The prevalence of allergic respiratory disease tends to increase in populations that adopt the so-called Westernized lifestyle. We investigated the association between atopy and several possible lifestyle-related factors in seven Danish population-based studies.A total of 20048 persons participated in the seven studies. We used logistic regression to analyse the associations between possible determinants and atopy defined as serum specific IgE or skin prick test positivity against inhalant allergens. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). In addition, individual participant data meta-analyses were performed.trend = 0.032.Atopy was significantly associated with younger age ; male sex , heavy drinking , never smoking , and higher educational level . Atopy was not associated with blood pressure, serum total cholesterol, physical activity or body mass except in women only, where we found a positive association  with pOf interest for preventive purposes, we found that atopy was associated with some of the reversible lifestyle-related factors that characterize a Westernized lifestyle. The prevalence of allergic respiratory disease such as allergic rhinitis and allergic asthma has increased over recent decades in countries living a Westernized, urbanized, and affluent lifestyle ,2. HowevMany of the previous studies on lifestyle-related factors of allergic respiratory disease have mainly been performed in children or adolescents, have not used objective measures of allergic respiratory disease, or been single-study analyses with limited power to detect associations. In seven Danish population-based studies of adults from different time periods, we investigated the association between several potential lifestyle-related factors of atopy, i.e. serum total cholesterol, systolic blood pressure, smoking habits, alcohol intake, leisure time physical activity, body mass index, age, gender and education, and atopy, defined as specific IgE or skin prick test positivity against inhalant allergens that are both well-accepted objective biomarkers of allergic respiratory disease.All the included studies were approved by the Ethics Committee of Copenhagen and the Danish Data Protection Agency. We followed the recommendations of the Declaration of Helsinki, and each participant gave informed written consent.We used the seven population based studies: Monica1, Inter99, Health2006, the 1936-cohort, Allergy98, Health2008 and Health2010. Participants were recruited from the Danish Central Personal Register as random samples of the background population living in the Western part of the Copenhagen Region . All stuThe Monica1 study took place from 1982 to 1984. A total of 4,807 persons aged 30, 40, 50 and 60 years old were invited, 3,785 persons participated, and thus the participation rate was 79% .The Health2010 study was conducted between 2010 and 2012 where 3732 persons between 18 and 69 years of age were invited. A total of 1522 persons participated which meant a 40.5% participation rate .ClinicalTrials.gov) that examined the effects of lifestyle intervention on the incidence of cardiovascular disease  pteronyssinus), grass, cat, and birch (In the Allergy98 study in addition dog and mugwort) . In the In the Health2010 study, skin prick testing (SPT) was performed by the Soluprick SQ®  system. The procedure was performed using lancets and a standard panel of aeroallergens comprising birch, grass (Phleum pratense) mugwort, horse, cat, dog, two house dust mites (Dermatophagoides pteronyssinis and D. farinae), and two moulds . A negative control and a positive control (10 mg/mL histamine) were also included. The mean wheal diameter was calculated as the average of the widest diameter and the perpendicular bisector. A positive SPT was defined as a mean wheal diameter ≥3 mm. Atopy was defined as a positive reaction to at least one of ten allergens.The analyses were performed with SAS, version 9.4 . P-values were two-sided and p-values <0.05 defined as statistically significant. Multivariate logistic regression analyses were used to model the cross-sectional associations between different covariates and atopy. In model 1, we adjusted for gender, age, and study population (with an indicator of the study population that the participant belonged to). In model 2, we further adjusted for birth year (except when using age as exposure), education, physical activity, smoking habits, alcohol intake, BMI, systolic pressure and serum total cholesterol. We used complete case analysis, i.e. persons with missing values in one or more of the covariates were excluded from the regression analyses.In additional analyses, we only included the six studies that defined atopy according to serum specific IgE positivity. We also stratified by gender the analyses regarding BMI and atopy.2-test. An overview of the results from meta-analyses is shown in We used Stata, version 12.1 , to perform meta-analyses of the fully adjusted study specific estimates obtained from logistic regression models for each study separately. This is an alternative to the analyses of the pooled studies, mainly to account for the higher correlation within studies than between studies and to assess the heterogeneity across the studies. We combined the OR estimates with the inverse variance method in random rather than the fixed effects models because of heterogeneity across studies for some of the analyses, detected by the IThe specific meta-analyses are shown in Participants’ birth years were distributed over the following decades (nineteen twenties: 5.1% (n = 874), nineteen thirties: 13.8% (n = 2368), nineteen forties: 24.6% (n = 4219), nineteen fifties: 29.3% (n = 5023), nineteen sixties: 18.1% (n = 3096); or nineteen seventies and above: 9.1% (n = 1565).The mean age of the study participants varied between approximately 40 years  to approximately 50 years  . In all In the adjusted analyses of the merged study data, atopy was significantly associated with young age, male sex, high intake of alcohol, never smoking, and education beyond basic school, but not with systolic blood pressure or serum cholesterol .The additional analyses including only the six studies using serum specific IgE positivity for the definition of atopy  showed similar results (data not shown). The meta-analyses of the study-specific estimates were quite similar to results of the pooled data analyses which shows that differences between the studies did not seriously bias our results –S10 Figstrend = 0.891. However, BMI was significantly associated with atopy in women . The p-value for trend among women was ptrend = 0.032.BMI was not associated with atopy in men only . The p-value for trend among men was pIn analyses including more than 20,000 persons, we found that atopy was significantly associated with younger age, male sex, heavy drinking, not smoking, and educational level, but not with blood pressure, serum cholesterol, physical activity or body mass index. The large sample size allowed us to estimate the independent effects of these factors with a reasonably high precision. Data come from a pool of seven large population-based studies conducted on Danish adults since the early 1980's up to recent years, and the use of objective factors of atopy and standardized methods in general enabled the exploration of disease prevalence and risk factors over time ,40.The observed positive trend between time and prevalence of atopy is well-known and in line with several previous reports using parts of the data used in the present analyses ,39,40. Tallergic rhinitis [Although smoking is a known risk factor for asthma, its association with development of allergic sensitization is controversial. In line with the observed lower prevalence of atopy among current smokers compared to never smokers in the present study, Linneberg et al found that smoking was associated with a lower prevalence  and incirhinitis . One posrhinitis . The assrhinitis . We founThe effect of alcohol consumption on sensitisation is also not clear. In 2003, Linneberg et al found that alcohol consumption was positively associated with serum total IgE but not with IgE sensitisation , and in Previous studies examining the association between obesity and atopy in adults have shown conflicting results . There aIn addition, theoretically both serum lipids and blood pressure could mediate a possible effect of obesity on atopy since obesity has a detrimental effect on both, and both are related to some form of inflammation . HoweverThe strengths of our study include the large population-based samples and the inclusion of multiple studies. Also a strength, is the use of objective factors of atopy, i.e. serum specific IgE positivity and skin prick test positivity against inhalant allergens, which may be more reliable than self-reported diagnoses and symptoms. Although different methods were employed for assessment of atopy, our previous comparison of e.g. the ADVIA Centaur Allergy Screen assay (used in the 1936-cohort and the Monica1 studies) against skin prick test reactivity  showed good agreement in our background population . In geneOne limitation is that the questionnaires used for collection of data on symptoms and diagnoses of diseases in the various studies differed markedly over time period and some studies lacked questions on allergic respiratory disease. Hence, we could not perform meaningful analyses for these outcomes across populations.In conclusion, in this large cross-sectional study we confirmed that atopy, objectively assessed by IgE or skin prick test sensitization to inhalant allergens, is associated with sex and age and in addition with several lifestyle-related factors. Although environment is clearly important in the aetiology allergic respiratory disease, lifestyle factors could also contribute to the allergy epidemic.S1 Fig(TIF)Click here for additional data file.S2 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S3 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S4 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S5 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S6 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S7 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S8 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S9 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S10 FigAbbreviations: a98, Allergy98; h06, Health2006; h08, Health2008; h10, Health2010; i99, Inter99; k36, 1936-cohort; m1, Monica1; OR, odds ratio; CI, confidence interval.(TIF)Click here for additional data file.S1 TableStudy participants were drawn as a random samples of the general population living in a defined area of the Western part of Copenhagen.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


LEPR gene Gln223Arg polymorphism (rs1137101) in oral squamous cell carcinoma (OSCC) and in potentially malignant oral lesions (PMOL) in comparison to normal oral mucosa in a Brazilian population. Smokers (n = 89) were selected from a representative sample of 471 individuals from the general population of Montes Claros, Brazil. Participants were age and gender matched to patients with OSCC (n = 25) and oral epithelial dysplasia (n = 25). We investigated the LEPR Gln223Arg polymorphism  in these groups. Genotype variants were assessed by RFLP-PCR, using MspI (HPAII) restriction endonuclease. The institutional review board of the Universidade Estadual de Montes Claros approved the study (process number 2667/2011). Written informed consent for this study was obtained from all participants. The GG genotype (Arg223Arg) appears to be the more relevant polymorphic variant in OSCC. It occurred, approximately, twice as frequently in OSCC patients than in the general population. In contrast, the A allele in its homozygosis form (Gln223Gln) is significantly associated with the development of PMOL; 80% of the samples from the PMOL group exhibit AA genotype. Our findings suggest new insights regarding LEPR gene variations in the development of OSCC and PMOL.The purpose of this study was to assess the  Leptin receptor protein (LEPR)  is a protein of the cytokine family, comprised of 167 amino acids. It is mainly synthesized in adipose tissue and is related to energy metabolism and body weight through hypothalamic regulation. Its function is achieved when it binds to its receptor, the Leptin receptor antagonists capable of blocking the effects of Leptin could lead to the development of new therapeutic procedures for the treatment of various types of cancer. One recently developed peptide was associated with the inhibition of several Leptin-induced pathway in breast and colorectal cancer, including JAK/STAT3, MAPK/ERK1/2 and PI3K/AKT, cyclin D1, and E-cadherin  and OSCC and/or PMOL. To test our hypothesis, we first performed a study with a sample of non-institutionalized adults from the city of Montes Claros, Minas Gerais, Brazil. Montes Claros has approximately 361.915 inhabitants and 95.1% of them live in the urban area. Sample size calculation was performed to estimate the number of participants need for a representative sample of the municipal population . From a representative sample of 724 individuals, we selected only smoking individuals without OSCC or PMOL (n = 89), who were matched for age, sex, and smoking habits with OSCC (n = 25) and oral epithelial dysplasia patients (n = 25). Diagnosis of OSCC and PMOL in participants was confirmed through histopathologic analysis. In this study, only oral epithelial dysplasia was considered as PMOL. The study was approved by the institutional review board of the Universidade Estadual de Montes Claros (process number 2667/2011). Written informed consent for this study was obtained from all participants.We performed a case-control study to verify a possible association between polymorphisms of the DNA was extracted from oral mucosa scrapings from a control group and from the lesions of participants diagnosed with OSCC or PMOL. DNA samples were isolated using silica particles, which absorb the DNA. Subsequently, DNA was washed to remove impurities and was eluted in TE buffer, as previously described  was assessed by RFLP-PCR. Polymerase chain reaction for the LEPR gene was performed using 500 ng of genomic DNA as a template. Other reagents were used, including 4 μM of each of the following primers: F: 5′-ACCCTTTAAGCTGGGTGTCCCAAATAG-3′; R: 5′CAATATTTATGGGCTGAACTGACATT-3′; 330 bp), 0.1 mM of each DNTP , 1X PCR buffer, 2.5 mM magnesium chloride, and 2.5 U of Platinum Taq DNA polymerase . The 330 bp PCR product was digested with MspI (HPAII) restriction endonuclease  that recognizes the restriction site (C/CGG). For this SNP, the A allele lacks a MspI restriction site. Thus, individuals carrying the A allele show only one PCR band (330-bp), while carriers of the G allele show two bands (293 and 37 bp)  shows significant association with PMOL; 80% of the samples exhibit the AA genotype. On the other hand, the GG genotype (Arg223Arg) appears to be the more common polymorphic variant in OSCC. It occurred, approximately, twice as frequently in OSCC patients than in the control group. The control group had higher frequencies of AG and AA variants. The GG genotype showed lower distribution in these samples; the A allele seems to be more important in this group. No association between gender and LEPR genotype variants were observed  is a hormone secreted from adipocytes that plays an important role in energetic metabolism, control of food intake, and obesity through its binding to LEPR receptors  is a risk factor in breast cancer  was associated with increased risk. Additionally, the risk of breast cancer associated to the G allele differed based on ethnicity  in cancer patients in comparison to the control group. The GG genotype was twice as common in the OSCC and PMOL group than in the control group. A previous study showed that breast cancer patients with the G allele were more likely to develop poorly differentiated tumors than those with the A allele  is an important risk factor in breast cancer  was significantly associated with PMOL with 80% of the samples exhibiting the AA genotype. This is the first report investigating the relationship between LEPR polymorphism and OSCC and PMOL. Other studies are needed to understand the role of LEPR variants in the development and progression of oral cancers, especially in relation to Leptin levels or in association with the stages of dysplasia. It is important to highlight that considering the complexity of gene expression control, it is not possible to know whether the results are influenced by other environmental variables involved.PMOL is a lesion with potential for becoming squamous cell carcinoma .


PSCA) gene, which encodes a prostate-specific antigen (PSA), was identified as a gene involved in cell adhesion and proliferation. The associations between the PSCA rs2294008 and rs2976392 single nucleotide polymorphisms (SNPs) and gastric cancer (GCa) susceptibility were still controversial. To derive a more precise estimation of the associations, we conducted a case-control study of 1,124 cases and 1,192 controls in an eastern Chinese population. We found that the rs2294008T variant genotypes were associated with an increased GCa risk in this study population . For SNP rs2976392, the variant A genotypes were also associated with an increased GCa risk . The results were further validated by a meta-analysis. In conclusion, the results indicated that the PSCA rs2294008 T and rs2976392 A alleles were low-penetrate risk factors for GCa in this study population. However, large and well-designed studies are warranted to validate our findings.The prostate stem cell antigen ( Helicobacter pylori(HP) infection might be a potential risk factor for an increased GCa risk in developing countries (70-90%) than in developed countries (25-50%) [HP carriers will develop GCa; therefore, other factors must play a role in GCa risk. Lifestyle factors such as tobacco smoking, alcohol use and dietary habits are also likely to be potential risk factors for GCa [Gastric cancer (GCa) is the most frequently occurring cancer and one of the leading causes of cancer-related deaths. There were 951,600 new GCa cases and 723,100 deaths in 2012, accounting for 8% of the cancer cases and 10% of cancer deaths in the world, respectively [ for GCa . AlthougPSCA) gene, which encodes a prostate-specific antigen (PSA), was identified as a gene involved in cell adhesion, proliferation and patient survival [in vivo functional studies [PSCA genetic variants in the etiology of GCa. Importantly, several GWAS studies have demonstrated an association between PSCA variants and cancer susceptibility [PSCA gene (rs2294008 C>T and rs2976392 G>A) were associated with an increased GCa risk [The prostate stem cell antigen .Baseline characteristics of individuals included in this study were consistent with those described in our previous study , but oneThe allele frequencies of SNPs rs2294008 and rs2976392 in cases and controls and their associations with GCa risk are presented in Table In the stratified analysis presented in Table PSCA rs2294008 and rs2976392 SNPs were strongly associated with an increased GCa risk .In addition to environmental and lifestyle factors for GCa risk, genetic factors are also important in identifying at-risk populations for prevention of GCa. Although PSCA is mainly expressed in the isthmus/neck region of the stomach where the GCa often occurs , it is iPSCA homozygotes (TT for rs2294008 and AA for rs2297692) were not statistically significant. This may be explained by a co-dominant genetic model, in which only the imbalanced paired protein subunits coded by the two different alleles will have an effect on the proteins’ functions; alternatively, the variant homozygotes may have experienced embryo lethal events, leading to a high rate of abortions; lastly, this finding may be simply due to chance, because of a systemic error in genotyping or because the small sample size of the subgroup may have insufficient statistical power to detect a weak effect or may have generated an unstable risk estimate. All these speculations should be further explored in future larger and mechanistic studies. Therefore, our results should be interpreted with caution.However, it was surprising that GCa risk for the subgroups of There are some limitations in the present study. First, although age, sex, smoking and drinking status, and tumor site were taken into consideration for subgroup analysis, other important risk factors such as diet and HP infection, which were missing in this study, might also contribute to the etiology of GCa. Second, new classification of GCa tumor types, which was not available for the patients diagnosed years ago, is also important, which may have a different genetic basis in the etiology. Third, the sample size of the cases in subgroups was largely reduced in the stratification analysis, which may have led to limited statistical power in subsequent analysis.PSCA rs2294008 T and rs2976392 A alleles may be low-penetrate risk factors for GCa. However, future studies should incorporate diet, HP infection status and Lauren classification to better understand the associations between the PSCA SNPs and GCa risk.In summary, our results indicated that the This study included GCa patients and cancer-free controls who were part of our ongoing molecular epidemiology study as described previously -21. BrieUsing to a standard protocol, we extracted genomic DNA from peripheral blood samples. The rs2294008 and rs2976392 SNPs were genotyped by the TaqMan assay with the ABI7900HT real-time PCR system as reported previously . Subject2 test was used to assess the differences in the distributions of demographic characteristics between cases and controls. The associations between SNPs and GCa risk were assessed by odds ratios (ORs) and 95% confidence intervals (CIs) in heterozygous, homogenous, and dominant models. ORs were calculated by univariate and multivariate logistic regression models. Logistic regression models were used to test for each genetic model with adjustment for age, sex, smoking and drinking status. The combined effect of the tested SNPs on GCa risk was also evaluated in logistic models. Furthermore, associations between the PSCA rs2294008 C>T and rs2976392 G>A SNPs and GCa risk were stratified by age, sex, smoking or drinking status, and primary tumor site. All the statistical processes were performed by using SAS software An individual who never smoked cigarettes was defined as a never smoker; who smoked cigarettes but quit more than one year before diagnosis (for cases) or before the interview (for controls) was defined as a former smoker; and who smoked currently or quit within one year before diagnosis (for cases) or before the interview (for controls) was defined as a current smoker. Ever smokers included both former smokers and current smokers. Those who drank alcoholic beverages at least once a week for one year or more were defined as drinkers, while the others were non-drinkers. The χP value greater than 0.10 for the Q-test indicates a lack of heterogeneity among studies, so the pooled OR estimate of the each study was calculated by the fixed-effects model (the Mantel–Haenszel method). Otherwise, the random-effects model (the DerSimonian and Laird method) was used [P<0.05 determined by the t test was suggested by Egger. All the statistical processes were achieved by using STATA version 10.0 . Whether results were conclusive could not be answered by traditional meta-analysis without keeping and balancing the type I and type II error. To address this problem, studies included in this meta-analysis were analogous to interim randomized controlled clinical trials. Sequential meta-analysis (SMA) was conducted to calculate the required information size in this meta-analysis. Lan DeMets sequential monitoring boundary was established to control the type I and II error by alpha and beta-spending function methods. Whether the monitoring boundary was crossed was used as a way to estimate the reliability of the results acquired from traditional meta-analysis. All steps were accomplished with the TSA software version 0.9.To further validate our results, we also performed a mini meta-analysis with studies searched from Medline, PubMed and Embase. Principles in search terms and inclusion and exclusion criteria were basically in accordance with previous studies , 24. Allwas used . To vali


The summary relative risk were 0.66  per 5 μg/100 mL of α‐carotene (studies [n] = 5), 0.84 (95% CI: 0.76–0.94) per 20 μg/100 mL of β‐carotene (n = 9), 0.66 (95% CI: 0.54–0.81) per 100 μg/100 mL of total carotenoids (n = 4), and 0.81 (95% CI: 0.73–0.90) per 70 μg/100 mL of retinol (n = 8). In stratified analysis by sex, the significant inverse associations for β‐carotene and retinol were observed only in men and not in women. Nonlinear associations were observed for β‐carotene, β‐cryptoxanthin, and lycopene, with stronger associations observed at lower concentrations. There were not enough data to conduct stratified analyses by smoking. In conclusion, higher blood concentrations of several carotenoids and retinol are associated with reduced lung cancer risk. Further studies in never and former smokers are needed to rule out confounding by smoking.Carotenoids and retinol are considered biomarkers of fruits and vegetables intake, and are of much interest because of their anti‐inflammatory and antioxidant properties; however, there is inconsistent evidence regarding their protective effects against lung cancer. We conducted a meta‐analysis of prospective studies of blood concentrations of carotenoids and retinol, and lung cancer risk. We identified relevant prospective studies published up to December 2014 by searching the PubMed and several other databases. We calculated summary estimates of lung cancer risk for the highest compared with lowest carotenoid and retinol concentrations and dose–response meta‐analyses using random effects models. We used fractional polynomial models to assess potential nonlinear relationships. Seventeen prospective studies (18 publications) including 3603 cases and 458,434 participants were included in the meta‐analysis. Blood concentrations of  Lung cancer is the first most common cancer among men and the third most common cancer among women worldwide with 1.82 million cases and 1.59 million deaths due to lung cancer in 2012 Diet may also play a role in lung cancer etiology β‐carotene (ATBC) and the β‐carotene and Retinol Efficacy Trial (CARET) showed an increased risk of lung cancer among high‐risk people supplemented with high doses of β‐carotene and/or α‐tocopherol According to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Second Expert Report from 2007, foods containing carotenoids may protect against lung cancer (strength graded as probable) A previous meta‐analysis of prospective observational studies suggested a significant inverse association between lycopene and total carotenoids and lung cancer risk, however, the number of studies on blood concentrations of carotenoids was limited and there was no exploration of the shape of the dose–response relationship between carotenoids and lung cancer More recently, two additional prospective studies have been published, including 11,003 participants and 368 lung cancer cases http://www.wcrf.org/sites/default/files/protocol_lung_cancer.pdf. We also handsearched the reference lists of relevant articles, reviews, and meta‐analyses identified in the search.PubMed and several other databases, including, Embase, CABAbstracts, ISI Web of Science, BIOSIS, LILACS, Cochrane library, CINAHL, AMED, National Research Register, and In Process Medline, were searched for studies on blood concentrations of carotenoids and retinol up to January 2006 by several reviewers at the Johns Hopkins University for the WCRF/AICR Second Expert Report Included were prospective cohort, nested case–control or case–cohorts studies that reported estimates of the relative risk (RR)  and 95% confidence intervals (CIs) of specific carotenoids, total carotenoids, or retinol in blood and lung cancer incidence or mortality. In case of multiple publications of the same study, the newest publication that included the largest number of cases was selected.The following data were extracted from each publication: first author's last name, publication year, country where the study was conducted, the study name, follow‐up period, sample size, sex, age, number of cases, laboratory method for analysis, concentrations of carotenoids or retinol, and associated RRs and 95% CIs, and variables used in adjustment in the analysis.http://www.wcrf.org/sites/default/files/SLR_lung.pdf). The search and extraction from January 2006 and up to December 2014 was conducted by the CUP team at Imperial College London.The search and data extraction of articles published up to December 2005 was conducted by several reviewers at the John Hopkins University during the systematic literature review for the WCRF/AICR Second Expert Report  was used for all analyses.β‐carotene α‐carotene (1205 cases) β‐cryptoxanthin (1205 cases) From 29,513 articles identified by the search of the Continuous Update Project, 28 articles (4 during the CUP and 24 during the SLR 2005), which met the inclusion criteria were included   or of publication or small‐study bias . The overall RR for the highest versus lowest analysis was 0.70  in seven studies . Only three studies could be included in nonlinear meta‐analysis and no evidence of nonlinearity was observed, Pnonlinearity = 0.11  were included in the dose–response meta‐analysis 80) Fig. A. There μg/100 mL was 0.84 (95% CI: 0.76–0.94)  and no evidence of publication or small‐study bias . An inverse association was observed in the highest versus lowest analysis  in 14 studies .Nine studies 2958 cases) were included in the dose–response meta‐analysis 58 cases β‐carotene , with the curve showing a slightly steeper slope in the low range of β‐carotene concentrations  . There was no evidence of publication bias with Egger's test (P = 0.23). Similarly, a nonsignificant inverse association was observed in the highest versus lowest analysis  in seven studies .Six studies 1174 cases) were included in the dose–response meta‐analysis  cases we2) Table A. There Pnonlinearity = 0.03, n = 4) and there was a slightly stronger association at lower blood concentrations of β‐cryptoxanthin, the association was nearly linear from 5 μg/mL and above   and publication bias . The overall RR for the high versus low analysis was 0.68  in six studies (Table Five studies (1066 cases) were included in the dose–response meta‐analysis 0) Table C. There Pnonlinearity = 0.01, n = 3)  with a weaker association beyond this level.There was some evidence of nonlinear dose–response of lung cancer and blood concentration of lycopene  and the RR for the highest versus lowest analysis was 0.86  (Table Five studies (896 cases) were included in the dose–response meta‐analysis Pnonlinearity = 0.51, n = 3)  Fig. B, althouμg/100 mL was 0.66   but the number of studies was small. The overall RR for the high versus low analysis was 0.64  in five studies (724 cases) .Four studies (693 cases) were included in the dose–response meta‐analysis μg/100 mL was 0.81  . The overall RR in high versus low analysis was 0.72  in 11 studies (3145 cases) . There was some evidence of a nonlinear dose–response of lung cancer and serum retinol , with wide CIs for higher exposures  were included in the dose–response meta‐analysis 55 cases 36) Fig. C. There tudies 315 cases  and inverse but not significant in women  for which statistical power was low  than in studies on lung cancer incidence , but there was no strong evidence of a difference of association as the CIs were overlapping  In terms of geographic location, the results were significant only in studies conducted in the United States (five studies) but not in Asia (three studies) Table .μg/100 mL were 0.76  and 1.01  in men and women, respectively.An inverse dose–response association was observed in men 2499 cases) and no association was observed in women (221 cases) (see Table 499 casesμg/100 mL). Only four studies remained in the analysis .The overall estimate was no longer statistically significant when the studies in high‐risk populations were excluded In stratified analysis by geographic location, the results were significant only in studies conducted in the Asia (three studies) but not in United States (three studies) Table .α‐carotene, β‐carotene, and total carotenoids, and lung cancer risk. An inverse association with blood concentrations of retinol was also observed. Subjects with the highest blood concentrations of total carotenoids and retinol had 19% and 34% lower RR of lung cancer when compared to those with the lowest blood concentrations, respectively. There was little evidence of heterogeneity in these analyses. Apart from the analysis of lycopene, there was no evidence of publication bias with the statistical tests used; however, the number of studies was limited.In this meta‐analysis, there was an inverse dose–response relationship of blood concentrations of To our knowledge, this is the first meta‐analysis to examine a potential nonlinear association between blood concentrations of carotenoids and retinol, and lung cancer risk. The nonlinear dose–response analyses suggested inverse associations for all carotenoids, and in general, there was a stronger dose–response relationship in the lowest range of carotenoid and retinol concentrations than at the highest range. Nonlinearity was most pronounced for lycopene and retinol, for which there was a flattening of the dose–response curve at the highest concentrations, while for most of the remaining carotenoids associations were slightly stronger at lowest compared to highest concentrations, but there was a clear inverse dose–response relationship with further reductions in risk with increasing carotenoid concentrations. These findings suggests that it might be most important to avoid low blood concentrations of lycopene and retinol, and that there is little further benefit in people with highest blood concentrations, while for alpha‐carotene, beta‐carotene, and beta‐cryptoxanthin there might be further reductions in risk with increasing blood concentrations.α‐carotene and β‐cryptoxanthin only in current smokers but not in never/former smokers, however, in a previous meta‐analysis of fruit and vegetable intakes (some of which are high in carotenoids) and lung cancer risk, we found similar summary RRs among never smokers as compared to current or former smokers This study has several limitations which should be considered when interpreting the results. Smoking tends to be associated with lower intakes of fruit and vegetables, high intakes of fat and higher consumption of alcohol β‐carotene Given the lack of data stratified by smoking status, further studies are needed in never smokers to rule out the potential confounding by smoking. Residual confounding by other factors potentially related to the blood levels of the biomarkers investigated and to lung cancer is also a possibility. When the studies in high‐risk populations—high‐risk miners, heavy smokers or people exposed to asbestos—were excluded from the meta‐analysis in sensitivity analysis, the inverse association with β‐carotene (n = 9) and retinol (n = 8), fewer studies reported on the other carotenoids (n = 4–6). The inverse associations were observed in men but not in women, and whether this is due to residual confounding, low number of cases in the analyses in women or gender differences is unclear and needs further study.Although there was a large number of studies that could be included in the dose–response analyses of α and β‐carotene, and β‐cryptoxanthin can be partially metabolized to retinol, particularly in people with depleted vitamin A concentrations Furthermore, blood concentrations of carotenoids and retinol may not only reflect dietary intake, but can be influenced by the lipid content of the diet, metabolism and absorption, and genetic variability α‐carotene, β‐carotene, and lutein/zeaxanthin β‐cryptoxanthin, α‐carotene and lycopene in plasma The results of this meta‐analysis provide further support that high blood concentrations of carotenoids and retinol, as biomarkers of fruits and vegetable intake, are associated with reduced lung cancer risk. Carotenoids are found in many different types of fruit and vegetables, and it has been shown in epidemiological studies that dietary intakes of green and raw vegetables, carrots and broccoli are correlated with blood concentrations of β‐carotene among smokers β‐carotene when administered as a supplement in high doses  to heavy smokers In contrast to the results of many observational studies and the current meta‐analysis, two large randomized controlled trials (RCT's), the ATBC and CARET, showed an increased risk of lung cancer with high‐dose supplemental Strength of this meta‐analysis is the inclusion of prospective cohort studies which avoids potential recall biases and that are less prone to selection biases than case–control studies. Some analyses included a large number of cases and had statistical power to detect relatively small associations but for some micronutrients the power may have been insufficient. Most studies, as mentioned previously, were adjusted for main confounders including smoking status, intensity, duration of smoking, and other smoking variables. Most of the studies measured the carotenoids and retinol blood concentrations using high‐performance liquid chromatography (HPLC). The cancer outcome in the included studies was identified through cancer registries, death certificates and hospital records, and loss to follow‐up was very low.α‐carotene, β‐carotene, lycopene, and retinol were inversely associated with lung cancer risk. However, because of the lack of data in never smokers, further large scale studies stratified by smoking status are needed to rule out residual confounding by smoking.In conclusion, higher blood concentrations of total carotenoids, None declared.Figure S1. (A) α‐carotene in blood and lung cancer, high versus low. (B) β‐carotene in blood and lung cancer, high versus low.Click here for additional data file.Figure S2. (A) β‐cryptoxanthin in blood and lung cancer, high versus low. (B) Lycopene in blood and lung cancer, high versus low.Click here for additional data file.Figure S3. (A) Lutein and zeaxanthin in blood and lung cancer, high versus low. (B) Retinol in blood and lung cancer, high versus low.Click here for additional data file.Figure S4. (A) β‐carotene in blood and lung cancer, 20 μg/100 mL. (B) Retinol in blood and lung cancer, 70 μg/100 mL , after exclusion of studies in high risk populations.Click here for additional data file.


Background: Approximately 10-14% of the clinically acknowledged pregnancies end with spontaneous abortion at Caucasian population. Possible immunologic causes of recurrent miscarriages have been extensively researched. The change in the cytokines balance synthesis in favor of those synthesized by Th2 cells with an increase of interleukin 6 (IL6) and interleukin10 (IL10) secretion is considered essential for maintaining a normal pregnancy. Objective: The study objective was to establish an association between interleukin 6 and 10 genes polymorphisms and etiology of recurrent pregnancy loss.Materials and Methods: The genetic polymorphism of interleukin 6 and 10 genes were studied by PCR-RFLP in the DNA of 69 women with recurrent pregnancy loss and 64 control women with at least one successful pregnancy and without known pregnancy loss. Statistical analysis was performed using Fisher test and differences were considered statistically significant with a p<0.05.Results: Our results demonstrated a role for -819 C/T but not for -592 C/A IL10, -1082 A/G IL10 and -174G/C IL6 polymorphisms in idiopathic recurrent spontaneous abortion (RSA) in Romanian population. Frequency of genotype -592 CC/-819 CC was higher in the control group than in experimental group (p=0.005). In contrast, genotype -592 AC/-819 CT was more frequent in the experimental group (p=0.05). In this study we have not detected genotype -174 C/C in IL6 gene in patients with spontaneous abortions, nor in the control group.Conclusion: This study demonstrated a possible association between IL-10 -819 C/T promoter polymorphism and idiopathic RSA among Romanian patients. Approximately 10-14% of the clinically acknowledged pregnancies end with spontaneous abortion at Caucasian population. In many of these cases the etiology remains unclear . PreviouSuccessful pregnancy has been demonstrated to be T helper 2 type phenomenons with a decreased T helper 1 activity . PlacentThe first studies on spontaneous recurrent miscarriage associated abnormal immune reactivity in the context of Th1-Th2 paradigm demonstrate in vitro that trophoblast antigens activate lymphocytes to produce embryotoxic cytokines i.e. TNF-α, IFN-γ and IL-2 , 5. TNF-Several studies have analyzed the possible correlations between 3 polymorphisms present at the level of the promoter of the codifying gene for IL10 and the abortion disease, namely polymorphisms -592C/A, -819C/T and -1082A/G. Conclusions varied based on the researched population groups , 12. SpoThis study aims at analyzing polymorphisms in the codifying genes for IL6 and IL10 (polymorphisms controlling the quantity of synthesized cytokines) and the influence of these polymorphisms over the pregnancy evolution at the Romanian population; this is the first study to be conducted in our country .This was a case-control retrospective study and has been performed in Bucharest at Department of Maternal and Fetal Medicine Life Memorial Hospital between 2008-2011. Cases comprised 69 women with two or more recurrent spontaneous abortions of unknown etiology. The control lot comprised 64 volunteer women, with no history of spontaneous abortions and at least one pregnancy carried to term without any complications.Toxoplasma gondii, rubella, cytomegalovirus (CMV), herpes simplex viruses (HSV-1 and HSV-2), varicella zoster virus (VZV) and human immunodeficiency virus (HIV-1 and HIV-2). Transvaginal ultrasound was performed to confirm spontaneous abortion. The study was performed based on an informed consent and was approved by UMF Carol Davila Bucharest Ethics Committee.Exclusion criteria included anatomical abnormalities, previously known systemic disease, endocrine disorders, previous venous or arterial thrombosis or a family history of thromboembolism. Chromosomal abnormalities were ruled out (karyotype) before inclusion in the study. As infection was linked with recurrent spontaneous abortion (RSA), all subjects included were confirmed to be negative for the TORCH agents oC for 2 min and 72oC 1 min and a final extension at 72oC for 10 min.The demographic characteristics of the patients were presented in IL-10 gene polymorphismsGene for interleukin 10 is located on chromosome 1 . GenomicSimilarly, for the -819C/T SNP (rs1800871), DNA was amplified using a common forward primer F:5’GACAACACTAC TAAGGCTCCTTTGGG A3’ and reverse primer R:5’GTGAGCAAACTGAGGCACAGA AAT3’ and for -1082G/A SNP (rs1800896): forward primer F: 5’GACAACACTACTAAGG CTCCTTTGGGA3’ and reverse primer R:5’GT GAGCAAACTGAGGCACAGAAAT 3’. Positive controls were selected by amplifying and sequencing two regions of the IL-10 promoter. A reagent control without DNA served as negative control.IL6 polymorphism Gene for interleukin 6 is located on chromosome 7 . For theStatistical analysisStatistical analysis was performed to determine odd ratio (OR) and 95% confidence intervals (95%CI) associated with recurrent pregnancy loss, using SPSS software . The p<0.05 was considered to be statistically significant.The demographics of the trial persons were indicated in With the exception of the -819C/C genotype, which was lower among patients than controls , and 819C/T genotype which was higher among patients than controls p=0.004; OR=2.95; 95% CI=1.43-6.08) the frequencies of IL-10-592C/A genotypes and 819 TT genotype were comparable between patients and controls . The preThe frequency of the genotypes and allelic frequencies are presented in Frequency of genotype -592 CC  /-819 CC  was higher in control group than experimental group (p=0.005). In contrast, genotype -592 AC (heterozygous) /-819 CT (heterozygous) was more frequent in the experimental group (p=0.05). The frequency of the genotype -819 CC  /-174 GG  was higher in the control lot compared to the experimental lot. By contrast, genotype -819 CT (heterozygous)/-174 GG  was more frequent in the experimental lot compared to the control lot. Genotype -1082AG (heterozygous)/-174 GG  was more frequent in the experimental lot compared to the control lot. Otherwise no statistically significant differences between two lots were registered. For polymorphisms -592 C/A şi -819 C/T allelic frequencies are in concordance with the frequencies reported previously at Caucasian population. For polymorphism -1082 A/G allelic frequencies are discordant with those reported at Caucasian population . For polA successful pregnancy depends on maintaining equilibrium between immunity mediated by Th1 cells and that mediated by Th2 cells . A predoThe etiology of recurrent abortions is heterogeneous , accentuated by the acquired or birth risk factors. In the current study we established a possible correlation between polymorphism -819 C/T in gene IL10 and recurrent abortions. A study conducted in 2006 has shown the correlation between polymorphisms -592 C/A and -819 C/T and early spontaneous abortions; another study performed on the population in Iran, has demonstrated the existence of the correlation only between the polymorphism -592 C/A and recurrent abortions . There wInsofar as its production varies as per the specific polymorphism, the role of IL-10 in RSA pathogenesis remains controversial , 20. It Others claimed that IL-10, absent in the serum of healthy pregnant women, was detected during abortion and labor , 25. TheDuring pregnancy, there is a detectable level of IL6 in maternal serum, that increases at birth 2021), Von Wollf and colleagues found an abnormal expression of IL6 mRNA in endometrium during the mid- secretory phase in women with RPL . Others 21, Von WThe frequency of allele C was 0.06 in the studied lot compared to 0.40-0.45 at the Caucasian population. Allele C has not been identified in position -174 in a study performed on 388 Japanese men and at only one person in a study performed on 259 Chinese men , 24.Taking into account the results obtained in this study, as well as the results of previous studies we may conclude that there is not only one genetic factor, but possibly several that are involved in the abortion disease etiology, as favoring factors , 25. If


SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans.To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter  interactions after adjusting for sex, ancestry proportion scores, civilian trauma exposure, and combat exposure.The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat-exposed veterans. Participants were genotyped for the 5-HTTLPR/rs25531 variants of the OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S’ allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample. In addition, no evidence for combat x 5-HTTLPR effects were observed in either sample.Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (The present study suggests that there may be an association between 5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found. Posttraumatic stress disorder (PTSD) is a complex disorder that develops following exposure to one or more traumatic events . AlthougSLC6A4) with selective-serotonin reuptake inhibitors (SSRIs) . Th. ThSLC6An levels . This van levels , 11]. T. TSLC6A4n levels , 13], , , ,  ma maSLC6A4n levels , and pann levels .A and LG alleles), is functionally triallelic , , , 15], , , 17], , , 19], , , 21]. F. F21]. Fanalyses , [21] foanalyses  did, howanalyses , [21] coThe present research had two primary objectives. Our first objective was to attempt to replicate Wang and colleagues’  finding Participants were recruited through fliers, advertisements and invitational letters to participate in one of several studies that assessed PTSD and collected a genetic sample, including the Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Registry study and several independent trauma research studies conducted through the Durham VA Medical Center. All studies were conducted in compliance with the Declaration of Helsinki and received approval from the Durham VA Institutional Review Board prior to enrolling participants. After written informed consent was obtained, a structured diagnostic interview was administered to participants along with a battery of self-reports.To be eligible for the current analyses, participants had to be: (1) a combat-exposed U.S. veteran, as defined by a score of 1 or higher on the Combat Exposure Scale (CES) ; (2) selPTSD diagnoses were determined using either the Structured Clinical Interview for DSM-IV Disorders (SCID)  or the CAcross studies, interviewers underwent extensive training, resulting in excellent reliability among clinical interviewers (Fleiss’ kappa = 0.94 among 22 interviewers). Interviewers also participated in ongoing supervision and monthly reliability meetings that included doctoral-level supervisors with expertise in the assessment and treatment of PTSD. A “current” diagnosis of PTSD  was used as the primary outcome variable in the current analyses.The CES  is a widThe Traumatic Life Events Questionnaire (TLEQ)  is a 23-A, and LG. We developed a high throughput restriction fragment length polymorphism-based method that allows for determination of both variants  with one assay. The 5-HTTLPR region was amplified by polymerase chain reaction using the oligonucleotide primers: 5'-/FAM/TGGCGTTGCCGCTCTGAATG-3', and 5'-AGGGACTGAGCTGGACAACCA resulting in PCR amplicons of length 528 for the L variant and 486 for the S variant. These fragments were then digested by restriction enzyme HpaII , which cuts at the SNP rs25531 site only if the G allele is present. The digestion results in fragments of length 340bp corresponding to the LA variant, 174bp for LG, and 297bp for the S variant. The digested PCR products were genotyped by size separation of the PCR fragment on the 3730 DNA Analyzer  utilizing the 500LIZ Size Standard from Applied Biosystems. Of the resulting fragments from the digestion, only those from the FAM labeled end of the PCR product can be detected on the 3730. The raw data was examined in GeneMapper to determine the alleles for each sample. The LA allele was detected at 340bp, LG allele at 174bp, and S allele at 297bp. The observed sizes were consistent with the theoretical fragment sizes calculated using HpaII to digest the PCR product.Genomic DNA was extracted from peripheral blood samples via alcohol and salt precipitation using Gentra Systems PUREGENE DNA Purification kit . Genotypes for 5-HTTLPR and rs25531 were combined into a triallelic polymorphism with the following alleles: S, LStatistical analyses were performed using SAS software . We tested for deviation from Hardy-Weinberg equilibrium (HWE) separately in cases and controls and by race/ethnicity group. To reduce the potential effects of population stratification, the NHB and NHW samples were analyzed separately. Principal components analysis (PCA) was run using the smartpca program from the software package EIGENSOFT . Binary SLC6A4 gene showed significant evidence for deviation from Hardy-Weinburg Equilibrium in PTSD cases or controls among either NHB or NHW (p > 0.05). As part of a larger ongoing genome-wide association study of PTSD, samples were genotyped on either the Illumina HumanHap650 Beadchip, Illumina Human1M-Duo Beadchip, or the Illumina HumanOmni2.5 Beadchip . Data from the 1000Genomes project (www.1000genomes.org) was used to impute missing genotypes. PCA was then run on the NHB and NHW samples separately and scree plots were used to determine the appropriate number of principal components (PCs) needed to adequately control for population substructure in each subset. It was determined that three PCs were necessary for both the NHB and NHW subsets. In turn, these PCs were used in the logistic regression models to reduce the potential effects of population stratification.Participant characteristics are provided in OR = 1.502, p = .0025) among NHB veterans, such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S’ allele. As can be seen in p <. 0001) and combat trauma (p <. 0001) also had significant effects on risk for PTSD in the logistic regression model. Only one of the three PCs included in the model had a significant effect (p = .0177). Sex also had a non-significant effect (p = .69) on PTSD risk in the main effects logistic regression model.A significant additive effect was observed for 5-HTTLPR (p = .0025), civilian trauma (p <. 0001), combat trauma (p <. 0001), and PC1 (p = .0247) all continued to have significant main effects on PTSD; however, no other variable in the model, including the 5-HTTLPR x combat exposure interaction term (p = .65), was significant.A second logistic regression model was conducted on the NHB sample to test for potential 5-HTTLPR x combat exposure effects on PTSD status. The results from this model were highly similar to the first. 5-HTTLPR (p = .4671) among NHW veterans. As can be seen in p <. 0001) and combat trauma exposure (p <. 0001).No main effect was observed for 5-HTTLPR (p = .24) nor the 5-HTTLPR x combat exposure interaction term (p = .51) was a significant predictor of PTSD status. Sex (p = .64) and the PCs  also had non-significant effects on PTSD in this model as well. In contrast, both civilian (p <. 0001) and combat trauma (p = .0002) continued to have significant main effects in this model.Similar results were obtained from the second logistic regression model that tested for 5-HTTLPR x combat exposure effects on PTSD. In this model, neither the 5-HTTLPR main effect  the use of a combat-exposed control group with no current or lifetime PTSD, (2) the inclusion of two ethnically diverse groups of veterans, (3) separate analysis of the NHB and NHW samples as well as the use of PCs to help to account for population stratification, and (4) a well-defined clinical phenotype. Limitations of the current study include: (1) a relatively small sample size for psychiatric genetics research (particularly GxE research), (2) the use of DSM-IV  criteria


Although there was no overall association between -1082A/G polymorphism and preeclampsia , such association existed among Asian  and South American  populations in the subgroup analysis stratified by continents.Emerging evidence shows that interleukin (IL)-10 gene polymorphisms can regulate its expression level and thus influence person's susceptibility to preeclampsia. However, various published results were inconsistent. To explore the association between maternal IL-10 gene polymorphisms and preeclampsia, we performed a meta-analysis based upon 11 individual studies here. Our meta-analysis results indicated that IL-10 -819C/T (C  Preeclampsia is a common pregnancy-specific disorder characterized by new-onset hypertension in combination with proteinuria after 20 weeks of gestation . It occuNormal pregnancy entails the shift of Th1/Th2 ratio towards Th2-type reactions ,6. Th1-tInterleukin-10, originally described as a crucial Th2-type cytokine because of its anti-inflammatory actions, plays a pivotal role in pregnancy maintenance and development ,13. It cet al. have pointed out that such association could be subject to ethnicity, no related meta-analysis based upon a specific ethnicity has been reported so far [As polymorphisms in regulatory regions of cytokine genes can influence their expression levels, they may be related to person's predisposition to certain diseases . Given td so far . BesidesA systematic literature search of PubMed, Web of Science and Scopus databases was conducted by two researchers independently for all relevant articles published before March 2014. The research key words included ‘pregnancy induced hypertension’, ‘gestational hypertension’, ‘preeclampsia’, ‘genotype’, ‘SNP’, ‘mutation’, ‘polymorphism’ ‘IL-10’ and ‘interleukin 10’.i) case–control studies or cohort studies focusing on the association between IL-10 polymorphism and preeclampsia; (ii) patients have been clinically diagnosed with preeclampsia and preeclampsia was defined as hypertension (≥140/90 mm Hg on two occasions ≥6 hrs apart) with proteinuria (>300 mg/24 hrs or ≥1+ dipstick in urine sample) after 20 weeks of gestation; (iii) the numbers of patients and normotensive pregnant women with various genotypes were available. The exclusion criteria of the meta-analysis were: (i) animal studies; (ii) meta-analyses, reviews, meeting abstracts or editorial comments; (iii) studies with duplicate data or incomplete data for odds ratio (OR) calculation; (iv) IL-10 polymorphic sites reported only once.Studies included for this meta-analysis should meet the following criteria: , the dominant model (WM+MM versus WW), the recessive model (MM versus WM+WW) and the co-dominant model (WM versus WW+MM) respectively. We calculated the OR and 95% CI for each study as well as the combined OR and corresponding 95% CI for all the included studies. The heterogeneity between individual studies was assessed using chi-squared-based Q-tests with the significance level set at P < 0.1. If the heterogeneity existed among the included studies, we calculated the pooled OR using the random-effect model (the DerSimonian and Laird method). Otherwise, we adopted the fixed-effect model (the Mantel–Haenszel method). The significance of the pooled OR was assessed by Z-test with P < 0.1 considered significant.We used Review Manager 5.2  and Stata  for all the statistical analysis. The association was evaluated with the use of the allelic model  was assessed by Fisher's exact test with We found a total of 375 articles after an initial search from the PubMed, Web of Science and Scopus databases. By reviewing the titles and abstracts, 355 of them were excluded because of no relevance to the association of IL-10 polymorphisms with preeclampsia. After excluding reviews, meta-analyses, studies without sufficient data or replication study, 12 eligible studies were finally included in this meta-analysis ,24,34–41Table Pheterogeneity = 0.002, I2 = 63%). The meta-analysis result showed that IL-10 -1082A/G polymorphism was not associated with the risk of preeclampsia under the allelic model , Europe , South America  and North America groups  than in the whole population  and the South America  subgroups under the allelic model. However, under the allelic model , there was no such association in the Europe  or the North America group  or co-dominant model , the fixed-effect model was used for these two genetic models. The random-effect model was used for the recessive model (GG versus GA+AA) because of the existence of significant heterogeneity . Under the dominant model, the pooled data indicated that the GG and GA phenotypes were linked to the increased risk of preeclampsia among Asian population , recessive  and co-dominant  models because of lack of between-study heterogeneity. Under the dominant model, the pooled data indicated that the GG and GA phenotypes were linked to the decreased risk of preeclampsia among South American population . The meta-analysis results showed that the C allele was associated to the risk of preeclampsia under the allelic model  and existed under the recessive  and co-dominant  models, the fixed-effect model was used for the dominant model and the random-effect model was used for the other two genetic models. Under the dominant model, the CC and CT genotypes were not significantly associated with the risk of preeclampsia . The pooled data demonstrated that the C allele was associated to the risk of preeclampsia under the allelic model  and existed under the recessive  and co-dominant  models, the fixed-effect model was used for the dominant model and the random-effect model was used for the other two genetic models. There was no evidence for any significant association under the dominant , either. Therefore, no evident publication bias existed in this meta-analysis.We used Begg's funnel plot and Egger's linear regression test to evaluate the potential publication bias of the included studies. We did not observe obvious asymmetry of the funnel plot under the allelic model  may result in bias. Further investigation is called upon to determine if these factors affect the results of our meta-analysis.We must admit that there are several limitations in the present study. The total number of the included studies was still relatively small, especially for the meta-analysis of IL-10 -819C/T and -592C/A polymorphisms' association with preeclampsia. The same problem also existed in the subgroup analysis of IL-10 -1082A/G polymorphism's association with preeclampsia stratified by continents. More studies are needed to investigate the role of geographical regions in determining the association between IL-10 -1082A/G polymorphism and preeclampsia. Moreover, other clinical factors like age, gestational weeks and subtypes of preeclampsia (early-onset, late-onset or complicated by other diseases, In conclusion, our meta-analysis results suggested that IL-10 -819C/T and -592C/A polymorphisms were associated with the risk of preeclampsia. Although IL-10 -1082A/G polymorphism had no obvious association with preeclampsia in the overall meta-analysis, it showed association with preeclampsia among Asian and South American populations. However, further studies are essential to validate the association between IL-10 polymorphisms and the risk of preeclampsia.


A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer . No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work . In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms. Colorectal cancer, which includes colon cancer and rectal cancer, is the third most common cancer in men and the second most common in women worldwide . It occuShift work is an important part of some kind of works including transportation, healthcare, and public service. In 2004–2005, the prevalence of shift work was 12.4% among the US female working population and 17.4% in European countries, while the trend was increasing rapidly . RecentlHowever, previous studies investigating the correlation between night shift work and risk of colorectal cancer have illustrated conflicting findings. Some studies have demonstrated a significant correlation –13, otheFigure Among the included articles, 3 were cohort studies –16 and 32 = 77.7%, p < 0.01). Subsequently, the pooled ORs grouped by study design were also calculated. We detected similar result in the case-control group as well , and a significant heterogeneity could not be avoided . On the contrary, no such correlation was found in the cohort group , with a moderate heterogeneity .Figure p < 0.01). However, no significant statistically difference was observed . In the analysis stratified by gender, a significant positive correlation between night shift work and risk of colorectal cancer was observed in both female and male groups . In the analysis stratified by district, night shift work illustrated a significant carcinogenic effect on colorectal cancer in the America , but no such effect was observed in Europe . In the analysis stratified by exposure assessment, a more significant correlation was observed in the self-administered questionnaire group  compared with the interview group . Nevertheless, no such correlation was found in the database group . In the analysis stratified by control factors, a statistically significant correlation was found between night shift work and increased risk of colorectal cancer in both the group adjusted for >3 control factors  and the group adjusted for ≤ 3 control factors . In the analysis stratified by study quality, both low-quality and high-quality group showed that night shift work was associated with high risk of colorectal cancer .In the analysis stratified by the specific type of colorectal cancer, night shift work was potentially associated with an increased risk of colon cancer and rectal cancer with a significant heterogeneity ( p = 0.27).Figure 2 = 77.7%, p < 0.01), the Galbraith plot test was carried out to explore the potential source of heterogeneity from the included studies. However, the result indicated that there was not a specific study could be the major source of heterogeneity . Three possible missing studies were identified by the trim-and-fill test .A dose-response analysis demonstrated that an increase in night shift work of 5 years was associated with an 11% increase in the risk of colorectal cancer in the population. Similar result was observed in a previous meta-analysis regarding the correlation between night shift work and risk of breast cancer, and a 13% increased risk of breast cancer was found by every 500 nights increase of shift work  [2 test were applied to assess the extent of heterogeneity among the included studies. A statistically significant heterogeneity was found among the included studies . Through the Galbraith plot test, we found that there was not a specific study could be the major source of heterogeneity. It meant that every included study contribute to the heterogeneity of this meta-analysis. We further conducted meta-regression analysis to evaluate the possible source of heterogeneity from the variables in every study. We found that type of cancer, gender, region, exposure assessment, study design, control factors, and study quality were identified as the possible sources of heterogeneity. Therefore, subgroup analysis was performed to analyze the possible source of heterogeneity and evaluate that whether such heterogeneity could be avoided. We detected a significant heterogeneity in the case-control group . On the contrary, a moderate heterogeneity was found in the cohort group , which suggested that cohort study should be a better choice in future studies to avoid potential heterogeneity. Furthermore, we found that heterogeneity could be avoided in the group adjusted for >3 control factors  and the high-quality group , indicating that adjusting for more control factors and recruiting high-quality researches were effective ways to avoid heterogeneity.Quantified Q test and ISeveral important molecular signal pathways involving in carcinogenesis are controlled by the circadian timing system . The claLong-term exposure to light-at-night and night shift work could disturb the human normal day-night rhythm and lead to circadian disruption. As a result, the internal pacemaker of the synchronization nuclei would be reset, and the output of melatonin would be suppressed , 27. MelHowever, our study has several limitations. Firstly, the definition of period time regarding night shift did not reach a consensus among different studies. Some of studies defined it as work full time in permanent night shifts for more than 1 year , 12, somIn conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.In order to get an overview on night shift work and risk of colorectal cancer, a comprehensive and systematic searching strategy was conducted. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases. (Scheduling or night shift or shift work),  and  were used as key words to select publications. We evaluated all possible articles by checking titles and abstracts, and those meeting the eligibility criteria were retrieved. In addition, other relevant publications were retrieved by evaluating the references of the included articles or reviews regarding the relationship between night shift work and risk of colorectal cancer. This study was planned and performed in accordance to the quality standards for meta-analysis , 35. A tEvery included articles were assessed that whether the following criteria were met: (1) cohort or case-control study of the possible relationship between night shift work and risk of colorectal cancer; (2) exact data extracted from every study group; (3) articles published before March 2015 written in English or Chinese; (4) results involving odds ratio (OR) or relative risk (RR), or providing sufficient data to calculate them. If the same population was chosen by more than one study, the one with the largest number of cases or the latest research period was qualified for inclusion. Studies with overlapping data or insufficient information were excluded.Information extracted from the studies included name of first author, year of publication, study design, country, sample size, assessment of exposure, adjusted effect estimates for night shift work, and adjusted or matched variables in each study. Considering colorectal cancer is a relatively rare disease, RR was accepted the same as OR. Thus, we used pooled OR to evaluate the possible correlation between night shift work and risk of colorectal cancer. Investigators were divided into two groups to extracted statistics independently from all possibly eligible studies in case of mistakes or omissions. We chose either group discussion or consulting to a third party to resolve any discrepancy.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp) by the two groups of authors. Any disagreement was discussed via re-evaluation of study with a third authorized party. The NOS is an eight-item form which allows for evaluating population selection, study comparability, and exposure. Interpretation of the scale is conducted by marking stars for high-quality elements. The number of stars is summed up and used to evaluate the quality of each study quantitatively. The score scale is 0–9. Score <7 was designated to be low-quality, otherwise to be high-quality study.The quality of each study was assessed via the Newcastle-Ottawa Quality Assessment Scale (NOS) . Moreover, we also carried out the meta-regression analysis and Galbraith plot test to explain the possible sources of heterogeneity [OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer. We used the random-effect model with the DerSimonian and Laird method to provide summarized estimation of the relationship between night shift work and risk of colorectal cancer when heterogeneity was found , otherwi studies , 38, andogeneity . And a rFor dose-response meta-analysis, we retrieved studies that included at least 3 levels of night shift work and supplied exact number of case and control groups in each category. The risk estimates were re-summarized via the method proposed by Greenland and Longnecker and Orsini et al , 41. AddSensitive analysis was performed to assess the effect of one study on the overall result. Cumulative analysis was conducted via ordering studies in accordance to publication year. We used Egger's and Begg's test to evaluate publication bias , 43. BesAll statistical analyses were performed via STATA version 11.


The relationship between ERCC2 polymorphisms and the risk of radiotoxicity remains inconclusive. The aim of our study is to systematically evaluate the association between ERCC2 polymorphisms and the risk of radiotoxicity.Publications were identified through a search of the PubMed and Web of Science databases up to August 15, 2015. The pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the association between ERCC2 polymorphisms and radiotoxicity. Trial sequential analysis (TSA) and power calculation were performed to evaluate the type 1 and type 2 errors.P = 0.01), but this association failed to get the confirmation of TSA.Eleven studies involving 2584 patients were ultimately included in this meta-analysis. Conventional meta-analysis identified a significant association between ERCC2 rs13181 polymorphism and radiotoxicity  contains supplementary material, which is available to authorized users. Radiotherapy is commonly used in cancer treatment. At least half of cancer patients will require radiotherapy with either curative or palliative intent . However‘Radiogenomics’ is the study of genetic variation associated with response to radiotherapy, with a main purpose of establishing single nucleotide polymorphism (SNP) based risk models that can stratify patients according to radio-sensitivity , 7. In tin vitro studies failed to relate the polymorphisms of ERCC2 to DNA repair capacity [ERCC2 protein is an essential component of the general transcription factor TFIIH complex that plays a key role in nucleotide excision repair (NER) and basal transcription –14. Besicapacity , 17–19.Two investigators independently searched the PubMed, and Web of Science databases through a comprehensive search strategy including the terms “SNP”, “ERCC2/XPD”, “radiotherapy” and “toxicity”  was applied [P <0.05 was considered significant for all the analyses except the heterogeneity tests. Meta-analyses were performed using Stata .The pooled OR and 95 % CI were calculated to assess the strength of the association between ERCC2 polymorphisms and the risk of radiotoxicity. Meta-analysis was first performed on each included polymorphism under 3 genetic comparison models: dominant model (mutant homozygote/heterozygote vs. wild type), recessive model (mutant homozygote vs. wild type/heterozygote) and allelic model . Subsequently, subgroup analyses were conducted by adverse effect. The heterogeneity between studies was assessed with the chi-squared based Q-test and atistics , 21. Whe applied ; otherwi applied . Sensiti applied , 25. If  applied . StatistD2) between studies [Trial sequential analysis (TSA) was performed for the analyses involving more than six studies. A two sided α = 0.05, β = 0.2 and a relative risk reduction (RRR) of 10 % were used. A required information size was estimated with the adjustment by diversity  and allelic model  by conventional meta-analysis . No significant association was found with acute skin toxicity  and gastrointestinal toxicity  (Table P = 0.02) .The heterogeneities between studies of all analyses were not significant. The pooled results present stable in the sensitivity analysis Fig. . The stup-value of egger’s test was 0.891, which indicated that no obvious publication bias exists in our meta-analysis of rs13181.The distribution of all the included studies of rs13181 in Begg’s funnel plot was visually symmetrical , and one study made the original significance vanish in leave-one-out sensitivity analysis. In addition, this conventional significance failed to get the confirmation of TSA. We applied TSA with the intention of drawing out more specific conclusions. TSA revealed that the z-curve failed to further cross the α-spending boundary after crossing the conventional boundary of z = −1.96, which means the correlation between rs13181 polymorphism and radiotoxicity risk still need the confirmation of subsequent studies. To safely conclude an effect of OR = 0.71, additional 1400 patients were needed.We performed subgroup analyses by adverse effect. Radiation-induced adverse effects can be classified as early or late effects according to the time before the manifestation of relevant clinical symptoms. Most radiogenomics studies reported early and late effects separately, and some SNPs exert inconformity effect on early and late effects. For instance, the pooled data of XRCC1 revealed that Arg399Gln (rs25487) polymorphism significantly correlated with an elevated risk of early radiotoxicity, while this SNP was ruled out any clinical relevance with late radiotoxicity . Meta-analysis of XRCC3 Thr241Met (rs861539) polymorphism also reported a similar result, that is a significant association with early radiotoxicity rather than late radiotoxicity [For interpreting the pooled result of a meta-analysis, adequate evaluation on the heterogeneity between studies is crucial (as was previously described in detail ). One ofBased on the radiogenomics studies throughout the last decade, it is safe to conclude that no SNP alone possesses the power to accurately predict the radio-sensitivity prior radiotherapy , 31. A sAlthough the minor allele of rs13181 polymorphism was identified with a protect effect against radiotoxicity, it is noteworthy that the correlation was borderline, and one included study made the overall meta-analysis loss the statistical significance in leave-one-out sensitivity analysis. In addition, this significant association identified by traditional meta-analysis failed to get the conformation of TSA. More studies with additional 1400 patients were needed to draw the firm conclusion at the level of OR = 0.71.Additional file 1: Figure S1.Begg’s funnel plot for the meta-analysis of rs13181. Supplementary material: The specific search strategy. (PDF 305 kb)


However, there were no significant associations among polymorphisms and MI for the following genetic models: frequency of the ε3 allele ; ε2ε2 vs. ε3ε3 analysis ; or ε2ε4 vs. ε3ε3 analysis . Our results suggested that the ε4 allele of ApoE is a risk factor for the development of MI and the ε2 allele of ApoE is a protective factor in the development of MI.A number of case-control studies have been conducted to clarify the association between ApoE polymorphisms and myocardial infarction (MI); however, the results are inconsistent. This meta-analysis was performed to clarify this issue using all the available evidence. Searching in PubMed retrieved all eligible articles. A total of 33 studies were included in this meta-analysis, including 18752 MI cases and 18963 controls. The pooled analysis based on all included studies showed that the MI patients had a decreased frequency of the ε2 allele  and an increased frequency of the ε4 allele ; The results also showed a decreased susceptibility of MI in the ε2ε3  Myocardial infarction (MI) is a leading cause of death worldwide, and is a multifactorial disease, influenced by genetic and environmental factors Apolipoprotein E (Apo E) is a serum glycoprotein found in circulating chylomicrons (remnants), very low density lipoproteins, intermediate density lipoproteins and high-density lipoproteins Numerous studies have been conducted to explore the association of this ApoE polymorphism and CHD; some of the studies found a significant association between the ApoE ε4 allele and CHD We searched all published studies in the Pubmed database  using the following combination of keywords: “Apolipoprotein E” OR “ApoE” AND “acute coronary syndrome” OR “myocardial infarction” AND “polymorphism” OR “polymorphisms” OR “variants” OR “variant”. In addition, manual searches for related articles were also performed to avoid missing any relevant studies.The inclusion criteria for identified articles were as follows: 1) Case-control studies with full text articles on the relationship of ApoE polymorphisms and MI; 2) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI). Those not designed as case-control studies, systemic reviews, those not written in English or Chinese, and those that provided no usable data, were excluded.Two authors independently extracted the data from all included studies using a predesigned data extraction table. The following information was extracted from each included article: first author, year of publication, ethnicity and country, source of controls, total numbers of MI cases and controls, distribution of genotypes and alleles in MI cases and controls, and evidence of conforming to the Hardy-Weinberg equilibrium (HWE).2) test and and I2 statistic to assess heterogeneity across studies. A fixed effect model (Mantel–Haenszel) was used in the absence of heterogeneity. Otherwise, the random effect model (DerSimonian–Laird) was adopted. The strength of the association between the ApoE gene polymorphism and MI was assessed by odds ratios (ORs) with the corresponding 95% CI for each study. The ORs and their 95% CIs were assessed for the following seven genetic models: 1) ε2ε2 vs. ε3ε3; 2) ε2ε3 vs. ε3ε3; 3) ε2ε4 vs. ε3ε3; 4) ε3ε4 vs. ε3ε3; 5) ε4ε4 vs. ε3ε3; 6) ε2 vs. ε3; 7) ε4 vs. ε3. The allele frequencies of ε2, ε3 and ε4 were also assessed using the same method. Cumulative meta-analysis was also performed for the above genetic models. Subgroup analysis for ethnicity (Asian and Caucasian) was also performed. To find potential outliers, influence analysis was performed by omitting each study in turn. A funnel plot, calculated using Begg’s and Egger’s tests, was adopted for assessing potential publication bias. Statistical analysis was conducted using STATA statistical software . A P value less than 0.05 was considered statistically significant.We firstly used chi-squared . Fifty-three articles were selected for detailed assessment, which excluded a further 20 articles  and five were not about MI). Finally, 33 studies were included in this meta-analysis, which included 18752 MI cases and 18963 controls. The detailed selection procedure is shown in vs. ε3ε3 analysis , and in the ε2 vs. ε3 analysis , and an increased susceptibility of MI in the ε3ε4 vs. ε3ε3 analysis  in the ε4ε4 vs. ε3ε3 analysis  and in the ε4 vs. ε3 analysis . However, there were no significant associations among polymorphisms and MI for the following genetic models: frequency of ε3 allele ; ε2ε2 vs. ε3ε3 analysis ; ε2ε4 vs. ε3ε3 analysis . The detailed results are shown in Figure S6).The meta-analysis of the included studies showed that there was significant association between the ApoE gene polymorphism and MI. The results showed that the MI patients had a decreased frequency of the ε2 allele ; ε2ε3 vs. ε3ε3 (p = 0.001); ε3ε4 vs. ε3ε3 (p = 0.001); ε4ε4 vs. ε3ε3 (p = 0.04), ε2 vs. ε3 (p = 0.04), ε2 vs. ε3 (p = 0.02) and the ε2 allele frequency (p = 0.001). A random effects model was adopted for these analyses.Significant between-study heterogeneity existed in the analyses of seven genetic models: ε2 ε2 vs. ε3ε3 analysis  and ε2 allele frequency  among Caucasian populations. We also found an increased susceptibility of MI in the ε3ε4 vs. ε3ε3 analysis , ε4ε4 vs. ε3ε3 analysis  and the ε4 allele frequency  among Caucasian populations. Among Asian populations, we also found an increased susceptibility of MI in the ε3ε4 vs. ε3ε3 analysis, ε4ε4 vs. ε3ε3 analysis and for the ε4 allele frequency; the detailed results are shown in Furthermore, we performed subgroup analysis based on ethnicity and found a decreased susceptibility of MI in the ε2ε3 vs. ε3ε3 analysis, ε3ε4 vs. ε3ε3 analysis and ε4ε4 vs. ε3ε3 analysis .We conducted influence analysis to assess the sensitivity of each individual study on the pooled ORs by sequential omission of each individual study. The results suggested that no individual study significantly affected the pooled ORs in the ε2 allele and ε4 allele frequency analysis Figure 5Table S1).Funnel plots examined potential publication bias qualitatively and no obvious asymmetry was observed in any genetic model, as shown in To the best of our knowledge, this is the first meta-analysis to evaluate the association between an ApoE polymorphism and susceptibility of MI. In this meta-analysis, we discovered an increased susceptibility of MI in the ε4 allele frequency analysis. Moreover, the individuals with ε2ε4 genotype, ε3ε4 genotype and ε4ε4 genotype had a significantly higher susceptibility of developing MI compared to those with the ε3ε3 genotype. Therefore, it is reasonable to assume that the ε4 allele of ApoE is an risk factor for the development of MI. These results were consistent with a previous meta-analysis, which showed that ε4 allele of ApoE is a risk factor for the development of CHD ApoE is a multifunctional protein that plays an important role in the metabolism of cholesterol and triglycerides, by binding to its receptors to help mediate clearance of chylomicron and remnant particles Although the primary results of this meta-analysis are suggestive, some limitations still exist. First, between-study heterogeneity existed in some of the genetic model analysis, which may have affected the results of the present meta-analysis, although a random effects model was adopted for these analyses. Second, publication bias may have occurred because our analyses were based wholly on published studies only in English and Chinese. Third, the results of this meta-analysis were based on unadjusted estimates because of the lack of adjusted estimates. Currently, some risk factors have been identified for MI, such as hypertension, hypercholesterolemia, diabetes, obesity and smoking. A more precise analysis should be performed if these data could be extracted from primary articles.In conclusion, this comprehensive meta-analysis has evaluated all published data currently available on the association between the ApoE polymorphism and MI. Our meta-analysis suggested that the ε4 allele of ApoE is an risk factor for the development of MI and the ε2 allele of ApoE is a protective factor in the development of MI. This may be explained by the fact that ε4 allele of ApoE elevates the plasma levels of total and low-density lipoprotein cholesterol while the ε2 allele of ApoE lowers the circulating cholesterol levels. Further studies with larger sample sizes are warranted among Asian populations.Figure S1Forest plot for ApoE gene polymorphism and MI risk in the genetic model of ε2ε3 vs. ε3ε3 analysis.(TIF)Click here for additional data file.Figure S2Forest plot for ApoE gene polymorphism and MI risk in the genetic model of ε3ε4 vs. ε3ε3 analysis.(TIF)Click here for additional data file.Figure S3Forest plot for ApoE gene polymorphism and MI risk in the genetic model of ε4ε4 vs. ε3ε3 analysis.(TIF)Click here for additional data file.Figure S4Forest plot for ApoE gene polymorphism and MI risk in the genetic model of ε2 vs. ε3 analysis.(TIF)Click here for additional data file.Figure S5Forest plot for ApoE gene polymorphism and MI risk in the genetic model of ε4 vs. ε3 analysis.(TIF)Click here for additional data file.Figure S6Cumulative meta-analysis of ApoE gene polymorphism and MI risk: A) ε2ε3 vs. ε3ε3 analysis; B) ε3ε4 vs. ε3ε3 analysi; C) ε4ε4 vs. ε3ε3 analysis.(TIF)Click here for additional data file.Figure S7Influence analysis of ApoE gene polymorphism and MI risk: A) ε2ε3 vs. ε3ε3 analysis; B) ε3ε4 vs. ε3ε3 analysi; C) ε4ε4 vs. ε3ε3 analysis.(TIF)Click here for additional data file.Table S1Results of Egger’s and Begger’s test.(XLS)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.