CYP2E1 encodes an enzyme that participates in the activation of several carcinogenic substances. Thus, numerous studies have investigated the association between CYP2E1 polymorphisms and colorectal cancer (CRC) risk, but inconclusive results have been obtained. We performed a meta-analysis to precisely evaluate the relationship of CYP2E1 rs2031920, rs3813867, and rs6413432 polymorphisms with the susceptibility to CRC. Scopus, Web of Science and PubMed databases were searched to identify eligible studies, and the association between the polymorphisms and CRC risk was then quantitatively synthesized using different genetic models. Eighteen studies with 23,598 subjects were selected for inclusion into the analysis. Significant association between rs2031920 and an increased CRC risk was observed in homozygous , recessive  and allele  models. Significant association was not found for rs3813867 and rs6413432 (P > 0.05). In conclusion, our results suggest that rs2031920, but not rs3813867 and rs6413432, is associated with the risk of CRC. In 2020 alone, nearly two million new CRC cases and one million CRC-related deaths were reported2. Age is a well-established risk factor for CRC along with other environmental risk factors such as physical inactivity, obesity, high intake of red, low intake of fiber, tobacco smoking, and alcohol consumption4. In addition, genetics has unequivocally been implicated as a key determinant in the development of CRC5. Polymorphisms in cancer-related genes may therefore influence interindividual susceptibility to CRC6.Colorectal cancer (CRC) is one of the most common cancers worldwide and is associated with significant morbidity and mortalityCYP2E1 encodes cytochrome P450 2E1 (CYP2E1), a phase I enzyme involved in the process of xenobiotic metabolism. CYP2E1 plays a key role in the conversion of xenobiotics into several highly reactive intermediate metabolites prior to their elimination by phase II enzymes7. For example, it is known to activate low-molecular-weight procarcinogens such as nitrosamines into active carcinogens directly involved in digestive tract oncogenesis. Consequently, higher CYP2E1 activity has been associated with higher rates of cancer progression8. The CYP2E1 gene contains more than ten well-characterized single nucleotide polymorphisms (SNPs) that may influence the activity of the enzyme and thus cancer risk9. The most commonly studied polymorphisms in CRC include rs3813867  and rs2031920  in the 5’-flanking regions of the gene, as well as rs6413432  in intron 6. These polymorphisms are known to have functional effects on cells. In particular, rs2031920 and rs3813867 have been associated with increased transcriptional and enzymatic activity of the gene. In addition, increased transcriptional activity of the CYP2E1 gene has been discovered in association with rs6413432, which is also associated with DNA single-strand breaks known to lead to cancer10. This is one of the reasons why we focused on these three polymorphisms in this study.11. However, there were also studies showing a lack of association between the same polymorphisms and the risk of CRC13. Likewise, for rs2031920, while Silva et al.14 showed that individuals carrying the variant allele had an increased risk of developing CRC, Kury et al.15 found no association between the polymorphism and the risk of CRC. Similar discrepancies were also noted for rs641343219. These inconsistencies between the studies may be attributed to the small sample size of each study and the different genetic backgrounds and lifestyles of study participants from different populations. Meta-analysis can be used to resolve these inconsistencies. However, the last meta-analyses focusing on these three polymorphisms was published almost 9 years ago21 and new studies in this area have recently been added, which may lead to a different study result. This is another reason why we focus on these three polymorphisms. Therefore, in this work, a meta-analysis was conducted to obtain a more precise estimate of the association between CYP2E1 rs3813867, rs2031920, and rs6413432 polymorphisms and CRC risk.In addition, although these polymorphisms are frequently studied, the association between these polymorphisms and the risk of CRC remains inconclusive. For example, a study in the Hungarian population showed that the variant allele of rs3813867 was positively associated with an increased risk of CRCCYP2E1 polymorphisms, were case-only studies, or did not contain useful information (N = 34); (ii) they were review articles (N = 23); (iii) the cases included patients with benign tumors such as adenomas (N = 3); (iv) they did not contain individual data for the rs3813867 and rs2031920 polymorphisms (N = 2); (v) study participants overlapped in more than one study (N = 1). Finally, 18 studies comprising a total of 10,302 cases and 13,296 controls were included in this meta-analysis.The flow diagram of the study selection process is shown in Fig. 23 and the rest were in English. Seven studies were conducted on Asians27, seven studies were conducted on Caucasians29, and the remaining four studies included participants of other descendants such as Brazilians, Saudi Arabians or mixed ethnicities30. The most commonly used method for genotyping the polymorphisms was polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP), while a few studies used Taqman or microarray-based approaches. For the rs6413432 polymorphism, the distribution of genotypes in controls was consistent with HWE in all the included studies. For rs2031920, however, the genotype distribution deviated significantly from HWE in three studies30. For rs3813867, only one study reported a significant deviation from the HWE22. All of the studies had high methodological quality  except for two studies30. The star ratings of the included studies are shown in Table The characteristics of the included studies are shown in Table CYP2E1 rs2031920 polymorphism with CRC risk are shown in Table P = 0.001), recessive , and allele models  , recessive , and allele models , an observation consistent with the overall analysis , recessive  and allele models  in the high quality studies. On the other hand, no significant association between rs2031920 and the risk of CRC was observed in the low quality studies under all five genetic models   are shown in Table CYP2E1 rs6413432 polymorphism with susceptibility to CRC is shown in Table P = 0.429); heterozygous model ; dominant model ; recessive model ; allele model  . However, for the heterozygous model, omitting.18and Kiss et al.11, respectively (Supplementary Information online). Indeed, the omission of Fernandes et al.18 also significantly altered the results of the homozygous and recessive models of rs6413432 (Supplementary Information online). For all other genetic models, the results did not change when any of the studies was omitted.For rs3813867, the result for the homozygous model was also unstable for the same reason. However, for the heterozygous and recessive models, the results appeared to be largely driven by Fernandes et alP > 0.05 for both Begg’s and Egger’s tests). However, both tests revealed a significant publication bias in the heterozygous  and dominant models . Apart from this, no publication bias was observed in the homozygous and recessive models in Begg’s test but appeared to be significant in Egger’s test . ‘Trim and fill’ analysis was performed for all four genetic models that showed significant publication bias in at least one of the tests. The homozygous, heterozygous, dominant, and recessive models were found to have four, three, five, and four missing studies, respectively. However, imputation of these missing studies did not significantly change the results .The presence of publication bias was examined using Begg’s and Egger’s tests and visually verified using funnel plots Figs. , 6, 7. FP = 0.624, Egger’s test P = 0.141; heterozygous, Begg’s test P = 0.083, Egger’s test P = 0.541; dominant, Begg’s test P = 0.138, Egger’s test P = 0.306). Similarly, no publication bias was detected for rs6413432 .For the rs3813867 polymorphism, no significant publication bias was detected by both the Begg’s and Egger’s tests  even in the absence of a substrate33. Excessive levels of the ROS accelerate cancer development by acting on messengers in intracellular signaling pathways, leading to activation of lipid peroxidation, DNA damage, and carcinogenesis34. For these reasons, CYP2E1 is one of the most intensively studied cytochrome genes in cancer35.CYP2E1 that can potentially affect the function of the gene. These include the rs2031920 and rs3813867 polymorphisms, which are located in the 5'-regulatory region of CYP2E1, as well as the rs6413432 polymorphism, which is located in intron 6 of the gene36. The rs2031920 polymorphism has been associated with higher transcriptional and enzymatic activity due to the replacement of cytosine with thymine at position 1,019 of the gene37. Meanwhile, the rs3813867 polymorphism of CYP2E1 results from the substitution of guanine with cytosine at the 1259th position, whereas rs6413432 involves a substitution of thymine with adenine at the 7678th position of the gene38. These substitutions may lead to altered binding affinity of transcription factors and other regulatory elements, causing changes in the amount of protein product and subsequently the risk of cancer39.Over the decades, several studies have focused on a few important polymorphisms of CYP2E1 polymorphisms and CRC risk remains inconclusive, as conflicting results have been reported in different studies. These conflicting results can be attributed to numerous factors, including the sample size of individual studies, ethnicity of study participants, geographical variations, as well as environmental factors such as dietary habits5. To address these discrepancies, we conducted a systematic review and meta-analysis to combine the results of previous studies, in order to yield a more accurate estimation on the association between CYP2E1 polymorphisms and CRC risk. In contrast to a pooled analysis, a meta-analysis considers the characteristics of individual studies and weighs them appropriately based on well-accepted statistical parameters, such as sample size, before combining them, thereby reducing the potential for erroneous conclusions40. We demonstrated a statistically significant association of the CYP2E1 rs2031920 polymorphism with CRC risk under the homozygous , recessive  and allele  models. This observation may be attributed to the location of the polymorphism, which falls within the transcriptional regulatory region of CYP2E1. Therefore, the nucleotide substitution of this polymorphism could affect the binding of transcription factors to the 5'-flanking region of CYP2E1, thereby altering its mRNA expression levels41. The positive association between rs2031920 polymorphism and cancer susceptibility has also been studied in tumor types other than CRC, including cancers of the head and neck43, esophagus41, lung44, stomach45, urological organs46, and urinary tract47. However, there were also a few studies suggesting the opposite association, whereby the rs2031920 polymorphism may serve as a protective factor as in the case of nasopharyngeal cancer in the Tunisia populations48 and bladder cancer in Asians49. These observations suggest that the distribution of allele or genotype frequency varies in different populations and association may be different between cancer types. Therefore, we stratified our meta-analysis by ethnicity to gain better insight into the impact of ethnic diversity on the association of these polymorphisms with the risk of CRC. That being said, subgroup analyses revealed slight differences in risk association between Asians and Caucasians. This could be explained by the higher allele frequency of the rs2031920 c2 allele in the Asian population compared to the Caucasian population, which is consistent with the observation of Wang et al.9 that different ethnic groups generally have not only differences in the living environment, dietary habits, and genetic backgrounds, but also in the frequency distribution of CYP2E1 genotypes.Despite being extensively investigated, the association between 12, Spain13 and Brazil8. In contrast, a significant association was found in the study by Kiss et al.11, whereas other studies by Kury et al.15 and Kim et al.25 found a positive association between the polymorphism and CRC risk only in individuals who regularly consumed red meat. These discrepancies highlight the possible existence of gene–gene or gene-environment interactions in influencing the effects of genetic polymorphisms on CRC risk51.The results of this meta-analysis suggested that there was no significant association of the rs3813867 polymorphism with susceptibility to CRC under all genetic models examined. Our finding was in agreement with previous studies that also found no association with CRC risk in study samples from Australia.29, in Saudi Arabians by Saeed et al.19, and in Malaysians by Chong et al.17. In other cancers, several previous studies also supported our findings, showing a non-significant association between the rs6413432 polymorphism and susceptibility to urinary cancer47 and gastric cancer52. In contrast to the aforementioned rs2031920 polymorphism, the functional effect of rs6413432 has not been conclusively proven, but it is thought to enhance transcriptional activity and affect CYP2E1 expression and the catalytic activity of the encoded enzyme53. Nevertheless, further studies are needed to increase statistical power to detect and confirm even the slightest effect of the rs6413432 polymorphism on the risk of CRC54.Similarly, no significant association was observed between rs6413432 polymorphism and CRC risk in our study, which is consistent with studies in other populations, such as in Lebanese by Darazy et al.20 and Jiang et al.21. However, because more studies were used  for analysis in the present work, our study power is higher and the risk estimate is therefore more reliable. In addition, the meta-analysis by Jiang et al.21 was limited to participants from Western populations only, and no study represented the Asian population. Thus, the results of our study are more representative of the global population. This, together with the inclusion of recent studies in this area of research, allows us to present the most up-to-date summary and assessment of the associations between the three CYP2E1 polymorphisms and the risk of CRC. Apart from that, unlike the previous meta-analyses by Jiang et al.21 and Peng et al.20, the current meta-analysis used Scopus as one of the databases to search for relevant articles. In general, Scopus includes a wider range of journals and also contains more articles than the Web of Science55, allowing more relevant studies to be identified and included in the analysis. We also performed an additional stratified analysis based on study quality using the Newcastle–Ottawa scale to provide a comprehensive picture of the evidence based on all included studies. These are the strengths of the present work.The results of our meta-analysis were consistent with previous meta-analyses by Peng et al62. The reproducibility of the study results  suggests that the study result was not likely due to chance alone. Although positive results from a single gene cannot usually be translated into clinical practice, knowledge of which low penetrance polymorphisms might influence the risk of CRC may shed light on which genetic pathways to focus on in designing a genetic screening panel in the future, which can undoubtedly contribute to a more individualized approach to medicine63.However, there are also several limitations that need to be acknowledged in the present study. For instance, the modest number of included studies might still be insufficient to find a significant association between the rs3813867 and rs6413432 polymorphisms and the risk of CRC, although the power to detect a significant association was improved by this meta-analysis. In addition, there is a lack of ethnic diversity as there were no data on African populations in these eighteen studies, which focused mainly on Asians and Caucasians. Another limitation is the concern for the occurrence of publication bias, as only published studies were included. Nevertheless, imputation using the ‘trim-and-fill’ analysis showed that the results are unlikely to change even in the absence of publication bias. Finally, gene–gene or gene-environment interactions, which are known to also contribute to the risk of CRC, were not examined in the present work because of the lack of information in the included studies. However, the lack of gene–gene or gene-environment studies does not change the fact that a single gene can influence the risk of CRC, albeit modestly, as has been demonstrated in many other studiesCYP2E1 rs2031920 polymorphism is associated with the risk of CRC. Although the rs3813867 and rs6413432 polymorphisms were not associated with the risk of CRC, subgroup analyses revealed some differences in the risk of association between Asians and Caucasians, and between high- and low-quality studies. Finally, in view of the limitations mentioned above, further studies with a better overall design are needed to verify the true association between CYP2E1 polymorphisms and CRC risk.In conclusion, the results of this meta-analysis suggest that the CYP2E1 gene polymorphisms and CRC risk; (2) case–control studies in design; and (3) contained sufficient data to estimate an odds ratio (OR) and its 95% confidence interval (CI). Non-research articles and studies conducted in non-human subjects were excluded. If more than one article was published by the same authors with the same or overlapping subjects, the study with the largest sample size or the most recent data was selected. References of eligible studies and relevant review articles were also screened to identify additional studies. The review was not prospectively registered.A literature search was performed in PubMed, Web of Science and Scopus databases up to February 24, 2022. The following keywords were used: “CYP2E1” AND “polymorphism” AND “colorectal cancer”. No language restriction was set. Studies were included if they met the following criteria: (1) examined the association between p-value was not reported, it was calculated using a Pearson’s χ2 test. All extracted information was recorded in an Excel spreadsheet.The following information was extracted from each included study: first author’s name, year of publication, ethnicity , country, total number of cases and controls, allele and genotype frequencies, genotyping methods, and deviation from Hardy–Weinberg equilibrium (HWE). When the HWE 64. Studies that received ≥ 5 stars were considered to be of high quality. The strength of association between the CYP2E1 polymorphisms and CRC risk was assessed using the odds ratio (OR) and the corresponding 95% confidence interval (CI). Statistical significance of the pooled ORs was determined using the Z-test, and a P < 0.05 was considered statistically significant. In addition, heterogeneity among the studies was assessed using Cochran’s Q statistic test and the I2 statistic to quantify the proportion of total variation due to heterogeneity. An I2 value ≥ 50% was considered as having significant statistical heterogeneity, for which a random-effects model (the DerSimonian–Laird method) was used to calculate the pooled OR. Meanwhile, when heterogeneity was low, the fixed-effects model (Mantel–Haenszel method) was used to calculate the pooled OR. Sensitivity analysis was also performed to assess the robustness of the results. In addition, subgroup analyses were performed according to the ethnicity of the participants and the methodological quality of the studies. To assess the presence of publication bias among the included studies, Begg’s funnel plot and Egger’s linear regression tests were performed. If publication bias was identified, a ‘trim and fill’ analysis was performed to detect missing studies. All analyses were performed using STATA software, version 14.0 .The quality of the included studies was assessed by two investigators using the Modified Newcastle–Ottawa Scale for Case–Control Studies of Genetic AssociationSupplementary Information.


Immune-mediated inflammatory diseases (IMIDs) have been associated with an increased risk of venous thromboembolism (VTE) in multiple observational studies. However, a direct causally relation between IMIDs and VTE remains unclear to date. Here, we used Mendelian randomization (MR) analysis to investigate causal associations between IMIDs and VTE.We collected genetic data from published genome-wide association studies (GWAS) for six common IMIDs, specifically inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriasis (PSO), and systemic lupus erythematosus (SLE); and summary-level data for VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) from the FinnGen database. Two-sample MR analysis using inverse variance weighting (IVW) was performed to identify causal associations between IMIDs and VTE/DVT/PE, and sensitivity analyses were implemented for robustness.IVW analysis showed a causal relationship between genetically predicted UC (one type of IBD) and the risk of VTE  and DVT , but we found no evidence of causality between UC and PE . In addition, no associations were observed between total IBD, CD, RA, SLE, or PSO and VTE/DVT/PE. Sensitivity analysis found no evidence for horizontal pleiotropy.This MR study provides new genetic evidence for the causal relationship between IMIDs and the risk of VTE. Our findings highlight the importance of active intervention and monitoring to mitigate VTE risk in patients with IBD, in particular those presenting with UC. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), affects ~10 million people worldwide every year, representing the third most common cardiovascular disease globally . The 30-The formation of venous thrombosis involves a complex pathophysiological process that is triggered by the interaction of multiple risk factors. An increasing number of studies suggest that inflammation is closely associated with VTE . SpecifiImmune-mediated inflammatory diseases (IMIDs) comprise a wide range of conditions, such as inflammatory bowel disease , rheumatoid arthritis (RA), skin inflammation , and connective tissue disease  –11. ReceDespite proposing the existence of a relationship between IMIDs and VTE, most of these studies were limited by observational designs and small sample sizes that hamper effective causal inferences and can be easily affected by several confounding factors. In contrast, Mendelian randomization (MR) analysis is an emerging method in epidemiological research that uses genetic variants as instrumental variables (IVs) to help assess the causal effects of exposure factors on outcomes while minimizing the impact of confounding factors and reverse causation .The availability of large-scale genome-wide association studies (GWAS) on IMIDs and cardiovascular disease made it possible to implement MR analysis to investigate the relationship between various diseases. For example, Gao et al.  establisvia exposure  and IMIDs . Multiple single-nucleotide polymorphisms (SNP) representing global human genetic variation were selected as instrumental variables (IVs). Three key hypotheses of classical MR analysis were adopted, as follows Figure 1exposure .https://r7.finngen.fi/)  . The corhttps://gwas.mrcieu.ac.uk/). SNPs associated with IBD were obtained from a GWAS study involving 25,042 patients and 34,915 controls, which were further subdivided into secondary outcomes of either UC  or CD  . Finally, summary statistics for SLE were derived from a GWAS including 5,201 cases and 9,066 controls (We retrieved the summary IMIDs GWAS dataset from the IEU OpenGWAS Database Project (ontrols) . The sump < 5.0 × 10-8 were selected as potential IVs. To ensure independence between the genetic variants used as IVs, we set the linkage disequilibrium (LD) threshold for grouping to r2 < 0.001 and a window size of 1000 kb. The SNP showing the lowest p-value at each locus was retained for analyses. The software PhenoScanner (SNPs associated with each IMID at the genome-wide significance threshold oScanner  was used2) and F-statistics were used to estimate the strength of the selected IVs ×MAF×β2 . The F-statistic was calculated as follows: F=R2(N-K-1)/[K(1-R2)], where R2 refers to the portion of exposure variance explained by the IVs, N represents the effective sample size, and K represents the number of variants included in the IV model. An F-statistic >10 indicates a strong correlation between the IVs and exposure (Variance (Rcted IVs . R2 was exposure .The “TwoSampleMR” and “MR-PRESSO” packages of the R software (version 4.13) were used to perform MR analysis. We used multiple MR methods to infer causal relationships between a total of six IMIDs and three VTE phenotypes, including inverse variance weighting (IVW) , median Each method makes different assumptions on the validity of IVs, but the IVW method is generally regarded as the most reliable, so in this study, IVW was used as the primary method to identify the causal relationship between exposure and outcome, while the other methods were used as complementary or to provide other information. IVW is essentially a meta-analysis method combining cumulative causal estimates of Wald ratios for each IV, while MR-PRESSO can automatically detect and remove outliers in IVW linear regression to provide corrected MR estimates .The Cochrane’s Q test was used to assess the heterogeneity of selected SNPs (P< 0.05), in which case the random effects IVW test was used to provide more conservative and robust estimates. Funnel plots were generated using the mr_funnel_plot function for visualizing the heterogeneity of IVs. In addition, directional pleiotropy was assessed and corrected based on the intercept obtained from the MR-Egger regression model analysis. Finally, we performed a leave-one-out sensitivity analysis to test whether the stability of the results was affected by a single SNP and generated a forest plot to illustrate the results.SNPs associated with IMIDs were selected as IVs based on established quality control criteria . The F-statistics of the vast majority of these SNPs were above the threshold of 10, which indicated that they strongly represent IMIDs in the MR analysis. The detailed characteristics of these IVs are displayed in p = 0.004) and DVT . The MR-Egger regression, Weighted median, and MR-PRESSO analyses showed that the IVW association pattern remained directionally consistent in most statistical models, demonstrating the robustness of the inferred causal relationships between UC and VTE/DVT (p = 0.055) , RA, SLE, and PSO; with VTE, DVT and PE. This allowed us to test a total of 18 causality pairs, of which two were statistically significant. As shown in Otherwise, there was no evidence of a causal relationship between UC and PE , IBD and VTE , IBD and PE , CD and VTE , CD and DVT , CD and PE , RA and VTE , RA and DVT , RA and PE , SLE and VTE , SLE and DVT , SLE and PE , PSO and VTE , PSO and DVT , PSO and PE  in the IVW analysis results (p > 0.05)  Table 2.The association between inflammatory diseases and the risk of venous thromboembolism has received increasing attention from the scientific community , 12, 33,IMIDs constitute a diverse and pervasive spectrum of diseases driven by immune and genetic pathways and characterized by alterations in the cellular homeostasis of the body . In addiIn this study, we showed a causal relationship between genetically predicted UC and VTE/DVT, as well as an elevated DVT risk in total IBD. Previous observational studies reported an increased risk of thrombosis in IBD patients , in accoThe IBD GWAS dataset used in this study combines UC and CD, whereby we performed separate MR analyses on total IBD, UC, and CD. Unlike previous studies which reported that the risk of VTE was increased in both CD and UC patients –37, the Our separate PE and DVT analyses showed that genetically predicted UC was causally associated with DVT only, despite evidence for increased risk for both DVT and PE in IBD patients (DVT risk is nearly twice that of PE) , 39. SinWhile previous controversial associations were found for other common IMIDs  and VTE/PE/DVT risk, such relationships were not apparent in our study. Galloway et al. reported an increased risk of VTE in RA patients compared to matched controls , but found no evidence for an association between psoriasis and VTE risk  . SimilarDespite extensive evidence from observational studies on the relationship between IMIDs and VTE risk, these approaches have obvious limitations and confounding factors, such as an inability to evaluate causal relationships between exposure and outcome. In addition, with glucocorticoids, immunosuppressants, and antithrombotic drugs widely used in the treatment of IMIDs, the role of these drugs in promoting or inhibiting thrombosis has become an important confounder in determining the relationship between IMIDs and the risk of VTE . For exaOur study is the first MR analysis to explore potential causal relationships between multiple IMIDs diseases  and VTE risk (including DVT and PE). When compared to previous observational studies, our MR design circumvents traditional confounding factors and problems associated with reverse causation. Moreover, we tested these relationships on populations with the same ethnicity using large-scale GWAS data, which provides strong and reliable IVs and strengthens inferences of causality that were confirmed by sensitivity analyses. However, a lack of demographic data  in the original study hampered further subgroup analyses. In addition, MR analyses were not performed in disease subcategories – for example, psoriasis included psoriasis-associated arthritis, which was not evaluated separately for an association with VTE risk. Due to the small number of available GWAS for our study subjects, we were unable to perform multi-database validation. Finally, it should be noted that GWAS data was used for people of European ancestry, whereby extrapolations to other ethnic groups are limited.This MR study provides new genetic evidence for the relationship between IMIDs and VTE risk. We found the existence of a causal association between UC and VTE/DVT risk, but no evidence for causal associations with other IMIDs, including CD, RA, SLE, and PSO. Our findings highlight the importance of active intervention and monitoring to mitigate VTE risk in patients with IBD, especially those presenting with ulcerative colitis. Future longitudinal clinical studies and experimental analyses are needed to confirm our findings.The original contributions presented in the study are included in the article/JW designed, guided, and funded the study. XL conducted most of the MR analysis and draft of the manuscript. XG draft the manuscript and prepare the figure and Table. JL, QN and YD conducted data acquisition and provided technical support. XF, ZY and PL critically revised the manuscript. All authors contributed to the article and approved the submitted version.


The present systematic review and meta-analysis aimed to ascertain if the circulating levels of apelin, as an important regulator of the cardiovascular homeostasis, differ in patients with cardiovascular diseases (CVDs) and controls.A comprehensive search was performed in electronic databases including PubMed, Scopus, EMBASE, and Web of Science to identify the studies addressing apelin in CVD up to April 5, 2021. Due to the presence of different units to measure the circulating levels of apelin across the included studies, they expressed the standardized mean difference (SMD) and their 95% confidence interval (CI) as summary effect size. A random-effects model comprising DerSimonian and Laird method was used to pool SMDs.2 = 97.3%, P<0.001). New combined biomarkers showed a significant decrease in SMD of apelin/high-density lipoprotein cholesterol (apelin/HDL-C) ratio , apelin/low-density lipoprotein cholesterol (apelin/LDL-C) ratio  and apelin/total cholesterol (apelin/TC) ratio . However, no significant differences were found in the SMD of apelin/triacylglycerol (apelin/TG) ratio in cases with CVDs compared to the control group .Twenty-four articles (30 studies) comprised of 1793 cases and 1416 controls were included. Pooled results obtained through random-effects model indicated that apelin concentrations in the cases’ blood samples were significantly lower than those of the control groups (SMD = -0.72, 95% CI: -1.25, -0.18, P = 0.009; IThe association of apelin with CVDs is different based on the region and disease subtypes. These findings account for the possible usefulness of apelin as an additional biomarker in the diagnosis of CVD in diabetic patients and in the diagnosis of patients with CAD. Moreover, apelin/HDL-c, apelin/LDL-c, and apelin/TC ratios could be offered as diagnostic markers for CVD. Cardiovascular diseases (CVDs) are one of the main life-threatening diseases with high prevalence , 2. GlobAlthough previouse reports confirm that apelin is involved in cardiovascular function, there is controversy about its causative association with CVDs . In addiPRISMA guideline  was used to design and perform the current meta-analysis  11]. Mo. Mo11]. Two independent authors (MH-B and SS) performed a comprehensive search to identify the relevant published English language studies through inception up to April 5, 2021. The controversies were checked by a third expert person (MN). Electronic databases including PubMed, Scopus, EMBASE, and Web of Science were searched by using the following MeSH  terms and text keywords: (Apelin) AND . We also conducted a manual search in the reference list’s included articles and pervious relevant reviews to increase the sensitivity of searches to find additional articles. Pubmed search strategy is presented in Supp 2. a in English published articles that met the inclusion criteria were selected. Inclusion criteria were as follows: original observational studies including cross-sectional, case-control, and clinical cohort studies; and studies providing detailed information regarding blood circulating levels of apelin in patients diagnosed with heart diseases such as coronary artery disease (CAD), myocardial infarction (MI), congenital heart disease (CHD), congestive heart failure (CHF), heart failure (HF), atrial fibrillation (AF), ischemic heart disease (IHD), hypertensive heart disease (HHD) and controls (participants without heart diseases and other chronic/metabolic diseases). Studies were also excluded if they investigated animal models, using animal models, tissue-based cultures, cell cultures, and mRNA expression; and case reports, conference abstracts, comments, review articles, editorials, and articles without insufficient data. The title and the abstract of each article were reviewed by two independent investigators (FM and HA). Following this initial screening step, potential articles were included in our full-text review process. Any existing discrepancies were resolved by consensus or consultation with a third author (AM).Following the identification of eligible studies, data extraction was done by three individual authors  using pre-designed data collection sheets in Excel. The first author’s name, publication year, geographical region, age, study design, study sample size, and apelin concentration in CVD patients and controls (means ± standard deviation (SD)) were collected. The quality of the study was evaluated using the Newcastle-Ottawa Quality Assessment Scale (NOS) , which iapelin2 / meanHDL2) × [(SDapelin2 / meanapelin2)– 2 (R× SDapelin × SDHDL / meanapelin × meanHDL) + (SDHDL2 / meanHDL2)]  , 14. TheanHDL2)] , 16. The < 0.05) . Subgrou2 = 97.3%, P<0.001). Findings of new combined markers demonstrated a significant decrease in SMD of apelin/HDL-c ratio , apelin/LDL-c ratio  and apelin/TC ratio . However, no significant differences were found in the SMD of the apelin/TG ratio in cases with CVDs compared to the control group . Forest plots that indicated the pooled SMD and each study on the apelin and new combined markers concentrations between cases and controls are shown in Based on the 30 selected studies, the meta-analysis finding indicated that the blood apelin concentrations among cases were significantly lower than those of the control groups  levels. The visual-filled funnel plots and Egger’s test were used to evaluate the potential publication bias across the included studies as shown in Supp 2. b in CVDs are the leading global cause of death worldwide. As highly prevalent diseases, the early detection and cure of CVDs is a critical issue , 6. In oApelin, an endogenous peptide ligand of the 7-transmembrane G-protein, coupled with its receptor (APJ), is a strong inotrope and vasodilator , 43. ApeThe findings obtained from the present study showed that the circulating levels of apelin in patients with CVD were significantly lower than those in the controls. Subgroup analyses based on medical comorbidities of diabetes/MetS revealed that apelin levels were significantly lower in CVD patients without diabetes and MetS than in the controls. Apelin synthesis in adipocytes is stimulated by insulin and its plasma levels are demonstrated to increase in relation to diabetes mellitus, IR, and hyperinsulinemia . FurtherDespite a number of unresolved questions, it appears that apelin has significant therapeutic potential. The observed cardiovascular roles of apelin suggest that this peptide could be considered a potential candidate for addition to the standard therapy of CVDs.It should be noted that this meta-analysis had strengths and limitations that must be taken into account. As the first comprehensive meta-analysis, the present study ascertained the association between apelin and CVDs. Publication bias was not detected in our study. Subgroup analysis was performed to identify the possible sources of heterogeneity. The findings of the present study may have important implications for future research into whether apelin and its receptor could have a clinical value in the prevention and treatment of the diseases. The obtained results should be interpreted with caution due to the high heterogeneity of the selected studies. Therefore, further large-scale studies are required to confirm these findings.The findings showed that the circulatory levels of apelin are significantly lower in CVD patients than in the controls. In addition, apelin levels were affected by the region and disease subtypes. Apelin could be considered an additional biomarker in the diagnosis of CVD in diabetic patients and patients with CAD. In addition, apelin/HDL-c, apelin/LDL-c, and apelin/TC ratios could be offered as diagnostic markers for CVD. However, as other factors, including smoking, dietary patterns, and coronary medication may also impact the plasma levels of apelin, further studies are required to define the risk factors affecting the levels of apelin and confirm these findings.S1 Checklist(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


It is necessary to evaluate the effects of competency-based training (CBT) model in the clinical training of new nurses, to provide insights to the management of nurses.We searched PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, Wanfang and Weipu Databases for the randomized controlled trials (RCTs) on the application effect of CBT in new nurse training up to December 15, 2021. Two investigators independently screened the literature, extracted the data and evaluated the quality of the literatures. RevMan 5.3 software was used for meta-analysis.A total of 7 RCTs involving 639 new nurses were included. Meta-analyses indicated that CBT improved the ability of clinical nursing care , critical thinking and innovation, interpersonal communication, professional construction and development, level of comprehensive knowledge and level of good personal traits.The results of Egger regression tests indicated that there were no statistical biases amongst the synthesized outcomes .CBT is beneficial for improving the competency of newly recruited nurses. More RCTs from different population and regions are needed to further elucidate the role of CBT in nurse management. Newly recruited nurses are most nurses who came to the hospital to participate in clinical nursing work within one year after graduating from a nursing school. They are the new force in the nursing team, and their job competencies not only have an important impact on their future careers, but also are related to the overall sustainable and healthy development of the nursing career ,2. HowevThe traditional effect evaluation method mostly adopts the final evaluation model of "one test determines all" . This evSeveral previous studies ,11 have We conducted and reported this systematic review and meta-analysis in compliance with the Statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .The two authors searched PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, Wanfang and Weipu Databases for published randomized controlled trials (RCTs) on the application effect of CBT in new nurse training. The search terms used in this meta-analysis were: ("competence" OR "competency" OR "training" OR "model" OR "education") AND ("new nurse" OR "new graduate nurses" OR "nurse"). The database retrieval time was from the establishment of the database to December 15, 2021. In the search process, the language was limited to Chinese and English. The reference lists of included studies were searched manually to avoid missing documents.The RCT inclusion criteria for this meta-analysis were as follows: (1) Research type: RCTs regarding the application of the training model based on CBT in the training of new nurses, the language was limited to Chinese and English. (2) Research population: new nurses who had nurse practitioner qualification certificate and had been engaged in nursing work within one year. (3) Intervention measures: the experimental group adopted the training mode based on CBT. The control group was trained using traditional teaching methods. (4) Related outcome indicators were reported.The literature exclusion criteria for this meta-analysis were as follows: (1) The duplicate publications with the same study data, setting or population; (2) Literature whose original data was not obtained through contacting the corresponding authors with email or telephone.Two researchers independently searched the above-mentioned database, and independently screened the literature according to the inclusion and exclusion criteria. The agreement rate between the two investigators was 90%. Then they extracted literature information, including basic information , sample size, intervention measures, outcome indicators, etc. In the process of literature inclusion, if there were differences of opinion, it was resolved by the third researcher for arbitration.Two researchers conducted independent quality evaluation of the included RCTs in accordance with the quality standards of the Cochrane Handbook. The evaluation items included: random sequence generation, allocation hiding, whether to blind the researchers and study population, the completeness of the result data, and the selectivity of report research results and other sources of bias. The risk of bias for every item was rated as being low, unclear and high accordingly. After the independent evaluation was completed, the two researchers discussed the results of the evaluation to reach a consensus. If there was disagreement, the third researcher would be consulted to resolve the disagreement.2) test to quantify the amount of dispersion , see Two RCTs ,23 repor2 = 0%, P = 0.79), so the fixed effects model was used for meta-analysis. The combined results showed that the ability of critical thinking and innovation of the CBT group was better than that of the traditional training group, the difference was statistically significant , see Three RCTs ,20,23 re2 = 28%, P<0.001), so the fix effects model was used for meta-analysis. The combined results showed that the ability of interpersonal communication of the CBT group was better than that of the traditional training group, the difference was statistically significant , see Four RCTs ,18,20,232 = 56%, P = 0.13), so the random effects model was used for meta-analysis. The combined results showed that the ability of professional construction and development of the CBT group was better than that of the traditional training group, the difference was statistically significant , see Two RCTs ,23 repor2 = 86%, P<0.001), so the random effects model was used for meta-analysis. The combined results showed that the level of comprehensive knowledge of the CBT group was better than that of the traditional training group, the difference was statistically significant , see Four RCTs ,21–23 re2 = 70%, P = 0.07), so the random effects model was used for meta-analysis. The combined results showed that the level of good personal traits of the CBT group was better than that of the traditional training group, the difference was statistically significant ], see Two RCTs ,23 reporWe removed individual studies one by one and performed sensitivity analysis. The results showed that the results of the meta-analysis of this study were stable. As shown in Job competency refers to the sum of the ability, skills, knowledge and characteristics of a particular organization that encourages employees to give full play to their potential so as to be competent for the job . Newly rThe fundamental task of a competent nurse is to provide effective nursing care to patients. Therefore, nurses must have strong professional knowledge and good operating skills. Besides, their sense of responsibility and clinical nursing ability are also particularly important . The traThe results of this meta-analysis show that the CBT can effectively improve the good personal characteristics and communication skills of new nurses. Good personal traits refer to the love of nursing profession, the high sense of responsibility and the spirit of being cautious, the spirit of unity and cooperation in work, etc . InterpeCritical thinking ability and innovation ability, professional construction and development ability are the deeper and more core parts of job competencies. They are important factors that determine nurses’ behavior. To some extent, they will directly affect the quality and development of hospital nursing work . The resThis meta-analysis has certain limitations that must be considered. Firstly, this study only retrieved Chinese and English literature, and there might be incomplete literature collection. Secondly, the included RCTs were all from China, and there might be certain regional and cultural biases. Different nurses in different places and populations may have different culture background and knowledge, the effects of CBT model may be also different, which need further investigations in various areas and populations. Thirdly, there were some differences in the evaluation indicators of clinical nursing ability, interpersonal communication ability, critical thinking and innovation ability in various studies. Besides, the sample size of included RCTs was small. the small sample size of seven precludes the researchers from making generalizations. Therefore, the results of this study may have certain clinical heterogeneity. Relying solely on heterogeneity alone is not an adequate argument for the use of random effects or fixed effects models, we have both performed analysis for every synthesized outcome by both random effects and fixed effects models, and the results do not substantially change. In the future, large samples and high-quality RCTs are needed to further assess the application effect of CBT.In summary, the results of this present meta-analysis have showed that CBT may effectively improve the competency of new nurses, help new nurses not only master knowledge and skills, but also the learning, behavior and abilities. Educational managers may use this training model to train new nurses to improve their job competencies, to be better qualified for nursing jobs, to meet patient care needsmand to ensure the quality of clinical care. However, with only seven studies, it is difficult to acknowledge that the results helped to reconcile the findings in existing literature, more studies on the effects of CBT in clinical nurse training are needed in the future.S1 Checklist(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.


Method. A systematic review and meta-analysis of various research was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. This trial is registered with PROSPERO CRD42021256452. The initial search included 646 articles; after the removal of noneligible studies, a total of 88 studies was finally selected. Data analysis was carried out using OpenMeta Analyst and Comprehensive Meta-Analysis 3.0 (CMA 3.0) software to investigate the prevalence of KRAS and BRAF mutations among patients with CRC in Asia. Results. The meta-analysis comprises of 25,525 sample sizes from Asia with most being male 15,743/25525 (61.7%). Overall prevalence of KRAS mutations was (59/88) 36.3% (95% CI: 34.5-38.2) with I2 = 85.54% . In 43/59 studies, frequency of KRAS mutations was majorly in codon 12 (76.6% (95% CI: 74.2–78.0)) and less in codon 13 (21.0% (95% CI: 19.1-23.0)). Overall prevalence of BRAF mutations was 5.6% (95% CI: 3.9-8.0) with I2 = 94.00% . When stratified according to location, a higher prevalence was observed in Indonesia (71.8%) while Pakistan has the lowest (13.5%). Conclusion. Total prevalence of KRAS and BRAF mutations in CRC was 36.6% and 5.6%, respectively, and the results conformed with several published studies on KRAS and BRAF mutations.Globally, colorectal carcinoma (CRC) is the third most common cancer and the third major cause of cancer-related death in both sexes. KRAS and BRAF mutations are almost mutually exclusively involved in the pathogenesis of CRC. Both are major culprits in treatment failure and poor prognosis for CRC.  Globally, cancer is a serious medical burden, and it is one of the main causes of death and morbidity throughout the world , 2. Withβ catenin pathway, MAPK/ERK pathway, PI3K/Akt pathway, and p53 pathway. Each pathway involves several sequential genetic modifications, such as chromosomal anomaly, gene mutations, and/or epigenetic changes, that turn normal colonic epithelium into colorectal cancer . Lik. Likβ cal cancer . MutatioRas proteins are tiny guanosine triphosphatases (GTPases) to which the KRAS and BRAF genes belong. Through the GTPase cascade, they govern a variety of intracellular activities such as proliferation, differentiation, immune response, and survival rate . The undCRD42021256452).The present study is a systematic review and meta-analysis of various researched and published papers that were carried out following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) . The stuIn the study, articles were retrieved from three electronic databases ; the eligible studies were searched and assessed using a combination of relevant keywords:  and (“BRAF” OR “BRAF” OR “c-BRAF” OR “KRAS” OR “K-RAS” OR “c-KRAS”) and (“Asia”). The full details of the search strategies for this study are in the supplementary search strategic file. A comprehensive search for the most relevant studies was carried out by combing through titles, keywords, and abstracts of various papers. The initial search included 646 articles  which weThe data extraction was carried out by using an Excel spreadsheet. Two reviewers (H.A.A. and A.A.I.) independently vetted the titles and abstracts and extracted crucial information required; study I.D, publication year, period and design, gender, data on the mutation of KRAS, and BRAF prevalence among patients diagnosed with colorectal cancer in Asia were diligently extracted. Any inconsistencies were handled through conversation with a third reviewer (S.M.S) to prevent any sort of prejudice, and any discrepancies were sorted out via dialogue involving other reviewers to avoid any kind of bias. The quality of the methodological approach for the studies included was appraised independently by two authors (A.H.A. and Y.W.) via the Joanna Briggs Institute (JBI) critical appraisal checklist for prevalence data  Supplem. A scoreQ test and quantified using I2 statistics. I2 values of 25%, 50%, and 75% were considered low, moderate, and high heterogeneities, respectively [P value < 0.001 was labelled statistically significant.Data analysis was carried out via the use of OpenMeta Analyst and Comprehensive Meta-Analysis 3.0 (CMA 3.0) software . The preectively . For allThis section is divided into subheadings to provide a concise and precise description of the experimental results and their interpretation, as well as the experimental conclusions that can be drawn from the outcomes.A total of 646 records were obtained by searching three electronic databases. After eliminating duplications and studies that do not favour the inclusion criteria, the remaining 498 were screened via titles and abstracts and by further excluding 261 records that satisfied the exclusion criteria and another 115 records that were done outside Asia; then, 122 records were left. Upon further scrutiny, another 34 records that did not merit the inclusion criteria as depicted in The characteristics of studies on KRAS and BRAF mutations are illustrated in Tables I2 = 85.54% and   . Further< 0.001) .n: 12)  .I2 = 91.95%, 91.21%, 87.18%, and 83.77%), respectively , which may have added to the overall heterogeneity found in the outcome.The country of Indonesia had the highest prevalence rates projection at 71.8% (95% CI: 55.9–83.6), while Pakistan had the lowest estimate of 13% (95% CI: 8.8-19.8) . GreaterP value < 0.001).On the period of study, studies done “after 2010” had the highest number of studies (28) during the study period  with theOn the tumour stage, KRAS mutation was reported highest in the late stage at 67.9% (95% CI: 59.3–75.5), while on location, the colon recorded the highest KRAS mutation of 61.2% (95% CI: 55.1–67.0). On the grading of KRAS mutation in CRC, “Moderate grading” recorded the highest KRAS mutation of 51.8% (95% CI: 42.9–61.2)   out of 88 studies that reported BRAF prevalence, the highest prevalence was reported by Jauhri et al.  at 7.1% < 0.001) . In all n: 7)  .I2 = 91.21% and 96.16%), respectively , which may have added to the overall heterogeneity found.India had the highest prevalence rate projection at 11.7% (95% CI: 6.2 – 21.0), while Taiwan had the lowest estimate of 1.1% (95% CI: 0.3-4.3) . GreaterP value < 0.001).On the period of study, studies done “after 2010” had the highest number of studies (17) during the study period  with theOn the tumour stage, BRAF mutation was reported highest in the “late stage” at 59.9% (95% CI: 48.2–70.7), while on location, “colon” recorded the highest BRAF mutation of 67.9% (95% CI: 37.3–42.5). On the grading of BRAF mutation in CRC, “moderate grading” recorded the highest BRAF mutation of 56.3% (95% CI: 43.3–68.6) , and 19.A funnel plot of random effects was generated to observe evidence of publication bias among the studies reporting KRAS gene mutation  and BRAFSeveral research today showed that mutations in the RAS family of genes especially the KRAS are linked to around a third of all malignancies; however, the incidence of the gene mutations varies greatly depending on the kind of cancer: often seen to be 40% in colorectal cancer, 15-20% in non-small-cell lung cancer, and 95% in pancreas carcinoma . Only a Colorectal cancer (CRC) is the third most frequent cancer in the world, with 2.0 million new cases in 2020, accounting for 11% of all new cancer cases . It was In this study, the prevalence of KRAS and BRAF mutations was investigated in 88 studies involving 25,527 CRC patients from various countries in Asia; the overall prevalence of KRAS gene mutations was found to be 36.3% (95% CI: 34.5-38.2). KRAS gene mutations are a well-investigated mutation in several carcinomas such as melanoma , non-smaThe dynamic of gene expression patterns on gender and age was investigated by some studies as a possible risk for developing CRC , 121. InAlthough human scientific knowledge has greatly advanced compared to decades ago, however, our study found that the prevalence of KRAS gene mutation was higher among patients screened “after 2010,” 36.7% (95% CI: 34.6-38.8), than when compared to those screened “before 2010,” 32.3% (95% CI: 28.8-36.0), probably due to medical advances and more medical screening . During On the location of KRAS and BRAF gene mutations, the colon 61% and 68%), respectively, was the most recorded mutation site which on the contrary is the rectum ; however%, respecBRAF is also a member of the RAF gene subfamily that, like KRAS, performs its function in the EGFR downstream cascade, but their mutations are less frequent than the KRAS gene mutations. Among the BRAF gene, BRAFV600E mutation is the most prevailing , and in This study possesses several merits and strengths. First, to the best of the author's knowledge, it has been the first systematic review and meta-analysis carried out on the prevalence of KRAS and BRAF mutations among Asians with CRC. Also, a well-detailed and comprehensive search strategy ensures that elaborate all-inclusive papers are included, thus leading to a very large population size of 25,525. This also ensures high confidence in the outcomes obtained since the included studies were of high methodology quality. However, this analysis was not without some limitations, with many linked to the data from the literature of the included studies such as small sample size, incomplete reports on sex, mean age, period of study conduction, differentiation, and location of the tumour, and lastly, mutation screening was done just for the BRAFV600E. All these parameters/characteristics that would be crucial in upholding the study appraisal were not reported in some of the studies analysed in this meta-analysis, thus accounting to some of the heterogeneity seen in the studies.This systematic review and meta-analysis study, which to the best of our knowledge, is the first to report on the prevalence of KRAS (36.6%) and BRAF (5.6%) mutations in CRC patients in Asia. The result showed that the rate of KRAS and BRAF gene mutations in CRC among Asians is rising. The adult age was more associated with CRC prevalence, and the males have increase fold and poorer outcome than their female counterparts. Despite some limitations, the meta-analysis yielded impressive results. The total prevalence of KRAS and BRAF mutations, 36.6% and 5.6%, respectively, differs in various countries in Asia according to this meta-analysis. Furthermore, when the findings of this study were compared to those of other studies, it was discovered that the prevalence of these mutations obtained in our analysis conformed with them.


Because the three single-nucleotide polymorphisms  have a linkage disequilibrium relationship, all three may increase the risk of IS.Several studies have reported that chromosome 9p21 is significantly associated with ischemic stroke (IS) risk, with the G allele associated with increased risk. However, controversial results have been reported in the literature. We systematically assessed the relationship between stroke and three 9p21 loci  in this meta-analysis. First, we searched the PubMed and Embase databases for relevant studies. We then calculated odds ratios using the chi-squared test. The evaluation of experimental data was performed using bias tests and sensitivity analyses. We analyzed data from 16 studies involving 18,584 individuals of Chinese ancestry, including 14,033 cases and 14,656 controls. Our results indicated that chromosome 9p21 is significantly associated with IS (odds ratio: 1.15, 95% confidence interval: 1.1–1.20,  Stroke is a severe disease and is the leading cause of disability and death in China . It is aWe searched the PubMed and Embase databases and selected all possible studies using the keywords “Stroke Chinese” and “rs2383206,” “rs2383207,” “rs10757278,” and “9p21.” The relevant literature was updated on 31 January 2022.The following selection criteria were used: (1) an association between the proposed SNPs and stroke was evaluated using a case–control design; (2) an accurate genotype number was provided or could be calculated ; (3) theTrial data from each identified study were extracted separately by two investigators (DW and XH). Any differences were eliminated by discussing the data extraction for each study using standard data collection tables. The data and information that were extracted for inclusion in the analysis included the first author’s name, publication year, language, population, study type, sample size, numbers, and frequencies of rs2383206, rs2383207, and rs10757278 polymorphism genotypes in the cases and controls, ORs, and 95% CIs. All extracted data are presented in http://www.r-project.org/) (Q test and I2 = (Q – (k – 1))/Q × 100%. The Q statistic approximately follows a χ2 distribution, with k-1 degrees of freedom   . For thenalysis) . When Ithan 0.1 , the Derthan 0.1 .In this meta-analysis, 18,584 participants were included: 14,033 in the IS group  and 14,656 cases in the control group . Eleven articles were selected, comprising 16 studies, of which six investigated rs2383207 , five inhttps://snipa.helmholtz-muenchen.de/snipa3/).The three SNPs—rs10757278, rs2383206, and rs2383207—are located within 10 kb of one another on chromosome 9p21 . Thus, we performed an analysis of the OR values of all studies involving rs2383206, rs2383207, and rs10757278 in which the G allele was a minor allele. Because  alleles . Chromosp = 0.7661, indicating no publication bias in the studies of 9p21 , and the two experiments were outliers. A second bias test revealed that bias = 1.4217, p = 0.0696   and Ding= 0.0696 . Sensitip < 0.0001, I2 = 0%, p = 0.71, We know from Stroke is currently the main cause of death in China; it has high morbidity, mortality, and disability rates . Stroke INK4 locus (ANRIL) variants rs2383207 and rs1333049 increases the risk of IS and coronary heart disease in Caucasian populations (Matthew Traylor et al. found that chromosome 9p21 and histone deacetylase were associated with stroke in individuals of European ancestry . Furtherulations . Notablyulations . In the In this meta-analysis, 18,584 participants were included; the IS and control groups contained 14,033 and 14,656 individuals, respectively. The three investigated SNPs have a linkage disequilibrium relationship, and we arrived at the same conclusions through unified analysis. All three SNPs were associated with IS risk. However, there was heterogeneity between the experimental results and studies; thus, bias detection and sensitivity analyses were carried out. In conclusion, our results indicate that rs2383206, rs2383207, and rs10757278 are significantly associated with IS risk and the G allele is associated with an increased risk of IS. Because the three SNPs in the present study have linkage disequilibrium and are in similar positions on chromosome 9p21, a unified analysis was performed. Environmental factors such as smoking and alcohol use may also be associated with IS risk, but not all studies considered these risk factors. Therefore, the influence of genes and the environment on IS pathogenesis needs to be further studied.


Likewise, the stratified meta-analysis showed the same pattern in the studies which measured RBP4 levels in the third trimester, as well as in the studies that investigated severe preeclampsia. Meta-regression did not identify any factor that significantly affected the overall estimate. There was no evidence of reporting bias . This meta-analysis with high heterogeneity showed that higher levels of RBP4 were associated with preeclampsia risk. More longitudinal studies spanning the three trimester periods are needed to clarify the association of RBP4 and its dynamics in preeclampsia cases throughout pregnancy.Retinol-binding protein 4 (RBP4) is claimed to be associated with the development of preeclampsia, yet the reports are inconclusive. This systematic review and meta-analysis aimed to assess the association between RBP4 levels and preeclampsia. The PubMed, Google Scholar and ScienceDirect databases were searched for studies that investigated RBP4 levels in preeclampsia patients and compared them with normal controls. The meta-analysis was conducted by calculating the standardized mean difference (SMD) of RBP4 between cases and controls. The meta package with the R software was used to perform all statistical analysis. A total of 13 studies, comprising 569 cases and 1411 controls, met the inclusion criteria and were thus included in the meta-analysis. According to the random effect model, the SMD of RBP4 was significantly higher in women with preeclampsia compared with normal controls [SMD of RBP4: 0.55 ng/mL; 95% CI ;  Preeclampsia is a major medical disorder that frequently occurs during pregnancy. It is characterized by increased blood pressure and proteinuria in previously healthy women. It is a prevalent problem worldwide that affects around 4.5% of all pregnancies . WithoutAdipokines constitute a group of cytokines that are released from the adipose tissues. These adipokines are believed to affect the energy metabolism process, trigger an inflammatory response and enhance angiogenesis . RetinolNevertheless, the published documents about the association between RBP4 and the development of preeclampsia in humans are inconclusive. Some studies have indicated increased levels of RBP4 in preeclampsia ,14,15,16In this systematic review and meta-analysis, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 recommendations , and theTwo researchers (H.Z.H. and T.A.) independently searched three electronic databases  for relevant articles that investigated the association between RBP4 and preeclampsia since inception, until 3 November 2022. The detailed search strategy used for each database is available in We included articles if they (1) were published in peer-reviewed journals, reported serum/plasma levels of RBP4 in women with preeclampsia and were in the normal control group; (2) were written in the English language; (3) provided RBP4 concentration as the mean (standard deviation [SD]) or the median (interquartile range [IQR]) and reported the measuring unit; and (4) employed a case-control, cohort and cross-sectional study design.The articles were excluded if they (1) were clinical trials, experimental studies, review articles, letters to the editor, case series or conference abstracts; (2) reported RBP4 without the measuring unit or without related measures of dispersion, namely SD, range or 25th–75th IQR; (3) measured RBP4 in patients with preeclampsia and another chronic disease or another pathology; and (4) were written in a language other than English.Two researchers (T.A. and H.Z.H.) independently extracted the studies’ data using a structured sheet, guided by the Joanna Briggs Institute reviewers’ data extraction form . The extIn this study, the primary outcome is the association between the plasma/serum levels of RBP4 in pregnant women with preeclampsia compared with normotensive pregnant controls. Preeclampsia is defined according to the following criteria used by the American College of Obstetricians and Gynecologists : detectiTwo researchers (T.A. and H.Z.H.) used the Newcastle–Ottawa Scale (NOS) to assess the methodological quality of each included study. The NOS assesses each study based on three major principles: recruitment of the participants, comparability of the study group and ascertainment of the outcomes of interest. Based on the NOS, the study is considered of high quality if it scores ≥ 7 stars. The maximum score in the NOS is 9 stars .p < 0.010 and I2 > 50% as an indicator of significant inter-study heterogeneity  (p = <0.0001) and (I2 = 89%) both indicated the presence of significant inter-study heterogeneity  was found nonsignificant.We investigated the presence of reporting bias visually, by depicting the studies in the funnel plot, and quantitatively, by performing an Egger’s test. The funnel plot showed a symmetrical plot of the included studies  and the We performed a stratified meta-analysis of the included studies, based on the trimester at which RBP4 was measured: third trimester ,18,22,23I2 = 90%]. A similar pattern was observed in the studies that investigated severe preeclampsia .The findings of the stratified meta-analysis are summarized in Although we noticed that the RBP4 SMD level increased by the years of publication, which can be attributed to the increased sensitivity of ELISA used, meta-regression analysis did not show any factor  that significantly changed the SMD of RBP4, including the study’s publication year .The major finding in this meta-analysis of 13 observational studies is that the RBP4 levels are higher in patients with preeclampsia compared with normal pregnant controls. The same pattern is observed in the studies that measured RBP4 during the third trimester of pregnancy and in studies that investigated severe preeclampsia only. To the best of our knowledge, this is the first meta-analysis that investigated the association between RBP4 levels and the risk of preeclampsia. However, two previously published meta-analyses on the association between RBP4 and the risk of gestational diabetes mellitus (GDM) have also reported higher levels of RBP4 among GDM cases ,34. NotaThe stratified meta-analysis indicates that RBP4 levels are significantly higher in the third trimester of pregnancy compared with the first trimester. This finding should be taken with caution, as only three studies in this meta-analysis have evaluated the RBP4 levels in the first trimester of pregnancy ,19,21. OIn this study, the stratified meta-analysis, based on preeclampsia severity, also indicates that RBP4 is significantly higher in the group with severe preeclampsia only. It has been mentioned that RBP4 is significantly higher in cases that develop severe preeclampsia compared with mild cases . MoreoveNulliparity is a known risk factor for developing preeclampsia. Nulliparous women have a 1.5 to 5.5 times increased risk of preeclampsia compared with multiparous women . MaternaAlthough the included studies in this meta-analysis are of moderate to high methodological quality and no evidence of reporting bias is detected, inter-study heterogeneity remains high. Zhang et al.  and VaisIn this study, we observed that the reported levels of RBP4 are widely different between the included studies. This can be attributed to the differences in genetic factors that can affect the expression of RBP4 and hence, its levels . MoreoveThe current meta-analysis has some limitations that need to be addressed for a better interpretation of the results. First, in the stratified meta-analysis, some of the groups only have three studies (stratification based on the trimester of pregnancy). This small number of studies with a small sample size will decrease the power for the estimation of RBP4 and increase the risk of bias. Moreover, only four studies recruited nulliparous women; however, they did not present their RBP4 separately. Accordingly, we could not perform stratified meta-analysis according to parity status, hence, we deduced a meaningful conclusion regarding the parity effect on RBP4 levels. Second, most of the included studies are retrospective case-control studies, so causality cannot be deduced. Third, inter-study heterogeneity is high, and the stratified meta-analysis and meta-regression could not identify major sources of this heterogeneity. Fourth, although RBP4 and preeclampsia both pertain to insulin resistance, a limited number of studies have investigated this relationship, so we could not include it in the meta-analysis. Therefore, further research is needed, which should use a larger sample size, a prospective design and longitudinal sampling for RBP4 to provide better insights into the RBP4 dynamics in preeclampsia cases.


The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism . Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity , mucositis , hypomagnesemia , and dehydration  than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents  in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents ( The incidence of colorectal cancer (CRC) is increasing each year, with 1.9 million new diagnoses worldwide in 2020 . The treDespite numerous studies on the advances of treatment modalities such as chemoradiation and gene therapy in metastatic CRC patients ,6,7,8,9,Previous studies on clinical effects of these agents, in terms of tumor responses and survival rates, demonstrated considerably higher efficacy of EGFR inhibitors than VEGF antibodies in left-sided colon cancer . NeverthThis study was performed in accordance with the Preferred Reporting Items for Network Meta-Analyses (PRISMA-NMA) guidelines . MEDLINETwo reviewers independently screened the titles and abstracts of all studies identified from the initial searches for eligibility. Any disagreements on eligibility of studies were further discussed until consensus was reached. The eligibility of studies was determined by prespecified inclusion criteria: (1) head-to-head randomized controlled trials (RCTs) evaluating safety of biological targeted agents with classic chemotherapy, (2) patients with RAS wild-type metastatic CRC, (3) studies evaluating SAEs between two different targeted agents, in metastatic CRC patients on the same backbone chemotherapy regimen including CAPEOX, FOLFOX, FOLFIRI, FOFOXIRI, or irinotecan, (4) administration of the intervention or the comparator as first- or second-line therapy, and (5) studies published in English. Duplicate studies, review articles, case reports, conference abstracts, study protocols, commentaries, editorials, proceedings, and studies without available full-texts were excluded from the analysis. Any studies evaluating investigational products without approval from the Food and Drug Administration (FDA) were excluded from the analysis. The following information was extracted from eligible studies: study characteristics , study population (inclusion and exclusion criteria and number of patients assigned to each treatment arm), study interventions and comparators  and safety outcomes. The safety outcomes were classified per common terminology criteria for Adverse Events (CTCAE) version 5.0, and SAE was defined as any AEs classified as grade 3 (severe AEs) or 4 (life-threatening or disabling AEs) per CTCAE guidelines . The SAEThe quality assessment of the studies included in this analysis was performed based on Cochrane Risk of Bias version 2.0 (RoB2) tool ,21, and 2 index was utilized to assess heterogeneity across the studies [2 < 50%), and the random-effect model was applied to analyze outcomes with high heterogeneity (I2 > 50%). Cochran’s Q was utilized to assess the extent of inconsistency, and any p-value < 0.05 was considered as significant [p-value, the better the rank of the intervention, and p-value is an equivalent to the Surface Under the Cumulative Ranking (SUCRA) score [p-values were estimated by two-sided tests and p-values < 0.05 were considered statistically significant.Pooled traditional pair-wise analysis on the safety outcomes were evaluated using R (version 4.1.0). Frequentist network meta-analyses were performed to combine direct and indirect effects and simultaneously compare SAE incidences of three different targeted therapeutic agents in combination with chemotherapy for management of metastatic CRC against a control group generated by the network ,23. The  studies , and thenificant ,25. The A) score . SubgrouThe study search and selection results per PRISMA-NMA guidelines are described in p-value of Cochran Q’s statistic was > 0.05 for all safety outcomes, indicating low risk of inconsistency. The network plot for the included studies is shown in The characteristics of the eligible studies for network meta-analysis and bias assessments are summarized in The risk of hematological SAE including anemia, febrile neutropenia, neutropenia, infection and thrombocytopenia was comparable among bevacizumab-based chemotherapy, cetuximab-based chemotherapy, and panitumumab-based chemotherapy . MoreoveThe risk of serious hypertension (HTN) was significantly higher in the bevacizumab-based chemotherapy group than either cetuximab-based chemotherapy  or panitumumab-based chemotherapy  . HoweverThe risk of serious skin toxicities involving rash or dermatitis was substantially higher with EGFR inhibitor-based chemotherapy : cetuximEGFR inhibitors including cetuximab and panitumumab markedly increased SAE risks pertaining to renal systems . Both ceCombining targeted biologics with classic CRC chemotherapy, such as CAPEOX, FOLFOX, FOLFIRI or FOLOXIRI, is effective in inhibiting tumor progression but at the cost of increased risk of AEs ,35,36. DSimilar to the results from a previous meta-analysis on the tolerability on SAE of first-line bevacizumab and cetuximab for RAS wild-type metastatic CRC patients , the higThe risk of serious thromboembolism, on the other hand, was substantially elevated with panitumumab-based chemotherapy  when compared to bevacizumab-  and cetuximab-based chemotherapy . According to previous studies , patientSkin toxicities, including acneiform skin rash and nail disorders, are well-known AEs of EGFR inhibitors , and preElectrolyte disorders including hypomagnesemia and hypokalemia are other AEs commonly observed in patients receiving EGFR inhibitor treatment. The network analysis revealed significantly higher incidence of serious hypomagnesemia and hypokalemia in cetuximab- and panitumumab-based chemotherapy, whereas the risk of serious hypocalcemia was insignificant among targeted therapeutic agents. Although some studies suggest that electrolyte disturbances, especially hypomagnesemia, may be associated with better clinical outcomes in terms of survival, appropriate management guidelines on electrolyte disturbances have yet to be established . FurtherBased on the health-related quality of life study, worsening quality of life was observed in patients during chemotherapy , and AEsThis study has several limitations. First, the study designs and outcome measurements were different among the studies included in the analysis, subsequently increasing heterogeneity across the studies. Moreover, due to the nature of cancer-related RCTs, which recruit vulnerable patient populations, the number of patients in each group was relatively small to perform subgroup analysis, and this may decrease the robustness of the study results. Moreover, subsequent analyses on the impact of various factors including age, gender, and comorbidities on AE risks of targeted therapeutic agents are limited at this point. Nonetheless, this study has strong external validity as patients received different backbone chemotherapy regimens including FOLFOX, FOLFIRI, and irinotecan. Additionally, the meaningful aspect of this study is that this study provides evidence on comprehensive network analysis of SAE profiles of the most commonly prescribed targeted therapeutic agents in metastatic CRC patients who are highly susceptible to increased risk of AEs from administration of multiple cytotoxic agents, thereby providing guidance on the selection of targeted therapeutic agents as well as AE management plans based on the SAE profiles. Nevertheless, further research on AE mechanism as well as risk factors in terms of patient characteristics associated with SAE of each targeted therapeutic agent is recommended to improve patient prognosis as well as quality of life. The risk of SAEs in hematological, neurological and GI system are statistically insignificant among bevacizumab-, cetuximab-, and panitumumab-based chemotherapy. The risk of serious HTN is the highest in the bevacizumab-based chemotherapy group. However, panitumumab-based chemotherapy has the highest risk of serious thromboembolism than cetuximab- and bevacizumab-based chemotherapy. Administration of the EGFR inhibitors, cetuximab and panitumumab, substantially elevated the risk of dermatological and renal SAEs. However, the risks of skin toxicities, mucositis, hypomagnesemia and dehydration are relatively higher in panitumumab-based chemotherapy than cetuximab-based chemotherapy. Hence, further studies investigating the mechanisms and risk factors associated with these SAEs to provide risk-stratified guidance on targeted agents to ensure patient safety.


Prevalence and subsequent conditions of childhood and adolescent obesity are increasing. It has been seen that obesity in youth is associated with adulthood cancer. This systematic review and meta-analysis aimed to determine the pooled association of childhood obesity with cancers in adulthood.In this systematic review, international electronic databases such as Scopus, PubMed, Web of Science, and EMBASE were searched using relevant keywords until February 2022. All Cohort studies assessing the association of childhood and adolescent obesity (under 18 years old) with the incidence and mortality of all types of cancers were included. Two independent reviewers screened and carried out the quality assessment of included studies. Between-studies heterogeneity was assessed using the I squared and Cochran’s Q tests. Random/fixed-effect meta-analyses were used to pool the appropriate effect sizes (Hazard ratios (HR)).Overall, 46 studies were found to be relevant and were included in this study. Based on the random-effects model meta-analysis, childhood obesity increased the hazard of cancer incidence and mortality in adulthood by 33% ) and by 28% ), respectively. In the subgroups meta-analysis, the HR of childhood obesity and adulthood cancer incidence mortality in women was higher than in men  vs HR= 1.20, 95%CI ) and  vs HR=1.20, 95%CI ) respectively.This study found that obesity in childhood and adolescence is associated with a significant increase in the incidence and mortality of cancers in adulthood. Prevention of childhood obesity, in addition to its short-term beneficial effects, can reduce the burden of cancer in adulthood. The data sets of this study are present in the Tables of the current manuscript. Moreover this study was registered online in PROSPERO (registration code: CRD42022331958).https://www.crd.york.ac.uk/Prospero/, identifier CRD42022331958. Obesity is a condition notorious for its associated morbidity and mortality ; and plaCancer has resulted in millions of deaths and morbidities throughout the years, thus earning its place among the most significant causes of mortality and morbidities worldwide . DespiteSimilar to epigenetic factors, obesity is a modifiable cancer risk factor . NumerouIn conducting this study, we adopted the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.A systematic search of the available literature was conducted across electronic databases . The search strategy is presented in full within the All Cohort studies with an English full text assessing the relationship between obesity in children and adolescents and cancers in adulthood were included in this study. All studies must have represented the targeted population in exposure (obesity in children and adolescents) and outcome . Studies must have appropriately determined cancer incidence and mortality and had proper documentation and measures regarding childhood and adolescent weight, height, and BMI. Studies without the aforementioned criteria were excluded After duplicate removal with EndNote X9, two investigators independently assessed the titles and abstracts and, lastly, the full texts of the remaining articles. Moreover, the reference lists of the included studies were hand-searched to find other relevant studies. Discrepancies were referred to the third investigator for resolution.A pre-designed data extraction data sheet consisting of the first author’s name, year of the study, age range or mean sex, the number of participants, type of malignancy, obesity definition, and measure  was used. Hazard ratios (HR), Odds ratios (OR), or Risk ratio (RR) (otherwise known as relative risk) alongside their 95% confidence interval (CI) as the effect size and studies’ adjustments for potential confounders were recorded. Two researchers extracted the data, and possible discrepancies were referred to the third researcher for resolution.The Newcastle-Ottawa Scale for cohort studies was used for quality assessment. We scored the studies based on selection, outcome, and comparability with this seven-item scale. The total score, which is the sum of the scores of its items, ranges from 0 to 9. We categorized the studies based on their scores . Two investigators scored the studies independently, and discrepancies were referred to the third researcher for resolution.The I squared, and Cochran’s Q tests were adapted to assess heterogeneity between studies. If the heterogeneity P-value was less than 0.1, a random-effect model (DerSimonian–Laird) was used to pool the effect sizes. Otherwise, a fixed model was adopted. Meta-analysis was performed for outcomes with at least two records with identical measurements. Only the HRs and RRs were combined and pooled in the Meta-analysis , 24.Binary BMI measurement was considered as the highest to the normal measure based on the study reports . Continuous BMI measure was considered as a one unit change in BMI Z-score or standard deviation (SD). The HRs or RRs of studies with two and above identical measures were pooled, and then a singular HR or RR for that study was used in the meta-analysis.Sub-group analysis was performed according to cancer types and sex. Egger’s test for each malignancy determined the level of publication bias. In cases where publication bias was present, trim fill analysis was performed to impute the missing data.STATA  version 17 was used for data analyses.Of the initial 9301 studies found in the initial search (plus hand-searched studies), 3721 were duplicates, the titles or title and abstracts of the remaining 5580 articles were evaluated, and 5063 were found to be irrelevant to this study. The full texts of the 513 remained articles were assessed, and 471 were excluded. Lastly, 46 articles remained in the study and were used for qualitative, and 42 were included in the quantitative data synthesis. The entire illustration of this process can be seen in The majority of the found studies were conducted in Europe , and Finland). Other studied countries included Israel, the USA, and Australia. Denmark and Israel had the most studies (17 studies); USA, Finland and Australia had the least number of studies, with only one study assessing them all together.The largest sample size was from Israel, with 19567635 participants. The smallest was from the UK, with an overall participant number of 6842. Of all the 46 studies,4 focused on cancer mortality/survival; the other 42 assessed cancer incidence. Moreover, out of these 42 articles, most studies assessed gastrointestinal (GI) related malignancies (18 studies) . These data, alongside other primary findings, are shown in The association of childhood and adolescence obesity-related indices with cancers in adulthood in included studies is shown in The pooled association between obesity in children and adolescents and the incidence and mortality of cancers in adulthood is shown in Sex stratified results among Women and men were , HR:1.39, 95%CI ) for cancer incidence and , HR:1.20, 95%CI ) for cancer mortality, respectively. Also, in the continuous data (per 1 Z-score/SD increase in BMI), the hazard of cancer incidence in obese individuals significantly increased by 9% ); Moreover, the hazard ratio based on continuous data in both men and women were statistically significant )  respectively).The pooled associations of BMI in the youth and cancers in adulthood sub-grouped by type of malignancy can be seen in To assess the possible causes of heterogeneity among studies meta-regression was performed for the binary and continuous overall incidence of cancer with sex, type of cancer and the country in which the study was conducted in as moderators. It was found that neither of the aforementioned variables were the underlying cause of the heterogeneity seen among studies (the β (SE) for continuous and binary overall incidence of cancer for the aforementioned variables respectively are as follow. sex: 0.04 (0.03) and 0.06 (0.07), country of study conduction: 0.003 (0.01) and 0.02 (0.04), cancer type: -0.001 (0.005) and -0.001 (0.01))Publication bias was assessed using Egger’s test and was present across the included studies in our analyses. However, after trim fill analysis, only cancer incidence based on continuous measure changed from ) to ), while other pooled HRs remained unchanged indicating that the meta-analysis results were not substantially affected by publication bias.This systematic review and meta-analysis showed a significant association between childhood and adolescent obesity and malignancies’ overall incidence and mortality in adulthood. Moreover, most cancer incidences, stratified by malignancy type, were directly and significantly associated with obesity under 18 years of age. These findings were in line with other studies as they also reported a significant association between cancer incidence and mortality with obesity in the youth , 26. OurThe exact mechanisms by which obesity in the youth affects cancer incidence and mortality in adulthood are not well understood. Some studies suggested the role of chronic inflammation and oxidative DNA damage, hormonal and cytokine dysregulation in obesity as possible underlying causes , 26. IndIn a systematic review and meta-analysis similar to this study on those aged under 30, a significant association between obesity and colorectal, endometrial, ovarian, thyroid, and pancreas malignancies were found. Furthermore the aforementioned study found that pre and post-menopausal obesity reduces the risk of breast cancer by 12 and 17 percent respectively  and RR:0.83 95%CI ) ; our finAlthough understanding the pathways by which obesity increases the risk of cancer incidence and mortality is essential in fighting it; regardless of the underlying pathologic pathways, the outcome is quite clear and the fact is that many cohort studies have shown that obesity in the youth increases the risk of malignancies in adulthood –36. ThisThis indicates that more thorough preventive measures must be taken to prevent the upcoming rise in cancer incidence. Moreover, the necessity of proper education cannot be ignored. Since not only education on obesity is needed, but in order to prevent it, we should educate people on how to get rid of obesity; as even now, many minors do suffer from obesity, and governments must take action to prevent and treat obese individuals, as soon as possible to prevent the conditions that arise from obesity.In this thorough systematic review and meta-analysis, only cohort studies with documented measurements for BMI were evaluated –69, theiThis study showed a clear association between childhood and adolescent obesity and cancer incidence and mortality in adulthood. Obesity is associated with an increased prevalence of various types of malignancies and a higher death rate due to cancer in adulthood. With regard to these findings, we must increase our efforts to battle obesity, and interventions in childhood and youth need to be balanced with the need to tackle adult obesity.The original contributions presented in the study are included in the article/The Ethic Committee of Alborz university of Medical Sciences (ABZUMS) approved and all methods of the study were carried out by relevant guidelines and regulations.NMK conceived the study, participated in study design, data collection  and wrote the manuscript. MQ, SA and ES aided in data collection , SM, LS, BHZ and AE helped in manuscript preparation. And interpreted the results. All authors contributed to the article and approved the submitted version.