allelic and genotypic frequencies in all tested genetic variants. These ethnic discrepancies of genetic variants suggest a distinct genetic background of amino acid catabolism between Taiwanese and Caucasian PD patients.Previous genome-wide association studies in Caucasian populations suggest that genetic loci in amino acid catabolism may be associated with Parkinson's disease (PD). However, these genetic disease associations were limitedly reported in Asian populations. Herein, we investigated the effect of top three PD-associated genetic variants related to amino acid catabolism in Caucasians listed on the top risk loci identified by meta-analysis of genome-wide association studies in PDGene database, including aminocarboxymuconate-semialdehyde decarboxylase- ( HoweverThis study was performed under a protocol approved by the institutional review boards of Chang Gung Memorial Hospital , and all examinations were performed after obtaining written informed consents.Patients with PD were enrolled from the neurological clinics of Chang Gung Memorial Hospital, Linkou Medical Center. PD patients were diagnosed according to the UK PD Society Brain Bank clinical diagnostic criteria . We alsoACMSD-TMEM163 rs6430538, MCCC1 rs12637471, and BCKDK-STX1B rs14235) involved in amino acid metabolism were selected from the risk loci identified by meta-analysis in PDGene database (http://www.pdgene.org/top_results). The single nucleotide polymorphism (SNP) genotyping was performed by Agena MassARRAY platform with iPLEX gold chemistry . By following the manufacture guide, the specific PCR primer and extension primer sequences (μl of the genomic DNA sample (10 ng/μl) was applied to multiplex PCR reaction in 5 μl containing 1 unit of Taq polymerase, 500 nmol of each PCR primer mix, and 2.5 mM of each dNTP . Thermocycling was at 94°C for 4 min followed by 45 cycles of 94°C for 20 s, 56°C for 30 s, and 72°C for 1 min than 72°C for 3 min. Unincorporated dNTPs were deactivated using 0.3 U of shrimp alkaline phosphatase. The single base extension reaction was done using iPLEX enzyme, terminator mix, and extension primer mix followed by 94°C for 30 sec followed by 40 cycles of 94°C for 5 sec and 5 inner cycle of 56°C for 5 s and 80°C for 5 sec than 72°C for 3 min . After the addition of a cation exchange resin to remove residual salt from the reactions, 7 nl of the purified primer extension reaction was loaded onto a matrix pad of a SpectroCHIP (Agena). SpectroCHIPs were analysed using a MassARRAY Analyzer 4 and the calling by clustering analysis with TYPER 4.0 software.Three genetic loci  and 598 control subjects , were recruited. To minimize the effect by the same SNP within the same family, only one proband with familial PD was recruited. The mean age at onset of PD symptoms was 62.53 ± 11.11 years (range 19∼93) and that of control subjects upon recruitment was 59.62 ± 12.66 years (range 17∼89). The allelic  and genoemale PD , EOPD, oemale PD  with conACMSD-TMEM163 rs6430538, MCCC1 rs12637471, and BCKDK-STX1B rs14235 are absent of association with PD. It is important to notice that the minor allelic frequency of ACMSD-TMEM163 rs6430538 in control subjects of our cohort (1.7%) is similar to that (2.5%) in Chinese/Japanese dataset from 1000 Genomes but very different from that (59.2%) in Caucasians of Utah dataset from 1000 Genome (http://www.1000genomes.org/home). MCCC1 rs12637471 minor allelic frequency (43.2%) in our control subjects is similar to that (41.7%) in Chinese/Japanese dataset but far different from that (75.8%) of Europeans. Minor allelic frequencies of BCKDK-STX1B rs14235 in our control subjects (9.6%) and Chinese/Japanese (9.2%) are also different from those (55%) of Europeans. These distinct genetic backgrounds suggest the differential effects of gene loci related to amino acid metabolism on PD risk between Asian and Caucasian populations.The present study shows that ACMSD encodes aminocarboxymuconate semialdehyde decarboxylase, which prevents the production of quinolinic acid from aminocarboxymuconate semialdehyde [ACMSD, such as rs640538, rs6710832, and rs6753334, have been reported in the studies from Caucasian populations [The aldehyde . Patientaldehyde . The PD-ulations , 12, 13.STX1B encodes a synaptic receptor for vesicle transport [STX1B rs8060857 demonstrates potential association with PD risk in Caucasian populations [By catalyzing the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA, MCCC1 is a critical enzyme in leucine catabolism . Consistransport . STX1B rulations , whereasulations , 21. In Our study result of genetic disease association in Taiwanese PD is inconsistent with those from other populations, especially from Caucasian. Different sample sizes and genetic heterogeneity among populations may be attributed to the varied findings across different studies. The roles of epigenetic factors and gene-gene interactions have not been evaluated. The potential interactions of unknown environmental factors with these genetic variants on the development of PD have not been explored. More large series of case-control studies in different ethnic populations will be necessary to clarify these results.


The link between use of solid biomass fuel  for cooking and/or heating and esophageal squamous cell carcinoma (ESCC) is inconclusive.We systematically reviewed the literature and performed a meta-analysis to determine whether cooking fuel type influences esophageal squamous cell carcinoma.We searched MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating cooking fuel and ESCC from 2000 until March 2019. We performed random effects meta-analysis stratified by the continent, World Bank’s country income classifications and fuel type and calculated pooled odds ratios and 95% CIs for the risk of esophageal squamous cell carcinoma in biomass fuel users compared with non-users.2) = 79%). In sub-group analyses by continent, Africa  and Asia  had the highest odds of ESCC. Use of wood as fuel had the highest odds of 3.90, 95% CI 2.25, 6.77, I2 = 63.5%). No significant publication bias was detected.Our analysis included 16 studies  with 16,189 participants  that compared risk of ESCC among those using nonsolid fuels and biomass fuels. We found use of biomass fuel was associated with Esophageal squamous cell carcinoma with a pooled odds ratio (OR) 3.02  contains supplementary material, which is available to authorized users. Globally, Esophageal Cancer is the seventh incident cancer and sixth leading cause of cancer-related deaths . Of the Various lifestyle and environmental exposures are associated with esophageal squamous cell carcinoma (ESCC)  However,In the poorer communities of Africa, Asia, and South America affected by ESCC, traditional solid biomass fuels  are the primary fuel source . Open fiIn order to reduce the burden of esophageal squamous cell carcinoma, identification of risk factors is the first step to development of targeted interventions. We conducted a systematic review and meta-analysis to evaluate the risk of esophageal cancer based on biomass fuel status.We carried out a systematic review and meta-analysis to test the association between biomass fuel and Esophageal squamous cell carcinoma along with a protocol developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)  and regiWe searched EMBASE, PubMed, MEDLINE, Web of Knowledge, and Cochrane Database of Systematic Reviews from the year 2000 onwards. The search terms were  AND . We checked the bibliography of relevant articles for additional studies that met the inclusion criteria. The search and study selection was carried out independently by SO and SJA and consensus reached by discussion.Studies were included if they: 1) evaluated esophageal cancer risks; 2) assessed cooking fuels ; 3) reported a measure of risk and its variance, or enough data to calculate these; 4) estimates were at least adjusted for smoking and alcohol; 5) were of English language. Studies were excluded if they were: (i) animal studies; (ii) in vitro studies; (iii) meta-analysis, systematic reviews and reviews; (iv) editorials; (v) studies exploring only pathogenesis; and (vi) studies published before the year 2000 to limit issues related to quality of study reporting and generalizability to contemporary clinical practice.Two reviewers (SO and SJA) independently screened all titles and abstracts retrieved from the search engines for studies that met the inclusion criteria. The full articles that met the inclusion criteria were reviewed and the final decision to include or exclude was made by consensus. Independent double extractions were performed by two reviewers (SO and SJA) collecting data related to study design, year, number of participants, mean age, male-to-female ratio, Countries in which study was performed, population setting, case selection criteria, control selection criteria, exposure assessment methods, the number of cases and controls, gender distribution, the type of fuel used, and risk of Esophageal squamous cell carcinoma associated with exposure, crude odds ratio (OR) and 95% confidence interval (95% CI), adjusted odds ratio (OR) and 95% CI, the variables adjusted for, and the limitations of the study.If the study did not report measures of risks, we calculated crude rate ratios with the provided number of events and sample size. For studies that provided multiple ORs based on various exposure groups, the OR representing the highest exposure group was selected.Traditional solid biomass fuel . There being no standardized method to assess use of biomass fuel, we critically reviewed all the studies to determine the respective exposure assessment method. All studies utilized questionnaire based methods to determine exposures qualitatively. Whenever multiple ORs were provided, we selected ORs related to coal exposure for our primary analyses since indoor air pollution attributed to coal exposures has higher carcinogenic potential than wood for lung cancer .Esophageal squamous cell carcinoma diagnosed by histology.The reviewers independently rated the quality of studies based on the Newcastle-Ottawa Scale . An idea2 statistic [Odds ratios (ORs) were pooled across studies using inverse-variance weighted DerSimonian-Laird random effect models to allow for between-study heterogeneity . We usedtatistic . We assetatistic  and visuWe carried out sensitivity analyses to examine the influence of single studies on the pooled ORs by omitting studies one by one and re-estimating the pooled OR. All analyses were conducted on the natural log scale.A-priori postulated sources of heterogeneity for which subgroup analyses were performed included type of biomass, continent , and socioeconomic status (World Bank’s country income classifications) . The lowA total 699 research articles were found to be potentially relevant from the electronic database search. After a detailed examination, in which some research articles with duplicate or inappropriate information were detected and excluded, 15 studies , 29–41 aAll 16 studies were of case–control study design with 16,189 participants: 5233 (range 75 to 830) cases of esophageal squamous cell carcinoma and 10,956 controls without disease (range 145 to 1779). Seven of them were large studies with more than 1000 participants , 38, 40.The main characteristics of the individual studies are listed in Table All studies showed a positive association between biomass fuel use and ESCC, 11 of them had statistically significant associations –39, 41. All studies except 2 , 38 contAll studies used histology to diagnose ESCC as stipulated in inclusion criteria. The quality assessment of included studies is summarized in Table 2 = 79%). Similarly, our observed associations between biomass and ESCC remained significantly elevated when analyses were restricted to studies that controlled for smoking and alcohol.Combining all the 16 case–control studies showed a significantly increased risk of esophageal squamous cell carcinoma with biomass fuel, pooled overall odds ratio , followed by upper middle-income  and lower middle-income countries   and Asia   and a combination of wood and charcoal OR 3.71  , and socioeconomic status (World Bank’s country income classification) were significant sources of the observed heterogeneity. Excluding studies one-by-one did not show any substantial change of pooled estimate.2 > 75%) for overall pooled effect; however, statistical power to evaluate other sources of heterogeneity was low. For assessment of publication bias, the Funnel plot .Statistical heterogeneity was considerable  . This isWe observed an increased risk of esophageal cancers among those in low income followed by low middle income and least in upper middle income. Based on stratification by continents, studies from Africa had the highest risk, followed by Asia, then South America, and least in East and Central Europe. Taken together, these analyses point to variation of biomass use by continent, type of fuel used, and socioeconomic status of populations at high risk for ESCC. In lower income settings of Africa and Asia, cheap biomass fuels such as wood, charcoal, dung, and crop residues are main source of cooking and heating fuel .Noteworthy, we found the ESCC risk varied with biomass type -- highest with wood. Though coal exposures tend to have higher carcinogenic potential than wood for lung cancer , it is uThis study has several strengths and limitations. This is the largest study to date with a sample of more than 5000 ESCC cases and estimates were pooled from 16 countries across five World Bank Regions from four continents to quantify the ESCC risk from use of biomass fuel with meta-analysis. The lack of studies from regions such as Australia, North America, and West Europe is likely not due to our English language restriction, but rather the prevalent use of nonsolid fuels as well as low burden ESCC in these regions making potential research unfeasible. This renders our results generalizable to different geographic locations. Another strength of our analysis is that all studies controlled for other known ESCC risk factors. A limitation of this study is that exposure measurements were restricted to one point in time yet biomass use may change over the life course and a single measurement may result in misclassification even among lifetime biomass users. In addition, the lack of individual patient data on exposure–response relationship between duration of biomass use and risk of ESCC limits further insight into the exposure–response relationship.In conclusion, using biomass fuel increases the risk of Esophageal squamous cell carcinoma. Importantly, ESCC risk differed by study setting and population. While current evidence demonstrates association between age, gender, and lifestyle  with ESCC, environmental factors might be responsible for the heightened risk in Eastern sub-Saharan Africa. Biomass fuel status should be considered in the risk assessment for Esophageal squamous cell carcinoma in low-income countries.Additional file 1:Figure S1. Funnel plot to evaluate publication bias (DOCX 75 kb)


CYP2E1 represents a major CYP isoform and is expressed in the human urothelial cells. Recent studies have investigated the association of CYP2E1 gene polymorphisms with bladder cancer risk but have shown contradictory results. Hence, we performed a systematic literature review and meta-analysis to assess the association between CYP2E1 gene polymorphisms and bladder cancer.Human cytochrome P450 (CYP) is an enzyme responsible for the metabolic activation of many carcinogens, including nitrosamines. CYP2E1 gene polymorphisms with bladder cancer risk. A meta-analysis was performed with Review Manager and Stata software. Combined odds ratios (ORs) were identified with 95% confidence intervals (CIs) in a random or fixed effects model.Systematic literature searches were conducted with PubMed, Excerpt Medica Database, Science Direct/Elsevier, China National Knowledge Infrastructure, and the Cochrane Library up to January 2018 for studies that involved the association of The protocol was approved by the institutional review board of each study center. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki.CYP2E1 gene polymorphisms and bladder cancer in all genetic models (P < .05). The combined ORs and 95% CIs were as follows for each model: additive model ; dominant model ; recessive model ; codominant model ; allele model . A subgroup study showed that there are also significant associations between CYP2E1 gene polymorphisms and bladder cancer in Asian people. However, there are no significant associations between CYP2E1 gene polymorphisms and bladder cancer in Caucasian populations.Eight studies were identified, including 1733 cases of bladder cancer and 1814 normal controls. Our results illustrated that there are significant associations between CYP2E1 gene polymorphisms and bladder cancer progression, and suggests that CYP2E1 gene polymorphisms might be a protective factor against bladder cancer in Asian people. However, studies with larger sample sizes are needed to confirm the correlation between CYP2E1 gene polymorphisms and bladder cancer.The present study provides evidence for an association between  The risks of bladder cancer are associated with tobacco smoking, some industrially related carcinogenic compounds amines, and amides, and some anticancer drugs such as phosphoramide mustards.,7 However, not all people exposed to these risk factors are develops bladder cancer, suggests that the variation in individual susceptibility may play an important role to bladder carcinogenesis.Globally, bladder cancer is the 10th most common cancer and accounts for 3.3% of all malignancies,,11 Therefore, phase I and phase II metabolizing enzymes genes may be an important risk factors of developing cancer. Human cytochrome P450 (CYP) is a phase I enzyme play an important role for the metabolic activation of many procarcinogens.CYP2E1 represents a major CYP isoform, and in the liver and to lesser extent in other organs and tissues, including human urothelial cells are constitutively expressed this gene. Many low-molecular-weight carcinogens, such as vinyl chloride, benzene, and tobacco-specific nitrosamines require this critical enzyme to metabolic activation.,15Currently, many studies have reported that genetic factors may play an important role in the risk of developing bladder cancer; many ultimate carcinogens and their genotoxicity functions require enzymatic bioactivation.CYP2E1 gene polymorphisms with bladder cancer risk, the reported results were inconsistent, with some studies reporting that CYP2E1 gene polymorphisms may increase the risk of bladder cancer, but not others.–23 Therefore, we systematically reviewed the available literature and performed a meta-analysis to evaluate the association of CYP2E1 gene polymorphisms with bladder cancer risk, which might shed valuable insights on our understanding of the biology of bladder cancer.However, although recent studies have investigated the association of 22.1CYP2E1 gene polymorphisms and bladder cancer risk. Two independent reviewers searched PubMed, Excerpt Medica Database, Science Direct/Elsevier, MEDLINE, China National Knowledge Infrastructure, and the Cochrane Library from inception to January 2018; the language or study type was not restricted. The search terms combined text words and MeSH terms. For example, the search terms for CYP2E1 gene were “cytochrome P450 family” or “cytochrome P450 2E1” or “cyp2E1,” “cyp2e1” or “CYP2E1”; terms for bladder cancer included “bladder cancer” or “bladder neoplasms” or “cancer of bladder” or “neoplasms, bladder”; search terms for polymorphism included “SNP” or “single nucleotide polymorphism” or “polymorphism” or “variation” or “mutation.” All related articles and abstracts were retrieved. In addition, references cited within relevant reviews were retrieved by hand, and only full articles were searched.This meta-analysis was restricted to published studies that investigated 2.22.2.1CYP2E1 gene polymorphisms with bladder cancer. The case groups were patients with bladder cancer and the controls were normal people. Genotyping for SNPs of CYP2E1 was conducted using polymerase chain reaction restriction fragment length polymorphism. Available data were extracted from the article, including eligible and genotyped cases and controls, and number of cases and controls for each CYP2E1 genotype.Included studies tested the association of 2.2.2Studies were excluded if they were case reports, meeting reports or review articles, published only in abstract form, included no control population, reported no available genotype frequency, or were a duplication of previous publications.2.3Two independent reviewers screened the titles and abstracts of all citations from the literature search. All relevant studies that appeared to meet the eligibility criteria were retrieved. If an ambiguous decision was made based on the title and abstract, full texts were needed for the analysis. The final decision of eligible studies was made by reviewing the articles. Disagreements were resolved by consensus or a third reviewer.2.4CYP2E1 genotype. Three reviewers extracted data from the studies. Disagreements were resolved by consensus. A quantitative meta-analysis was performed by 2 reviewers using Review Manager software  and Stata software . Available data were analyzed in the meta-analysis.Data included demographic data  and outcome data of eligible and genotyped cases and controls, plus number of cases and controls for each P value and the I square statistic (I2) in the pooled analyses, which represented the percentage of total variation across studies. If the P value was <.1 or the I2 value was >50%, the summary estimate was analyzed in a random-effects model. Otherwise, a fixed-effects model was applied. We investigated the association between CYP2E1 gene polymorphisms and bladder cancer risk in allelic [allele (C2 vs C1)], additive (C2C2 vs C1C1), dominant (C2C2 and C2C1 vs C1C1), recessive (C2C2 vs C2C1 and C1C1), and codominant models (C2C1 vs C1C1). In addition, publication biases were detected by visual symmetry of funnel plots, with asymmetry suggesting possible publication bias. If the P-value was less than 0.05, publication bias was determined to exist.To calculate combined odds ratio (OR) and 95% confidence intervals (CIs), heterogeneity was assessed by the 33.1Figure –23 and all tested for CYP2E1 gene polymorphisms using restriction fragment-length-polymorphism analysis after polymerase chain reaction amplification.Table 3.2CYP2E1 gene polymorphisms and bladder cancer in all genetic models (P < .05). The combined OR and its 95% CIs were as follows for each model: additive model  . However, there were no significant associations between CYP2E1 gene polymorphisms and bladder cancer in Caucasian individuals (P > .05) ], which suggest that the results were statistically stable and reliable ] Fig. A; recess95% CI 0.8–0.82] (05) Fig. B, 5B, 6B05) Fig. A, 11A, sble Fig. B, 11B.4CYP2E1 gene polymorphisms with bladder cancer risk were analyzed. For the additive, dominant, recessive, codominant, and allele models, 1, 2, 2, 1, and 2 studies, respectively, reported a significant association between CYP2E1 gene polymorphisms and bladder cancer. Our results revealed that, on the whole, significant associations between CYP2E1 gene polymorphisms and bladder cancer were found in all genetic models. The subgroup study showed that there are also significant associations between CYP2E1 gene polymorphisms and bladder cancer in Asian populations. However, no significant associations between CYP2E1 gene polymorphisms and bladder cancer were identified in Caucasian populations. Thus, these data indicate that CYP2E1 gene polymorphisms might be a protective factor against bladder cancer in Asian individuals.In our study, 8 reports that studied the association of ,25 CYP2E1 represents a major CYP isoform, in the liver, kidney, and other organs and tissues, such as urothelial cells are constitutively expressed this gene. It participates in phase I metabolic oxidization and activates many carcinogenic compounds, such as alkanes, alkenes, and aromatic and halogenated hydrocarbons.,27The CYP superfamily is an important enzyme and plays a considerable role in the metabolism of endogenous and exogenous compounds, such as numerous carcinogens such as nitrosamines. The enzyme also produce reactive free radicals through oxidation of other compounds, such as ethanol, and may initiate lipid peroxidation and consequently carcinogenesis.,29There is strong experimental evidence that CYP2E1 is an important activator of carcinogenic compounds.CYP2E1 have been identified and a variant C2 allele recognized by RsaI digestion in the 5′-flanking region of the gene appears to be associated with decreased enzyme activity or noninducibility, some in vitro studies showed that the C2 allele decreased the expression of a reporter gene construct.,33 Our results showed that the C2 allele distribution frequency in the control group was significantly higher than that in patients with bladder cancer, suggesting that CYP2E1 gene polymorphisms might be a protective factor against bladder cancer.Several restriction fragment length polymorphisms of the CYP2E1 C1/C1 genotype and bladder cancer risk may be related to the expression levels of the gene. The CYP2E1 C1/C1 genotype shows higher transcriptional activity compared with the CYP2E1 C2/C2 genotype. Therefore, upon exposure, the enzymatic activity of bladder procarcinogens in C2/C2 subjects may compete poorly compared with C1/C1,–37 leading to increased cancer susceptibility. In our subanalysis, there were no significant associations between CYP2E1 gene polymorphisms and bladder cancer in Caucasian people. This may be because of racial differences in polymorphism distribution.,39 Another study found that the frequency of the C2 allele in Asian populations is higher than that in Caucasians. However, this hypothesis requires further investigation before drawing conclusions.The potential molecular basis for the association between the CYP2E1 gene variants and bladder cancer.There are some limitations in our study, which need to be taken into consideration when interpreting the results of this meta-analysis. First, the sample size of each study was relatively small, with a total of 1733 patients with bladder cancer and 1814 normal controls investigated in all 8 studies; furthermore, only 2 studies were selected in our subanalysis study. Second, several studies related to the subject were excluded because of a lack of control data. As such, it is hard to make definitive conclusions about the clinical value of CYP2E1 gene polymorphisms and bladder cancer progression. These data suggest that CYP2E1 gene polymorphisms might be a protective factor against bladder cancer in Asian people. The possible mechanism may occur via CYP2E1 gene C2 allele mutations, weakening the expression of the gene and enzymatic bioactivation procarcinogens to become ultimate carcinogens and cause genotoxicity. However, studies with larger sample sizes are needed to definitively determine the correlation between CYP2E1 gene polymorphisms and bladder cancer.In summary, the results of this meta-analysis suggest that the current article adds to the evidence of an association between ,9.Conceptualization: Xiangrui Yin, Shengqiang Qian, Yu Guo.Data curation: Xiangrui Yin, Shengqiang Qian, Yu Guo.Formal analysis: Xiangrui Yin, Wei Xiong, Wei Tang, Shengqiang Qian, Yu Guo.Funding acquisition: Xiangrui Yin, Wei Xiong, Wei Tang, Wang Xi, Yu Guo.Investigation: Wei Xiong, Wei Tang.Methodology: Wei Xiong, You Wang, Wei Tang.Project administration: Wei Xiong, You Wang, Wei Tang, Yu Guo.Resources: You Wang, Wei Tang, Wang Xi.Software: You Wang, Wei Tang, Wang Xi, Shengqiang Qian.Supervision: You Wang, Wang Xi, Shengqiang Qian.Validation: You Wang, Wang Xi, Shengqiang Qian.Visualization: You Wang, Wang Xi, Shengqiang Qian.Writing – original draft: Xiangrui Yin, Wang Xi, Yu Guo.Writing – review and editing: Xiangrui Yin.


Background and Objective: Evidence indicates that genetic factors may be involved in the risk of ischemic stroke (IS). The aim of this study was to assess the effect of genetic polymorphisms located in exons or untranslated regions of MTHFR as well as FV genes on ischemic stroke. Materials and Methods: In this case-control study, 106 patients with IS and 157 healthy volunteers (age <50 years) were genotyped for MTHFR C677T, A1298C, C2572A and C4869G, FVL, and prothrombin G20210A polymorphisms. Results: The MTHFR 677CT genotype was more frequent in patients and increased risk of IS with Odds Ratio = 1.9. The MTHFR A1298C and C2572A polymorphisms were not associated with IS in dominant and recessive models. Our findings showed a significant decrease in the MTHFR4869CG genotype in IS patients, and this variant was associated with a decreased risk of IS in the dominant model. The CAAT haplotype was associated with increased risk, and the GAAC haplotype was associated with decreased risk of IS compared to other haplotypes. There was no relation between FVL G1691A polymorphism and IS risk. Conclusions: The present study showed that the MTHFR 677CT genotype was more frequent and the MTHFR 4869CG genotype was less frequent in young IS patients. Stroke is a set of devastating and debilitating diseases that are the result of blockage to blood vessels in the brain. Stroke is the third debilitating and second deadliest disease in the world, and is responsible for about 10% of all deaths. Five and a half million people die annually from ischemic stroke (IS), and the resulting disability-adjusted life years (DALYs) loss was equivalent to US $44 million in 2011 . CommonlIS represents approximately 10% of all cerebrovascular diseases. The exact etiology of IS is complicated; it has numerous risk factors such as diabetes mellitus, hypertension, and age. Also, the complexity of genetic and environmental factors could be involved . It is bFVL, G1691A), methylenetetrahydrofolate reductase polymorphisms (MTHFR C677T and A1298C), prothrombin gene , and plasminogen activator inhibitor-1 (PAI-1) variants—and their relation to various vascular diseases is known [Thrombophilia is a widespread range of changes that promote conditions for vascular thrombosis due to hematological changes that induce blood hypercoagulability; these can be inherited or acquired ,12. Amonis known .MTHFR gene are associated with hyperhomocysteinemia (HHcy) and have a critical role in modulating plasma homocysteine concentrations—which predispose the carrier to thrombosis and IS [MTHFR C677T polymorphism were highest in the regions where the diet has a low folate content [FVL, the substitution of arginine by glutamine at 506 amino acid residue increases its resistance to degradation by activated protein C and accentuates the venous thromboembolism risk. At position 20210 of the 3′-UTR region of the Factor II gene, a G to A transition has been associated with higher levels of prothrombin and more risk for venous thrombosis [MTHFR gene . The inclusion criteria for IS patients was the existence of IS at the present hospital admission, which the computerized tomography (CT) or magnetic resonance imaging (MRI) scan and clinical symptoms confirmed. The exclusion criteria were patients who had experienced an acute hemorrhagic stroke or other neurological diseases, a known malignancy, renal and liver disease, hematologic disorders, and hypothyroidism. Cases with IS of a cardioembolic origin  in both groups were also excluded.The questionnaire was completed by skilled nurses to collect data on demographic, clinical, and lifestyle characteristics of patients and controls.Blood pressure was measured for all subjects in the seated position with the back supported and legs uncrossed. Participants rested for at least 5 min before the assay. Blood pressure was measured using a routine mercury sphygmomanometer device . We repeated all assays twice and the average values were considered.Smokers were known as those who smoked tobacco regularly up to six months prior with constant or intermittent usage (at least one cigarette per week).MTHFR, FVL, and prothrombin polymorphisms, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed as previously described [Blood samples taken from the study subjects were drained into tubes containing Ethylenediaminetetraacetic acid (EDTA) and kept in a −20 °C freezer. To extract genomic DNA, the salting out method was performed on peripheral blood leukocytes. To analyze escribed ,20.t tests. Logistic regression analyses, adjusted for age and gender, were employed to calculate the associations between genotypes and disease based on Odds Ratio (OR) and 95% Confidence Interval (CI). HaploView software was used to analyze the frequency and Linkage Disequilibrium (LD) of haplotypes. p < 0.05 was considered the level of significance.SPSS version 20  was employed to analyze the data. The Kolmogorov–Smirnov test was used to evaluate the normality of quantitative variables. The clinical data and demographic characteristics of the study groups were compared by the Fisher exact and student MTHFR polymorphisms in IS patients and the control group are shown in The alleles and genotypes’ frequency of MTHFR 677 CT genotype was statistically higher in the IS group, and this genotype was associated with a 1.9-fold greater risk of IS (OR 1.9 (95% CI 1.1–3.4); p = 0.028). The 677TT genotype was more frequent in IS patients, but not statistically different (OR 1.8 (95% CI 0.7–5); p = 0.26). Moreover, the MTHFR C677T polymorphism was associated with a higher risk of IS in dominant (OR 1.9 (95% CI 1.1–3.3); p = 0.019) but not recessive models (OR 1.5 (95% CI 0.6–4.2); p = 0.4).The frequency of individuals carrying the MTHFR 1298AC and CC genotypes did not differ between the two groups, therefore this polymorphism was not associated with IS risk.The frequency of individuals carrying the MTHFR 2572AC and CC genotypes were not statistically different between patients and controls (p = 0.12 and p = 0.23 respectively), and this variant was not associated with IS in dominant and recessive models.The frequencies of the MTHFR 4869CG genotype was significantly reduced in the IS group, and this genotype was associated with decreased IS risk (OR 0.4 (95% CI 0.2–0.9); p = 0.016). In addition, MTHFR C4869G polymorphism was associated with lower risk of IS in the dominant (OR 0.4 (95% CI 0.2–0.8); p = 0.01) model.The frequency of the MTHFR C4869G, C2572A, A1298C, and C677T polymorphisms in IS and control groups. The CCAC haplotype was the most frequent haplotype in IS and control groups. The frequency of individuals carrying the CAAT haplotype was statistically higher in IS patients than controls (8.5 vs. 3.2%) compared to other haplotypes, and this haplotype was associated with a 2.8-fold higher risk of IS (OR 2.8 (95% CI 1.3–6.2); p = 0.01). However, the frequency of the GAAC haplotype was significantly lower in IS patients than controls (3.8 vs. 9.2%) compared to other haplotypes, and this haplotype could be a protective genetic factor against IS (OR 0.4 (95% CI 0.2–0.9); p = 0.02). MTHFR polymorphisms in the total studied population.FVL 1691GA genotype was higher in IS patients; however, the difference was not significant (OR 2 (95% CI 0.9–4.3); p = 0.09). We did not observe the FVL 1691AA genotype in IS and control groups. Moreover, we did not find the prothrombin 20210A allele in our study population.The frequency of the Hyperhomocysteinemia (HHcy) is a pathological complication described by an increase in the plasma level of total homocysteine . NumerouMTHFR plays an important role in the metabolism of homocysteine. MTHFR reduces the 5,10-methylene tetrahydrofolate to 5-methyltetrahydrofolate and plays the methyl donor role in methionine production from homocysteine [Evidence has shown that elevated homocysteine levels could be due to genetic defects in enzymes involved in its metabolism, or environmental factors such as vitamin B12 or folic acid deficiency . MTHFR pcysteine .MTHFR variant  and elevated homocysteine levels—therefore the MTHFR-encoding gene has been introduced as a genetic determinant of HHcy [Genome-wide association studies (GWAS) on plasma homocysteine level have reported on the association between the  of HHcy .MTHFR gene have been found to be associated with various diseases. The C667T polymorphism in the MTHFR gene , is the most consistently associated with total homocysteine (tHcy), resulting in decreased enzyme activity and elevated homocysteine levels. The MTHFR A1298C polymorphism  results in a thermos-labile form of enzyme, which may play a role in the regulation of the plasma homocysteine level [Several polymorphisms in the ne level .MTHFR gene, and are potentially located in the microRNAs (miRNAs) binding sites. The MTHFR 2572C > A and 4869C > G variants are located in the 3′-UTR region, and bioinformatics analysis showed that these substitutions create binding sites for several miRNAs, leading to suppression of the translation stage and thus regulating its expression [Moreover, several polymorphisms have been identified in the 3′-UTR region of the pression .Factor V Leiden  is a modified form of Factor V leading to activated protein C resistance (APCR) and increased blood clotting. It is introduced as one of the essential genetic risk factors for inherited thrombophilia [Factor V is an important protein in the blood coagulation cascade, and its deficiency plays a role in bleeding disorders. bophilia .MTHFR 677CT genotype was higher in IS patients than in controls. In addition, the MTHFR C677T polymorphism was associated with increased risk of IS in the dominant model. There was no association between the MTHFR A1298C and C2572A variants and IS. The MTHFR 4869CG genotype was associated with lower IS risk, and this polymorphism could be a protective factor in the dominant model. The CCAC haplotype was the most frequent haplotype in both the IS and control groups. Haplotype analysis revealed that the CAAT haplotype of the MTHFR C4869G, C2572A, A1298C, and C677T polymorphisms was higher, while the GAAC haplotype was significantly lower in IS patients compared to other haplotypes—and these haplotypes could be considered as risk and protective factors, respectively. There are numerous studies on the relationship between the MTHFR C677T and A1298C variants and IS in various ages—and several meta-analyses were performed to assess them. In the meta-analysis performed by Song et al. on 22 case-control studies from January 2000 to October 2014, the C677T polymorphism was introduced as a risk factor for IS in dominant, recessive, and allelic models [C677T variant and IS risk in young and middle-aged Asian males [C677T variant on IS risk in Asians in dominant and recessive models, as well as in Caucasians in recessive but not dominant models [In the present study, the frequency of the c models . In anotan males . Kumar et models . Howevert models . Abhinant models .A1298C polymorphism on adult IS, mainly in Asian populations [MTHFR A1298C and C677T polymorphisms and IS [A meta-analysis by Zhang et al. included 15 studies showing the effect of ulations . Sareckaulations . Wei et s and IS .MTHFR gene are few. Recently, Kim et al. analyzed four polymorphisms in the 3′-UTR region of the MTHFR gene and IS. Despite the current study results, they found an association between 2572CC and 6685TT genotypes and IS in the cardioembolism subgroup. In spite of our findings, they showed no association between MTHFR 4869C > G polymorphism and IS [MTHFR rs142884651 polymorphism in the 3′-UTR region and decreased risk of IS found in a study conducted by Shi et al. They showed that the MTHFR 4869C > G variant was associated with increased risk of IS (TC and CC vs. TT), with a poor short-term IS outcome. Indeed, they found elevated serum tHcy levels in MTHFR rs868014TC or CC genotypes [Despite the numerous studies and meta-analyses performed on the association between these common polymorphisms and IS, the published reports on the possible effects of variants in the 3′-UTR region of the m and IS . There wenotypes .FVL 1691GA genotype in IS patients, but the difference was not significant. We did not find the prothrombin 20210A allele in our study population.In addition, we observed a higher frequency of the FVL G1691A and prothrombin G20210A polymorphisms and IS in various ethnic groups—and meta-analyses were performed to evaluate the possible effects of these variants on IS susceptibility. In the two separate meta-analyses performed by Hamiz et al. and Bentley et al., prothrombin G20210A, FVL G1691A, and MTHFR C677T polymorphisms were considered as risk factors for IS [Similar to other thrombophilia-related genes, several studies assessed the relationship between s for IS ,42. Howes for IS . Althougs for IS .MTHFR polymorphisms on homocysteine levels.Some limitations were in the current study that may affect our findings, particularly the relatively low sample size because of the small population in the southeast of Iran. In addition, the different ethnic groups in southeastern Iran and environmental factors could be consider as the other limitations of this investigation. Indeed, if the homocysteine levels in IS patients and controls had been assayed, the findings would have become more appreciated—mainly regarding the possible effects of MTHFR C677T polymorphism was associated with increased risk of IS in the dominant model. However, there was no relation between A1298C and C2572A polymorphisms and IS risk. The MTHFR C4869G polymorphism was associated with lower risk of IS in the dominant model. Moreover, for the first time we found that the CAAT and GAAC haplotypes of MTHFR C4869G, C2572A, A1298C, and C677T polymorphisms were associated with higher and lower risk of IS, respectively.


Previous studies investigating the association between metabolic syndrome (MetS) and incidence of gastric cancer (GC) showed inconsistent results. The aim of the study was to evaluate the influence of MetS on GC risk in a meta-analysis.Cohort studies that evaluating the association between MetS and GC were identified via systematic search of PubMed, Embase, Web of Science, and Scopus databases. Pooled analyses were performed via a random-effect model or a fixed effect model according to the heterogeneity among the studies. Predefined subgroup analyses were performed to evaluate whether gender or ethnic group of the patients affected the results.2 = 79%). Subgroup analyses showed that MetS was not associated with a significantly affected risk of GC in male or female patients, and in Asians or Caucasians. Moreover, meta-analysis of four datasets showed that MetS defined by the International Diabetes Federation criteria was also not associated with a significant affected risk of GC .Overall, eight cohort studies with 8,745,671 participants were included, and 37,245 GC cases occurred during follow-up. Results showed that MetS defined by the revised National Cholesterol Education Program’s Adults Treatment Panel III criteria was not associated with a significantly affected GC risk (adjusted risk ratio [RR]: 1.03, p = 0.59; IThese results indicated that current evidence from epidemiological studies does not support that patients with MetS are at higher risk for the development of GC. Metabolic syndrome (MetS) refers to a group of metabolic disorders characterized by the manifestations of central obesity, insulin resistance, high blood pressure, and dyslipidemia –3. The pThe meta-analysis was designed and performed in accordance with the MOOSE   and CochElectronic databases of PubMed, Embase, Web of Science, and Scopus were systematically searched using the combination of the following terms: (1) metabolic syndrome” OR “insulin resistance syndrome” OR “syndrome X”; (2) “cancer” OR “tumor” OR “neoplasm” OR “carcinoma”; and (3) “cohort” OR “prospective” OR “retrospective” OR “follow-up” OR “followed”. We applied this extensive search strategy to avoid missing of potentially related studies. The search was limited to studies published in English. The reference lists of original and review articles were also analyzed manually. The final literature search was performed on August 20, 2019.Studies were included if they met the following criteria: (1) published as full-length article in English; (2) designed as cohort studies with the minimal follow-up duration of 1 year; (3) included adult participants that were without GC at baseline; (4) participants with MetS were identified as exposure of interest at baseline; (5) participants without MetS at baseline were included as controls; (6) documented the incidence of GC during follow-up; and (7) reported the adjusted risk ratios  and their corresponding 95% confidence intervals (CIs). Definitions of MetS were consistent with that was applied in the original studies. Reviews, editorials, preclinical studies, and non-cohort studies were excluded.Literature search, data extraction, and study quality assessment were independently performed by two authors according to the predefined inclusion criteria. If inconsistencies occurred, discussion with the corresponding author was suggested to resolve these issues. The following data were extracted: (1) name of the first author, publication year, study location, and study design; (2) characteristics and numbers of the participants, criteria for the diagnosis of MetS, and follow-up period; and (3) number of GC cases during follow-up, and variables adjusted when presenting the RRs. The quality of each study was evaluated using the Newcastle–Ottawa Scale . This scThe association between MetS and GC incidence was measured by RRs in this study. To stabilize its variance and normalized the distribution, RR data and its corresponding stand error (SE) from each study was logarithmically transformed .2 statistic was also calculated. A significant heterogeneity was considered if I2 > 50%. A random effect model was used to pool the results if significant heterogeneity was found; otherwise a fixed effect model was applied. Sensitivity analyses, by omitting one study at a time, were performed to evaluate the potential influence of certain study on the outcome of the meta-analysis [The Cochrane’s Q test was performed to evaluate the heterogeneity among the include cohort studies , 23, andanalysis . To evalanalysis . Potentianalysis . The RevThe flowchart of database search was shown in Fig. Overall, this meta-analysis included eight cohorts , 15–19 o2 = 79%). Sensitivity analyses by excluding one study at a time retrieved similar results (adjusted RR: 1.00–1.05). Results of subgroup analysis according to the gender of the participants showed that Mets was not associated with significantly affected risk of GC in men  or in women  or in the Caucasian participants  were not well controlled in the included studies. Well-designed large-scale cohort studies with adequate adjustment of these factors should be performed to validate our findings.Our meta-analysis has limitations. Firstly, as a nature of meta-analysis of observational studies, we could not exclude other factors that may confound the association between MetS and GC risk, such as treatments with metformin. Secondly, although we analyzed MetS by revised NCEP-ATP III or IDF criteria separately, association between MetS defined by other criteria and GC risk should also be explore. Thirdly, only four datasets from two studies were included for the association between IDF defined MetS and GC risk. Therefore, these findings should be confirmed in future studies. Fourthly, GC is a heterogeneous disease. The association between MetS and different subtypes of GC should be evaluated in the future. Finally, some commonly known risk factors for GC (including In conclusion, results of our meta-analysis showed that presence of MetS is not associated with an increased risk of GC in general population. The influences of each component of MetS on pathogenesis of GC should be evaluated in future studies.


IL-6) gene polymorphisms have been associated with several components of the CVD. Thus, in this study, we thoroughly reviewed and meta-analyzed evidence on the association between the IL-6 (rs1800795) gene polymorphism and CVD. We systematically searched in the PubMed, Web of Sciences, and Scopus databases. The analyses were performed using five study groups based on (1) a combined pool of the overall populations, (2) the country of birth, (3) the continent of birth, (4) the diagnosis and (5) both location (country or continent) and diagnosis. The analysis included the allelic, homozygote, heterozygote, dominant and recessive models. The meta-analysis showed that -174G>C (rs1800795) is a risk factor for CVD  and that this risk increases in the Chinese population. Additionally, we found that carriers of the C allele of 174G>C (rs1800795) polymorphism have an increase in the risk of coronary artery disease under the hereditary models assessed in the study. Using robust data, we found that IL-6 (rs1800795) -174G>C gene polymorphism is associated with CVD risk.Cardiovascular diseases (CVD) are group of complex and multifactorial pathologies, in which interleukin-6 ( It is well known that inflammation plays a pivotal role in the development and progression of the CVD. Currently, one of the pro-inflammatory cytokines mainly studied is the interleukin-6 (IL-6)  is define as the “pathological conditions involving the cardiovascular system including the heart; the blood vessels; or the pericardium” according to the MeSH   upstream from the start site of transcription  . The exal., 2015; Liaquatal., 2015). The pral., 2005; Li et aal., 2005; Kelbermal., 2005; Kou et al., 2005; Lalouscal., 2005). The -1al., 2013; Sekuri al., 2013; Sie et al., 2013). Therefal., 2013; Weger eal., 2013; Yang etal., 2013). G>CIL-6 (rs1800795) gene polymorphism as a probable risk factor in coronary artery disease (CAD), ischemic stroke (IS), MI, and peripheral arterial occlusive disease (PAOD) due to the share underlying pathophysiology related to endothelial dysfunction and atherosclerosis  and these diseases under allele, homozygote, heterozygote, dominant and recessive models. Based on the positive correlation observed, we explored the association by country and continent according to the models of inheritance.Therefore, we aimed to perform a systematic review and a series of updated meta-analyses to evaluate the participation of -174oon, 2018). We focG>CIL-6 (rs1800795). Finally, we explored the data by diagnosis and location. The specific objective of this analysis was to clarify the role of 174G>C IL-6 (rs1800795) gene polymorphism in cardiovascular diseases.The different diagnosis include CAD, IS, MI, and PAOD. We grouped results by CAD diagnosis to determine the presence of an association with -174The systematic review protocol and data extraction for the meta-analysis was designed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). This study has been previously registered in PROSPERO (PROSPERO 2019 CRD42019125559).IL-6 gene polymorphisms as risk factors of cardiovascular diseases. The search algorithm used to recognize the eligible studies was as follows: (“IL-6 gene” or “rs1800795” or “-174G/C”) and . Furthermore, we conducted a manual search to retrieve pertinent articles cited in previous meta-analyses, systematic reviews, cohort and case-control studies, among others. We carried out an exhaustive electronic search in databases including PubMed, Web of Sciences and Scopus to identify studies that evaluated the role of IL-6 gene polymorphisms and its role in patients with cardiovascular diseases, (2) included a case and comparison group design, (3) presented either clearly stated genotypes or sufficient information for estimation, (4) removed duplicate sample data, (5) were published in peer-reviewed journals, and (6) were written in English.We included full-length research studies that (1) addressed an independent association between The following information was independently extracted in each study by four investigators, while a fifth researcher verified and solved any discrepancies in the following categories: the surname of the first author, publication year, country of origin, ethnicity, diagnosis of cases and source of controls, inclusion/exclusion criteria of cases and controls, number of cases and controls, and case and control genotype frequencies. When the studies included subjects of more than one ethnicity or diagnosis type, the genotype data were extracted separately. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). The quality of the studies included in the analysis was assessed separately by two researchers using the Newcastle-Ottawa Scales (NOS); these scales are based on three main aspects: selection, comparability and ascertainment of exposure. Only studies with a score of six stars or more were included in the meta-analysis  carrier with disease, b) carrier without disease, c) non-carrier with disease, d) non-carrier without disease, the term “carrier” refers to the allele C of IL-6 (rs1800795 or -174G>C). Then, the relation between IL-6 (rs1800795 or -174G/C) polymorphism and CVD was addressed by the pooled ORs and their corresponding 95% confidence intervals under five genetic models, namely the allelic model (C vs G), the dominant model (CC+GC vs GG), the recessive model (CC vs CG+GG), the homozygous model (CC vs GG) and the co-dominant model (GC vs GG). To assess the significance of the pooled ORs, we used a Z test and considered a P <0.05 as statistically significant. For the meta-analysis, a total of 16 groups were created based on five categories: (1) combined from the overall population, (2) based on the country of birth , (3) based on the continent of birth (Europeans and Africans), (4) dependent on diagnosis , and (5) based on both the diagnosis and the country or continent of origin  and (6) based on smoking habits.Firstly, using a chi-squared test, we tested the Hardy-Weinberg equilibrium (HWE) for genotype frequencies in cases and controls, where 2 statistic. The I2 results were (a) 0-25 absent, (b) 25-50 low, (c) 50-75 moderate, and (d) 75-100 high.In addition, the heterogeneity between the studies was analyzed by a Q-statistic test and the inconsistency was evaluated by an I2 >50 % and Q test P value ≤ 0.1 were taken as indicators of substantial heterogeneity, in which case, the effect model we used was random-effects (DerSimonian-Laird method), failing that, the fixed effect model (Mantel-Haenszel method). Alternatively, IP <0.05 was considered as a significant publication bias. The comprehensive meta-analysis software version 2  was used for all the analyses, and all p-values were two-tailed. The sensitivity analysis was conducted by sequentially omitting one article to evaluate the influence of an individual study and validate the reliability of the results. Furthermore, the publication bias was diagnosed with Begg's funnel plot and Egger's regression test; After excluding the overlapping articles of the literature search and applying the selection criteria mentioned previously, 74 research articles  as a probable risk factor for CVD. The findings reveal a statistical association of this polymorphic variant in four of the five models proposed previously .We evaluated the participation of -174recessive model, a statistical association was only observed in the presence of heterogeneity . There was no evidence of publication bias in the five genetics models proposed, all models are shown in the Supplementary Figures.Regarding the allelic OR=1.36, CI 95%=1.26-1.48, Z p value= <0.0001 .In this analysis, we performed a meta-analysis in four different countries: China, India Turkey, and the United Kingdom. Firstly, in the Chinese population, there was no evidence of heterogeneity in the genetic models and rs1800795 was a risk factor due to its association with CVD ;  in the presence of moderate heterogeneity, this was not maintained in its absence of heterogeneity. As for the articles with Turkish and Indian samples, the same five genetic models were carried out; however, the data did not show an association of -174G>C variant as a probable risk factor in those populations.Secondly, we evaluated the polymorphism involvement in a sample population from the United Kingdom; the result shows a significant association with risk under the The Egger test was not statistically significant in the five genetic models performed, thus suggesting the absence of publication bias.G>C variant is a significant risk factor for CVD under the dominant model ; , also reveals an association of this variant with CVD in the presence of high heterogeneity. Nevertheless, after excluding the studies that predispose to heterogeneity, this association was not observed. Regarding the African population, no statistical association was observed under any genetic model.Moreover, under the Begg's funnel or Egger's test did no present asymmetry or statistical significance, thus suggesting the absence of publication bias in the genetic models analyzed .G>C for CAD; under the five models used, a significant association was observed . Then, we evaluated this association in subjects with PAOD and found a protective effect of the -174G>C polymorphism under the recessive model , heterozygous , and dominant models . Nonetheless, in the presence of heterogeneity, an association was found under the recessive model , but not when the articles favoring heterogeneity were excluded. We did not find publication bias using Egger's test in the genetics models previously mentioned .In some articles, a hospital population was included in the control group; herein, only healthy subjects were used as controls. The results of this analysis revealed a role of -174G>C as a possible marker. We did not find publication bias using Egger's test in the five genetic models conducted .Finally, we conducted an analysis with two filter criteria: diagnosis  and geographical location (India or Europe), which allowed for the formation of four groups: India + CAD, Europe + CAD, Europe + MI and Europe + IS Table 2. Using fFinally, due to the importance that could have some risk factors in CVD we performed an analysis by the smoking habits. The articles with available data showing the genotype distribution by tobacco used were only six articles  IL-6 gene polymorphism as a probable risk factor for cardiovascular diseases. First, we explored the participation of -174G>C (rs1800795) polymorphism as a possible risk factor for CVD in the overall population of the included studies.It is well known that inflammatory mediators, especially IL-6, are central to the development of cardiovascular diseases. A considerable number of the polymorphisms were identified in the C), homozygous (CC), heterozygous (CG) and dominant (CC + CG) models. In accordance with the present results, previous studies have demonstrated that higher levels of IL-6 are associated with the -174CC genotype or C allele in patients . Taken IL-6 gene transcription and predisposing to greater myocardial or vascular injury. Several studies and the large sample size included in this meta-analysis provided more reliable information related to the association of IL-6 (rs1800795) gene polymorphism and CVD. This shows the influence of the polymorphism in increasing G>C in CVD by performing a sub-analysis on different nationalities and geographic locations. The results showed that in the studies within the Chinese population, there was a strong association of the IL-6 (rs1800795) polymorphism with CVD.Additionally, previous studies have suggested that there could be differences in gene frequencies between populations  of having CVD. Our results suggest that the risk in the Chinese population is higher than in other populations analyzed in this study. We analyzed the same association with subjects born in the United Kingdom, Turkey or India. Under a heterozygous model, we only found a significant association for the British population after discarding the heterogeneity.Indeed, depending on the model, Additionally, we made a diagram of the allelic frequencies of the cases by populations, in which the distribution of the risk allele is observed Figure 8. G>C, especially in complex and multifactorial diseases such as CVD. Afterward, we decided to explore this issue more precisely with the following analysis. Depending on the sample nationality, the available data allowed for the formation of two groups (Europeans and Africans), for which the same methodological procedure was used. Under a dominant model , only one statistically significant association was observed after measuring heterogeneity in the European population.A possible explanation for this might be that, in different populations, the underlying genetic mechanisms that predispose to the same pathology may be achieved by different genotypes affecting distinct mediating mechanisms. Therefore, the influence of the population genomes needs to be taken into account when considering the effect of -174By taking the previous analysis into consideration, we can suggest that this association might be influenced by the studies of participants born in the United Kingdom. These findings confirmed the assumption that ethnicity increases the level of complexity of genetic functional studies, considering the differences in gene frequencies between populations .An initial objective of the project was to better understand the influence of both the genes and the specific DNA sequence variants responsible for the etiology of cardiovascular diseases. For this reason, we evaluated the role of -174G>C have an increased risk for CAD between 1.10 times and 1.50 times. It is well known that high basal IL-6 plasma levels, which exert pro-inflammatory and pro-coagulant effects, have proven to be predictive of CVDs . Our real., 2013). Taken C carriers with CVD.On the other hand, we were aware that there could be other variables affecting the results. For that reason, a more selective analysis was performed which only included healthy subjects as a comparison group. We found a 1.02 to 1.25 fold increased risk of cardiovascular diseases, supports our previous association of -174C allele of -174G>C is associated with protection . In fact, Flex et al. reported that GG homozygous subjects have a 4.6-fold risk of developing PAOD compared with CC homozygous patients ; this ral., 2000). ConseqG>C on circulating IL-6 is more complex and may be dependent on multiple variables. Hence, our final approach involved examining the role of -174G>C in not only Europeans with CAD, MI, and IS, but also in India participants with CAD. The aforementioned subjects were organized into four groups: Europe + CAD, Europe + MI, Europe + IS and India + CAD. Of interest, even after the heterogeneity was discarded in the analyses, no association with -174G>C polymorphism was found. Additionally, we know that the effect of -174Furthermore, it is well known that there are several risk factors involved in the CVDs. One of the most common studied is the smoking habits, which it has been hypothesized that could play a role as risk factor. Nevertheless, in our findings no relationship was revealed. However, this could be an effect of a small sample size, due to only six studies the data was available to perfom the analysis. Another reason could be that almost all of the studies included are conducted in Caucasians  is associated with increased risk for CVD.In conclusion our results indicate that This association is mainly observed in Chinese and British populations and patients with CAD.G>C polymorphism was also found to be a protective factor for PAOD. Further research is needed to fully understand the participation of the -174G>C variant in CVD.However, the -174Thelma Beatriz González-Castro and Yazmín Hernández-Díaz contributed equally as first authors.The authors are grateful to all study participants and to the Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico and Universidad Juárez Autónoma de Tabasco, Tabasco, Mexico.