Based on the existing systematic reviews and meta-analyses, we conducted this umbrella review aiming at evaluating the quality of evidence, validity and biases of the relationship between vitamin C (VC) intake and incidence and outcomes of multiple cancers. We identified 22 cancer outcomes within 3,562 articles. VC consumption was associated with lower incidence of bladder cancer, breast cancer, cervical tumors, endometrial cancer, esophageal cancer, gastric cancer, glioma, lung cancer, pancreatic cancer, prostate cancer, renal cell cancer, and total cancer occurrence. VC intake was also related to decreased risk of breast cancer prognosis . With the aging and growth of human beings and also changes in the prevalence and distribution of cancer risk factors (some of them are socioeconomic development related), the burden of cancer incidence and mortality is rapidly growing . Cancer Vitamin C (VC), as a wound improving and infectious reducing agent, has been known and used for decades . It is aVC could not be synthesized by the human body, and people could only obtain VC through foods or drugs . It is oThe association between VC and various cancer outcomes has been evaluated in a large amount of cohort, case-control, and randomized controlled studies. Multiple systematic reviews and meta-analyses summarized results from these studies. However, a comprehensive overview into the correlation between VC and cancers is still in deficiency. Therefore, we are conducting this study aiming at making a comprehensive review of the association between VC and cancer outcomes reported in systematic reviews and meta-analyses and assessing the validity and also level of existing evidence.We comprehensively searched and evaluated published evidence on the association between VC intake and multiple cancer outcomes from a large number of systematic reviews and meta-analyses , 9. SystWe searched systematic reviews and meta-analyses of observational studies and interventional studies from MEDLINE, Embase, and Cochrane Database of Systematic Reviews and Web of Science from the inception to April 2021. The searching strategy was VC AND systematic review OR meta-analyses. The SIGN guidance for systematic reviews and meta-analyses was used for literature search , 12. TwoMeta-analyses and systematic reviews with meta-analysis of observational (cohort and case-control) and interventional studies  evaluating VC intake and cancer outcomes in humans were included regardless of the race, gender, country, or region of participants. If two or more cancer outcomes existed in a single article, data of each outcome would be extracted separately. If one cancer outcome was assessed by more than one studies, article with the largest number of participants would be included. Furthermore, articles reporting VC intake with therapeutic utilities were also excluded only if nontherapeutic intake was also reported. Articles written in languages other than English and not involving humans were also excluded.The following data were extracted by ZYC and YH independently from eligible studies: (1) name of the first author, (2) journal, (3) year of publication, (4) category of exposure , (5) outcome, (6) number of included studies, (7) number of participants in each study, (8) study design  and nonrandomized controlled trial (NRCT), (9) follow-up time, (10) type of comparisons , (11) the estimated summary effect , and corresponding 95% confidence intervals (CIs).Methodological quality of included articles was evaluated following the AMSTAR items, and this is a reliable strategy in assessing the quality of systematic reviews and meta-analyses , 13. TheI2 statistic and Cochran's Q test were used to estimate the heterogeneity between studies. Estimation of publication bias in each meta-analysis was presented as result of Egger's regression test .We extracted data of VC consumption and cancer outcomes, and estimated summary effect with 95% CI reported in each meta-analysis if available , 15. If ion test . Dose-reThe detailed process of literature search and selection was presented in In the estimation of highest VC intake vs. lowest, significant inverse associations were seen in VC intake and incidence of several cancers of the urogenital system: bladder cancer  , breast When estimating the dose-response effect of these associations, we found that every 50 mg/1,000 kcal increment of VC intake was related to a 15% (95% CI 0.73–0.98) decrease in the risk of endometrial carcinoma, and a 150 mg/day increment of dietary VC intake was related to 9% (95% CI 0.84–0.98) lower incidence of prostate cancer .In subgroup analysis, we found that VC intake was significantly related to the risk of breast cancer in case-control studies  and in studies of Asia  ; risk ofComparing the relationship between highest vs. lowest intake of ascorbic acid and the incidence of digestive system cancers, we found that highest intake of VC was related to the reduced risk of esophageal cancer  , gastricWhen subgroup analysis was conducted, significant associations of VC intake and pancreatic cancer risk were found in case-control studies , cohort studies , Caucasian , and Asian  and also mixed population  .In the estimation of highest VC intake vs. lowest, we detected an inverse association of the risks of nervous system neoplasms: incidence of cervical neoplasms   and glioIn subgroup analyses of cervical neoplasms, significant effect was observed in histological subtypes. VC intake was associated with reduced risk of invasive cervical carcinoma , considering stratification of geographic area, and studies from Europe and America showed that VC intake had a significant correlation with the risk of cervical neoplasm . When stratified by study design, inverse association of VC intake and risk of cervical neoplasm was revealed in population-based case-control  and hospital-based case-control studies . When stratified by dose of VC intake, all the investigated concentrations of VC intake were significantly correlated with reduced incidence of cervical neoplasm  .We also detected significant associations in ascorbic acid intake with incidence of lung cancer   and totaResults from subgroup analyses showed that significant relationship between VC and total cancer incidence was observed in studies in Asia , study with cases more than 1,000 , study quality of 7–9 points  .Q-test p <0.10. Nine meta-analyses reported low level of heterogeneity (I2 <25%).Twelve meta-analyses among all 19 included articles showed Nine studies of included studies were reported to have significant publication bias, whereas this was not detected in five studies.AMSTAR scores were estimated in our umbrella review, ranging from 4 to 8 points . The anticancer phenomenon of VC has been reported by a large number of population-based studies and pooled by many meta-analysis and systematic reviews. We conducted this umbrella review aiming at investigating the relationship between VC intake and cancers comprehensively. In total, 57 meta-analyses involving 19 unique outcomes of the correlation between ascorbic intake and cancers were included. As per the results of our study, intake of ascorbic acid was related to lower risk of several cancers involving different systems . Although these results showed the anticancer potential of ascorbic acid, studies into the underlying mechanism of this effect are still ongoing.As one of the most common antioxidants obtained from fruits and vegetables , VC was Ascorbate could reduce metal ions such as iron, copper, etc. , thus gu2+)-dependent dioxygenase superfamily (2+) and 2-ketoglutarate-dependent  through Fe2+/2-oxoglutarate (2OG)-dioxygenase-dependent pathway, which was also ascorbate dependent , 54. Conerfamily , 58. TET to Fe2+ , thus pl to Fe2+ . It was dent way . The autdent way .In another study , the aut2+ (Fe3+ reduced by ascorbate) could react easily with oxygen and thus could lead to the formation of reactive oxygen species (ROS) and H2O2 and generated a highly reactive hydroxyl radical  and strength of evidence (GRADE) of those included literature. Furthermore, a low publication bias rate was detected among the included meta-analyses. Although methodological patterns were used properly, selection bias may still exist. To minimize this bias, we have two authors who conducted these jobs with those methods described above to achieve this work.However, several limitations existed in our study. First, only two of the included studies were classified as high quality according to the GRADE method due to the nature of most meta-analyses being conducted based on observational studies. Second, considering that the most commonly seen resources of VC are fruits and vegetables, people can hardly intake VC as the only antioxidant agent or crucial nutrient in their daily life. Those micronutrients taken together might influence the effect of ascorbic acid on cancers. However, these factors were not assessed in subgroup analyses in the included meta-analyses. Finally, the definition of highest intake and lowest intake was not clearly quantified, thus making it hard to define the effect size of the correlations to a standardized baseline, and dose-response analysis was also conducted in no more than half of included meta-analyses. Considering these shortages of this study, further studies looking into this topic are still needed and should be of better quality.After comprehensively review of literatures, we concluded that intake of VC was related to lower risk of multiple cancers of diverse systems. As VC was a commonly seen and easily acquired micronutrient, increase of VC enriched foods was highly recommended. At the same time, we are looking forward to seeing population-based studies of higher quality, and laboratory investigations into the mechanism of the anticancer effect of VC are guaranteed in the future.ZC and YH conducted this research and wrote the paper. LL, PH, and QW designed the study and had primary responsibility for final content. SQ, BC, JL, and YB provided essential materials. DC analyzed data. All authors read and approved the final draft.This study was funded by the National Natural Science Foundation of China (grant number 82000721) and Program from Department of Science and Technology of Sichuan Province (grant number 2020YJ0054).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to determine the relationship between the high dietary acid load (DAL) and the risk of cancer.Five databases of PubMed, Web of Sciences, Scopus, Cochrane Library, and Google Scholar was searched to elicit original studies on humans, up to June 2021. Quality of the articles, risk of bias, and heterogeneity were assessed. A random-effects meta-analysis model was applied to estimate pooled effect size with a 95% confidence interval. Sensitivity analysis was performed using a fixed-effects model. Subgroup analyses were carried out based on gender, age, type of cancer, and type of DAL assessment indicator.p < 0.001]. The risk of cancer increased 41% (p < 0.001) and 53% (p = 0.03) by high PRAL and NEAP, respectively. High DAL was associated with 32% (p < 0.001) and 79% (p < 0.001) increased risk of breast and colorectal cancers, respectively. High DAL was associated with 32% (p = 0.001) and 76% (p = 0.007) increased risk of cancer incident in women and men, respectively. The risk of cancer incident increased 35% (p < 0.001) and 49% (p < 0.001) at age ≤ and > of 50, respectively.Seventeen effect sizes from 10 articles were included in the analysis. Overall, individuals with the highest DAL were associated with a 66% increased risk of cancer compared to those with the lowest DAL (High DAL may be associated with a higher risk of cancer incidence not only in the whole studied population but also across cancer types, both genders, both DAL assessment indicators, and also among both high- and low-risk age groups for cancer. Cancer is a major burden of disease and health concern worldwide. It is the second leading cause of mortality in many countries  and accoIt has recently been suggested that diet composition may influence the body's acid-base balance . Some diAs the DAL correlates with the urinary acid load, it has been suggested as a simple and useful method to evaluate the acidity of a diet . PotentiPRAL (mEq/day) = 0.4888 × protein intake (g/day) + 0.0366 × phosphorus (mg/day) – 0.0205 × potassium (mg/day) – 0.0125 × calcium (mg/day) – 0.0263 × magnesium (mg/day)NEAP is assessed from the ratio of protein and potassium in the diet and calculated using the following formula:NEAP (mEq/day) = 54.5 × protein (g/day)/potassium (mEq/ day) – 10.2It has been shown that greater intake of a diet with high acid load may contribute to the increased risk of health conditions such as cardiovascular diseases , hypertehttps://ethics.research.ac.ir/IR.TBZMED.REC.1400.560.This systematic review and meta-analysis study follows the updated 2020 Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines . The proAn extensive systematic search of the literature was performed in electronic databases of PubMed, Web of Sciences, Scopus, Cochrane Library, and Google Scholar up to June 2021, with no publication date restriction. This was supplemented by searching for reference lists and citation tracking of included studies, and relevant reviews. The keywords and medical subject headings (MeSH) terms used for the search were as follows: “acid load OR dietary acid load OR potential renal acid load OR net endogenous acid production” AND “cancer.” The full search method for each database is available in The articles from the initial searches were imported into an EndNote software and duplicates were removed. Titles and abstracts of the remained articles were independently screened for potential eligibility by two reviewers (M.K and V.M) and any discrepancy was resolved by discussion or third researcher.The inclusion criteria were as follows: studies that considered the association between DAL and cancer; studies with prospective or retrospective cohort and case-control design; studies that expressed odds ratios (ORs) or hazard ratios (HRs) or relative risks (RRs) beside 95% confidence intervals (CIs) for the association between DAL and cancer. Studies with cross-sectional design, letters, comments, short communications, surveys, environmental, and animal studies were excluded.The required data were extracted from each eligible study by two independent researchers and any disagreement between the two researchers was resolved by discussion or by a third researcher. The extracted information was as follows: Name of the first author, year of publication, country, study design, type of studied cancer, number of participants, mean age and gender of participants, follow-up time for cohort studies, method of food intake assessment, method of DAL assessment, confounding variables, outcomes, and information regarding OR or HR or RR and 95% CI. If a study used both of the PRAL and NEAP indicators for assessing DAL, we considered that study as two separate studies in meta-analysis.The Newcastle Ottawa (NOS) scale  was usedI2 values as heterogeneity indices. I2 value > 50% between-study heterogeneity was considered significant. When between-study heterogeneity was significant, we performed subgroup analyses based on participants' gender, the mean age of the participants, type of cancer, and type of DAL assessment indicator to determine possible sources of heterogeneity. Publication bias was assessed using Egger's and Begg's regression asymmetry test (A random-effects model was used to estimate the pooled effect size (d) for comparison of the highest vs. the lowest categories of the DAL and to consider the heterogeneity between the studies . The rantry test . Small stry test . Sensitip-value <0.05 was reflecting the statistical significance of all tests.STATA version 14.0 was applied to perform statistical analyses. A n = 217), irrelevant (n = 460), animal (n = 2), review (n = 3), and in-vitro/in-vivo articles (n = 11), 12 publications met the topic and scope of the study during the first screening phase. Two studies were also removed during the second screening phase because these studies were conference. Finally, three cohorts  used the food frequency questionnaire (FFQ) tool for assessment of the food intake. In most the papers, effect sizes were adjusted for age (n = 10), BMI (n = 9), sex (n = 3), smoking (n = 8), alcohol consumption (n = 7), physical activity (n = 3), energy intake (n = 9), comorbidities (n = 4), cancer family history (n = 8), menopausal status (n = 4), education (n = 6), residence (n = 3), race (n = 3), and other dietary variables (n = 6). DAL assessment indicator was PRAL in nine studies and NEAP in seven studies. All cohort and four case-control studies obtained the NOS score of 9 and were of high quality and the score of other studies were 8 , demonstrating a significant positive relationship . As shown in Seventeen effect sizes from 10 studies were included in this analysis. Comparing the highest against the lowest DAL, the pooled effect size for the risk of overall cancer was 1.66 , p = 0.03] by high PRAL and NEAP, respectively. High DAL was associated with 32%  and 79%  increased risk of breast and colorectal cancers occurrence, respectively. High DAL was associated with 32%  and 76%  increased risk of cancer incidence in women and men, respectively. The risk of cancer incidence increased by 35%  and 49%  among people with age ≤ and > of 50, respectively.As shown in p = 0.038). Therefore, we did the trim-and-fill method and found that adding missing studies did not change the overall effect size [d = 0.36 (95% CI: 0.16-0.56)] . Based on the visual inspection of the funnel plot, we found an asymmetry ; however6-0.56)] .In the present meta-analysis of observational studies, a significant association was observed between higher DAL and the risk of cancer occurrence in the entire population. We found that the risk of cancer increased by 66% in participants with higher DAL compared to the participants with lower DAL. The positive association remained significant across cancer types, both genders, both DAL assessment indicators (PRAL and NEAP), and also among both high- and low-risk age groups for cancer.It is well known that factors such as sex, age, obesity, energy intake, smoking status, and physical activity level have a role in cancer development. On the other hand, the association of these factors with DAL has been evidenced in numerous researches. It has been shown that DAL has larger effects in the elderly than younger individuals and in women compared with men  and eldeCollectively, the above-mentioned factors may contribute to the relationship between high DAL and cancer incidence. However, all the studies reviewed have addressed this concern and considered the confounding effect of the factors in the DAL-cancer relationship analysis.The exact mechanism connecting high DAL to the risk of cancer remains yet unclear. There are several potential hormonal and non-hormonal mechanistic pathways to demonstrate the long-term effect of diet-dependent acidosis on carcinogenesis as follows:1) An acidosis diet May increase carcinogenesis by reduction of adiponectin secretion.Adiponectin is a 244-amino acid protein secreted mainly by adipocytes and act as an endogenous insulin sensitizer. Low circulating adiponectin level is supposed to have a critical role in the development and progression of multiple malignancies . As showin-vivo and in-vitro studies showed that metabolic acidosis prevented adiponectin gene expression and reduced adiponectin serum levels  An acidosis diet May increase carcinogenesis by elevation of cortisol production.Cortisol is a stress hormone that controls numerous processes throughout the body, such as metabolism and performance of the immune system. A growing body of evidence is suggesting a positive relationship between high cortisol levels and the progression of cancer –50. HighThe amount of protein in a diet or an acidifying diet or metabolic acidosis condition in the body may enhance the production of cortisol. Slag et al. showed that consumption of a high protein diet contributed to the increased release of cortisol in healthy individuals . Also, L3) An acidosis diet May increase carcinogenesis by elevation of circulating IGF-1 level.The insulin-like growth factor is a hormone with a critical role in the growth and mediates the anabolic effects of growth hormone or protein synthesis in muscle and skeletal tissues. Elevated circulating IGF-1 level promotes tumorigenesis, angiogenesis, and metastasis –58. IGF-Diet protein level or acidity or metabolic acidosis state of the body may elevate the production of IGF-1. An extensive body of studies have consistently indicated that intake of a high protein diet up-regulates the IGF-1 level. Schüler et al. reported that consumption of a high protein diet significantly increased IGF-1 levels in patients with type 2 diabetes . GiovannConcerning the association between DAL and IGF-1 concentration, research is too scarce. In a study, Lim et al. did not find any interaction effects between DAL and IGF-1 . Moreove4) An acidosis diet May increase carcinogenesis by elevation of insulin resistance.Insulin resistance (IR) is a pathological condition that presents when a disturbance occurs in the biological response to insulin. IR is well known to raise the risk of metabolic diseases such as cancer , 69. TheConsumption of a high protein diet, DAL, and metabolic acidosis may impact IR level. Results of a systematic review and meta-analysis of randomized controlled trials showed that intake of a high-protein diet may reduce IR levels in patients with type 2 diabetes . MorengaConcerning the association between DAL and IR level, Lee et al., in a study on 5,406 participants, concluded that DAL was positively correlated to the development of IR . Also, AThe inclusion of several prospective cohort studies with large sample sizes, in the present review, enhances the power of the findings. All the studies, except one, used the standard FFQ method to assess food intake, and all the studies used two validated measurements of PRAL and NEAP for DAL assessment which make it possible to compare results among studies. Studying various types of cancer across the studies was a limitation of the present study, which may impact the comparability of the findings. All the included studies were observational and there was no intervention study.The findings indicate that higher DAL may be associated with a higher risk of cancer incidence across cancer types, study populations, both genders, both DAL assessment indicators (PRAL and NEAP), and also among both high- and low-risk age groups for cancer.This finding highlights that high DAL, which reveals the metabolic and nutritional status of an individual, may have long-term effects on human health. As a primary prevention strategy against cancer, the elevation of knowledge and attitudes of people at the community level, toward harms of diets with high acid load through training and advertising may navigate people to healthier dietary habits. Moreover, at the clinical level, the providing of dietary recommendations regarding foods with low DAL may be of help to prevent the development and progression of cancer.Further evidence from interventional investigations is required to affirm findings from observational studies. Further researches are needed to evaluate: effect/association of the high DAL on/with the serum adiponectin and IGF-1 level, the relationship between dietary-induced metabolic acidosis with IGF-1, and the effect/association of high DAL on/with cellular proliferation, apoptosis, and signaling pathways involved in these events.The original contributions presented in the study are included in the article/SK and MA contributed to the concept, design, interpretation of the data, and preparation of the manuscript. MK and VM contributed to the articles searching process, data extraction and analysis. SK is responsible for design, writing, and final content of the manuscript. All authors have read and approved the final version of the manuscript.This study was funded by Tabriz University of Medical Sciences, Tabriz , Iran (grant number 68371).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To assess the association of HSD17B13 rs72613567:TA allelic variant with liver disease, we performed the current review and meta-analysis.Seven studies were identified by a search of CNKI,CBM,MEDLINE, PubMed, EMBASE, and CENTRAL databases from inception to November 2021. Odds ratios (ORs) with 95% confidence interval (CI) were calculated using random effects model or fixed effects model based on the between-study heterogeneity. The Stata 14.0 software was employed for data analysis.Statistical analysis showed that the HSD17B13 rs72613567:TA allelic variant can decrease the risk of hepatocellular carcinoma(HCC) in nonalcoholic fatty liver disease (NAFLD) patients, alcoholic fatty liver disease (ALD) patients and viral hepatitis patients  or healthy controls. Besides, the HSD17B13 rs72613567:TA allelic variant can also provide protection from nonalcoholic fatty liver disease (NAFLD) not only in entire population  but also in healthy people . No significant publication bias found in this airticle.The present findings suggest HSD17B13 rs72613567:TA allelic variant can reduce the risk of HCC and NAFLD in the entire population studied.The online version contains supplementary material available at 10.1186/s12876-021-02067-y. Chronic liver disease (CLD) is a progressive deterioration of liver functions for more than six months with a broad spectrum of etiologies, including viral infection, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease(ALD), autoimmune diseases, even hepatocellular carcinoma (HCC) . CLD is The current meta-analysis complied with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42020178246) .Relevant publications were identified through searching PubMed (Medline), China National Knowledge Infrastructure (CNKI), CBM, EMBASE and CENTRAL web databases using the following search terms: “Hydroxysteroid 17-β dehydrogenase 13” and “Liver Diseases”. What is more, we also checked the references of relevant articles to find any other potentially relevant papers. Table Inclusion criteria: (1) involving the associations between HSD17B13 rs72613567: TA allelic variant and liver disease; (2) case–control studies or cohort studies; (3) if two (or more) studies included the same population, the most recent was included to avoid repeated statistics; (4) providing complete data on genotype frequencies. (5) the diagnosis criteria of HCC or NAFLD is explained in the study. (6) no restrictions on language and age of participants. Exclusion criteria: (1) no clear diagnostic criteria for liver disease described; (2) not reported the genotype frequencies; (3) the OR values and 95% CI were not available by calculation; (4) case reports; (5) in vitro or animal studies.The information extracted by two independent investigators from each study included:the first author's surname, publication year, country in which the study was conducted, total numbers of patients in the case and control groups, sex ratio, as well as the numbers of cases and controls with the TA and T genotypes, whether genotype distribution was consistent with the Hardy–Weinberg equilibrium (HWE). Any disagreement was resolved by discussing with the third author until we reached a group consensus.I2 -statistic for all qualifed studies. If P < 0.05 or I2 > 50%, indicating significant heterogeneity, the random-effects model was applied to calculate pooled ORs. otherwise, the fixed-effects model was utilized. The suitability test was used to check whether the gene distribution of the control group consistent with the Hardy–Weinberg equilibrium, and the PH-W > 0.05 was regarded as consistent with the HWE. We also performed sensitivity analysis to explore the effect of a single study on overall results by removing one study sequentially. Egger's regression asymmetry test, Begger's regression asymmetry test and funnel plot were employed to assess publication bias.All the statistical analyses were performed with stata 14.0 software , with probability value of < 0.05 considered to be statistically signifcant.Summary odds ratio (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the association of the TA/T polymorphism in the HSD17B13 gene with liver disease under allele genetic contrast. Heterogeneity was measured by Cochran’s Chi square-based Q test and Figure The main results of the meta-analysis are displayed in Table Five articles were included in the HSD17B13 rs72613567: TA allelic variant and risk of NAFLD. Using random-effect model, we found the HSD17B13 rs72613567: TA allelic variant can reduce the risk of NAFLD in the entire population: TA vs T OR = 0.669, 95% CI = 0.524–0.856, P = 0.001 , and use suitable mathematical models to perform quantitative analysis of multiple identical or similar research results, increasing the test efficiency of research results.To our knowledge, this is the first meta-analysis to analyze the effects of HSD17B13 rs72613567: TA allelic variant on the risk of NAFLD in healthy population and viral hepatitis patients. And for the first time, the result was obtained that HSD17B13 rs72613567 can reduce the risk of NAFLD. Besides, we not only analysis the association between HSD17B13 rs72613567: TA allelic variant and susceptibility to hepatocellular carcinoma (HCC) compared with healthy controls, but also compared with CLD. That means that HSD17B13 rs72613567 can not only reduce the risk of HCC in healthy people, but also have a protective effect in patients with CLD.Currently, there is no specific treatment for HCC and NAFLD. The results got in the meta-analysis demonstrated that HSD17B13 rs72613567 can protect against HCC and NAFLD. This could be the light for seeking a therapeutic target for HCC and NAFLD. Along with the advance of genomic studies, genome editing techniques have also tremendously developed. Using Gene editing techniques such as transcriptional activator-like effector nuclease (TALEN) and CRISPR-associated nuclease , the HSDMeanwhile, there are still some limitations in this article. Firstly, due to the lack of a unified document quality evaluation standard, the included articles are subjectively selected and evaluated, which may affect the stability of the meta-analysis results. Secondly, since meta-analysis itself is a retrospective study, there is a degree of bias. Thirdly, due to the limited number of articles included, the credibility of the results of the meta-analysis may be impacted. Fourthly, this study only included case control studies, which may affect the credibility of the results. Fifthly, obesity, age, gender, alcohol intake, intake of the fungal metabolite aflatoxin, and hepatitis B and C infections may contribute to HCC and NAFLD, but we did not take these into consideration. Due to these limitations, we still need to expand the sample size to further and systematically evaluate studies.In summary, the polymorphism of HSD17B13 rs72613567: TA allelic variant can reduce the risk of HCC and NAFLD.The present findings suggest HSD17B13 rs72613567:TA allelic variant can reduce the risk of hepatocellular carcinoma and NAFLD in the entire population studied.Additional file 1. Sensitivity analysis and bias analysis figures.


GAK rs1564282 variant in Parkinson’s disease (PD) in Europeans was identified using a series of published genome-wide association studies. Recently, some studies focused on the association between rs1564282 and PD risk in Chinese populations but with inconsistent results. Thus, we conducted an updated meta-analysis with a total of 7,881 samples  from eligible studies. After excluding significant heterogeneity, we showed that the rs1564282 variant was significantly associated with PD in Chinese populations . The sensitivity analysis showed that the association between rs1564282 and PD was not greatly influenced, and there was no significant publication bias among the included studies. Consequently, this meta-analysis indicates that the GAK rs1564282 variant is significantly associated with susceptibility to PD in Chinese populations.The susceptibility of the  GAK/DGKQ as a new PD risk region in a Caucasian population (GAK rs1564282 variant was associated with the increasing risk of PD (Parkinson’s disease (PD) is the second-most common neurodegenerative disease after Alzheimer’s disease . With thpulation . The folsk of PD . Subsequp = 0.017)  . Then a = 0.017) .In 2013, Chen et al. recruited 376 PD patients and 277 healthy controls from west China and identified an association between rs1564282 and PD . The preIn 2015, Yu et al. analyzed 534 PD patients and 435 neurologically healthy controls from west China and found that rs156428 was significantly associated with PD .The inconsistent association results from the previous studies may be due to at least two reasons: genetic heterogeneity and small sample sizes. Firstly, genetic heterogeneity among the previous studies may lead to the inconsistency. Although all the previous studies included Chinese populations, their population compositions (or structures) and geographical environment at largely varied. In other words, the associations between the risk variants and PD may be different among different populations. Secondly, the smaller sample sizes of the previous studies may also contribute to the inconsistency. In these previous studies, Tseng et al. recruited 978 and 777 samples from Taiwan and Singapore population respectively while the Tian et al. used 2049 individuals for analysis. The results of these studies showed that larger sample sizes provided greater power in discovering significant genetic associations. Because of the inconsistent results, the association between rs1564282 and PD in Chinese populations needs further research. Thus, we conducted a new meta-analysis to investigate the association between rs1564282 and PD via combining previous case–control cohort data.http://www.ncbi.nlm.nih.gov/pubmed), Google Scholar (https://scholar.google.com/), China National Knowledge Infrastructure  and Wanfang Medicine database (http://www.wanfangdata.com.cn/). We screened all the relevant studies using the following terms: “Parkinson’s disease”, “GAK” and “Chinese or China”. Literature published before July 31, 2021 was selected. The detailed content of the inclusion and exclusion criteria is given in the Study Selection section.A systemic literature search was performed in four databases: PubMed (The eligible studies satisfied the inclusion criteria: 1) case–control designed studies in humans, 2) studies calculating the association between rs1564282 variant and PD and 3) studies providing the number of rs1564282 genotypes or adequate data for the calculation of the odds radio (OR) and a 95% confidence interval (CI). Studies that did not satisfy the inclusion criteria were excluded.Two investigators independently extracted the following available data from studies: 1) name of the first author; 2) year of publication; 3) population of study; 4) numbers of PD cases and controls; 5) genotype distribution of rs1564282 in cases and controls; and 6) OR with 95% CI or data for calculating OR and 95% CI.The additive genetic model was used to estimate the association between rs1564282 and PD: the T allele versus the C allele.p < 0.001. We conducted the heterogeneity test using Cochran’s Q test and I2 statistic . The p-value of Cochran’s Q test <0.1 means a significant heterogeneity exists among the studies. The statistic I2 , with a higher percentage indicating a greater degree of heterogeneity (p < 0.1 of Q statistic and I2 > 50%), a random-effect model was used for meta-analysis, otherwise a fixed-effect model was chosen. The statistical significance of OR was calculated utilizing a Z-test, with p < 0.05 considered significant. We completed the sensitivity analysis through removing any study from the included studies in turn to evaluate the influence of each study on pooled OR and related p-value (http://www.r-project.org/).The Hardy–Weinberg equilibrium (HWE) of rs1564282 in the control for each study was calculated respectively with a chi-squared test at tatistic . The Q sogeneity . If ther p-value . Publica p-value . The sigUtilizing our literature search methods, we obtained 20 articles from four databases . Firstlyp < 0.001. Neither Cochran’s Q test nor I2 statistic identified significant heterogeneity of rs1564282 polymorphism among the seven studies in Chinese populations (p = 0.44 and I2 = 0%).We evaluated the HWE of rs1564282 in controls for each study respectively. We did not find significant deviation from HWE at GAK rs1564282 and PD with p = 1.00E-04, OR = 1.28 and 95% CI = 1.16–1.42. More information on the meta-analysis results are shown in Because there was no significant heterogeneity of rs1564282 polymorphism, we computed the general OR with 95% CI using a fixed-effect model. The meta-analysis results demonstrated significant association between The sensitivity analysis was conducted by removing each study at a time. We found that omitting any eligible study did not substantially influence the overall association between rs1564282 and PD .p = 0.77).The funnel plot was used to estimate the publication bias of the included studies. The shape of the funnel plot was symmetrical and inverted . The regGAK rs1564282 and PD was first reported in a familial PD GWAS and replicated by following studies in European populations  in the cortex of PD cases than controls using microarray data  by forming a complex   . Song etvo model . Throughvo model . Researcvo model . Furthervo model . Recent fication .SNCA, LRRK2 and MCCC1 genes had genome-wide significant associations with PD susceptibility in both Chinese and European population (MAPT and GBA genes might be “European-specific variant loci” (GALC, IL1R2, SATB1, BIN3 and COQ7 genes (So far, PD GWASs and relevant large-scale meta-analyses have identified tens of risk loci in European population . As a vipulation . In the nt loci” . In subsQ7 genes .GAK rs1564282 variant on PD in Chinese populations.Several studies estimated the underlying association between rs1564282 and PD risk in Chinese populations in China and Singapore . However


Studies have reported controversial findings regarding the flaxseed oil effect on antioxidant status biomarkers. The present meta-analysis aimed to determine the impact of flaxseed oil on the serum level of biomarkers of oxidative stress.  A systematic search was conducted up to November 2020 on PubMed, Embase, Web of Science, Scopus, and Cochrane Central Library. Random-effects model was employed to perform meta-analysis. Subgroup analysis was carried out to determine the effect across different ranges of dosages and durations. μmol/L; 95% CI: −0.89, −0.15; P=0.006, I2 = 71.3, P < 0.001) and increase in total antioxidant capacity (TAC) levels . No significant effect was observed on glutathione (GSH).  Eight trials were included with a total sample size of 429 individuals with a mean age range of 25 to 70 years. The results indicated that flaxseed oil supplementation led to a significant decrease in malondialdehyde (MDA) levels (SMD: −0.52  Our findings revealed that flaxseed oil supplementation might play a beneficial role in the reinforcement of the antioxidant defense system and amelioration of oxidative stress in adults. Oxidative stress (OS) is an imperfection in the balance between reactive oxygen/nitrogen species (ROS/RNS) and the total antioxidant capacity of organisms . An incrFlaxseed oil is a rich source of alpha-linolenic acid and some effective phytochemicals such as lignan (secoisolariciresinol diglucoside-SDG), phenolic acids, and flavonoids –14. It h∗” was used to increase the sensitivity of our search strategy.The scientific international databases, including PubMed, Embase, Web of Science, Scopus, and Cochrane Central Library, were searched for relevant studies published up to November 2020. In the search strategy, MeSH terms and keywords were included without using language limitations (except Persian language). The search was conducted using the following search pattern: [(“Flax” [MeSH])OR (“flaxseed” [tiab]) OR (“flaxseed” [tiab]) OR (“linseed”[tiab]) OR (“lignan” [tiab]) OR (“whole flaxseed” [tiab]) OR (“ground flaxseed” [tiab]) OR (“flaxseed oil” [tiab]) OR (“Linum usitatissimum” [tiab]) AND [(“Oxidative Stress” [MeSH) OR (“Oxidative Stress” [tiab]) OR  OR (“anti-oxidant” [tiab]) OR (“Oxidant” [tiab]) OR (“reactive oxygen species” [tiab]) OR OR(“glutathione” [tiab]) OR (“TAC” [Title/Abstract]) OR (“GSH”[tiab]) OR (“MDA” [tiab])] AND [(“InterventionStudies” [tiab) OR (“intervention” [tiab) OR  OR (“randomized” [tiab]) OR (“randomised” [tiab]) OR (“random” [tiab]) OR (“randomly” [tiab]) OR (“placebo” [tiab]) OR (“assignment” [tiab]) OR  OR  OR (“RCT” [tiab]) OR (“double blinded” [tiab]) OR  OR ]. The wild-card term “RCTs with the following criteria were included in our meta-analysis: either crossover or parallel design, investigating the effect of flaxseed oil on oxidative stress parameters and providing sufficient data on oxidative stress parameters  at baseline and the end point for both intervention and control groups. Other studies, including in vitro, in vivo, and ex vivo studies, observational studies , and quasi-experimental studies, were excluded from this meta-analysis. Besides, studies on pregnant and lactating women were excluded.Two independent reviewers (MA and ZF) screened the articles according to the inclusion criteria. The title and abstract of the studies were reviewed in the first step. Then, relevant studies were evaluated to ensure the suitability of a study for full-text assessment. Any disagreement was resolved by discussion with the senior author (AO).From the selected studies, the following data were extracted and entered in the review: first authors' name, publication year, sample size, study location, mean age of participants, the dose of flaxseed oil, study design, study duration, and baseline and end-point values (as means and SDs) for MDA, GSH, and TAC in both intervention and control groups.The Cochrane Collaboration's risk of bias tool was employed to assess the risk of bias for each study. The tool consists of seven domains, including random sequence generation, allocation concealment, performance bias, reporting bias, detection bias, attrition bias, and other sources of biases. If the study contains a methodological defect, each domain was given a “high-risk” score that may affect its findings; if there was no defect for that domain, a “low-risk” score was given; if the information was insufficient to determine the effect, an “uncertain risk” score was given. If the trial had “low risk” for all domains, a high-quality study was considered a totally low risk of bias. Risk bias assessments were performed independently by two reviewers , 28.I2 statistics and Cochrane's Q-test. I2 value > 50% or P < 0.1 for the Q-test was considered as significant heterogeneity [n ≤ 26/n > 26), mean age of participants (≤48/>48 years), and the type of flaxseed products (flaxseed oil/omega-3 fatty acid from flaxseed oil). The sensitivity analysis was used to determine the dependence of overall effect size on a particular study. Egger's test and visual inspection of the funnel plot were used for identifying publication bias. In case of the presence of publication bias, trim-and-fill analysis was performed to simulate a model without publication bias by presenting a new effect size with inserting new fictitious studies. All the statistical analyses were performed using Stata, version 16 . P < 0.05 was considered as the significance level.To obtain the overall effect size, mean and SD changes in the flaxseed oil and control groups were analyzed. When mean and SD changes were not reported in the included studies, the values were calculated by subtracting baseline values from end-point values. Medians, standard errors (SEs), confidence intervals (CIs), and interquartile ranges (IQRs) were transformed into means and SDs using the method of Hozo et al. . We applogeneity , 31. If Eight effect sizes from 8 RCTs published between 2011 and 2020 were included in the systematic review and meta-analysis. The flow diagram of the study selection procedure is presented in In all trials, except the study conducted by Pilar et al. , particiμmol/L; 95% CI: −0.89, −0.15; P=0.006) , in which mean age, treatment dosage, sample size, and duration of studies were shown as sources of it  . The leves of it . There wes of it .μmol/L; 95% CI: −0.12, 1.01; P=0.122)  in which the mean age of individuals was identified as the source of high heterogeneity following subgroup analysis (Combining the data of 4 studies showed no significant effect on GSH levels (SMD: 0.45 P=0.122) . There wanalysis . Howeveranalysis .P=0.01)  decreased by subgrouping subjects by their mean age and flaxseed type.A significant increase in the TAC level was observed by flaxseed oil supplementation in the combined analysis of 5 studies  . SignifiThe overall effect size regarding the effects of flaxseed oil on GSH levels was sensitive to Soleimani et al. . The stuP=0.089) (P=0.221)    and TAC P=0.221) . Moreovectively) .γ), reducing malondialdehyde levels by preventing them from being exposed to free radicals [κB-induced gene expression [In this meta-analysis, our results showed that flaxseed oil supplementation significantly decreases MDA serum levels and increases the TAC levels significantly. No significant effect was observed on GSH levels. After subgroup analysis based on administered dosage, sample size, mean age, and duration, the level of heterogeneity was reduced. Flaxseed oil supplementation for ≤8 weeks significantly reduced MDA levels, whereas interventions for >8 weeks did not. In addition, the dose-dependent subgroup analysis showed that a flaxseed oil dosage of ≤2000 mg/day led to a significant decrease in the MDA level. Some leading causes of the observed variation in the findings may be food intake, physical activity, and the participant's clinical state. In the study conducted by Jamilian et al., a 6-week supplementation with 2000 mg/day flaxseed oil in patients with GDM significantly decreased MDA levels . Similarradicals . Other mradicals . Also, spression , modificpression , and NADpression  which ispression .Increasing TAC levels via flaxseed oil supplementation was another important finding of this meta-analysis. The mean age of participants and flaxseed type were found to be potential sources of heterogeneity in subgroup analysis. In addition, the subgroup analysis in terms of mean age (>48), dosage, duration, and type of flaxseed products (omega-3 fatty acid from flaxseed oil) did not result in any significant difference. Moreover, in a study on patients with polycystic ovary syndrome , 1000 mgResults obtained from the analysis showed that flaxseed oil supplementation had no significant effect on the GSH level. The mean age of participants was found to be a possible source of heterogeneity in subgroup analyses. The heterogeneity was more considerable in studies with mean age >48. However, GSH levels were significantly increased in participants aged <48 and in the studies that used flaxseed oil-derived omega-3 fatty acids. Previous studies have shown that 2000 mg/day of flaxseed oil supplementation can increase GSH levels . On the An earlier meta-analysis  showed aThe following are some of the meta-analysis strengths: all of the included articles were RCTs from the last ten years, providing a relevant and up-to-date review. The majority of the included studies had a low risk of bias and were of high methodological quality. Our study also has some limitations: although significant between-study heterogeneity was observed, the potential sources of heterogeneity were revealed to be the differences in the treatment dose and duration. Moreover, the number of studies included in this review was few.Overall, the results of this meta-analysis showed that flaxseed oil supplementation reduced MDA levels. Moreover, flaxseed oil supplementation increased the TAC levels but was not effective on GSH levels. It seems that flaxseed oil could be considered as an effective agent in augmenting the antioxidant defense system which indicates the efficiency of being set in the regular diet. However, additional clinical trials with larger sample sizes in various health conditions are required to clarify this more accurately.


Maternal tobacco exposure during pregnancy is known to cause a potential hazard to the offspring's health. So far, published studies have shown no consistent results with whether tobacco exposure in utero is causally linked to the development of allergic rhinitis in offspring. The aim of this study was to comprehensively evaluate the association between maternal tobacco exposure during pregnancy and allergic rhinitis in offspring by meta-analysis and to provide reference for clinical work.Literatures were searched in CNKI, Wanfang Data, VIP, SinoMed, PubMed, Web of science and Embase up to September 30,2020. Screening, inclusion, quality assessment, data extraction and data analysis of the literatures were conducted. Meta-analysis was performed with Revman 5.3 and State15.1 software. Odds ratio (OR) and 95%CI were used as observation indicators.We had retrieved 16 articles with 22 independent datasets and 11,49,879 sample size. When all the studies were analyzed together, the results showed that maternal smoking exposure during pregnancy would increase the risk of allergic rhinitis in offspring , especially maternal passive smoking during pregnancy . But subgroup analysis showed that maternal active smoking during pregnancy was only significantly associated with offspring allergic rhinitis in cross-sectional studies  and study done in America study .Tobacco exposure during pregnancy could increase the risk of allergic rhinitis in offspring. The importance of avoiding prenatal tobacco exposure should be emphasized more for the health of next generation in the public. In the past several decades, the prevalence has increased in the world. However, the aetiology of allergic rhinitis is not well established.Allergic rhinitis is a prevalent and immunoglobulin E mediated non-infectious chronic inflammatory disease, referring to individual nasal mucosa contacting with allergens, and typical symptoms include sneezing, pruritus, rhinorrhea and nasal congestion, can be accompanied by eye symptoms such as itchy eyes, watery eyes, and conjunctival congestion symptoms. in general population was associated with the development of allergic rhinitis in the non-pregnant state. Because a large amount of smoke produced in the smoking process causes serious pollution to the working and living environment, which may increase the allergens in the air, including a variety of harmful components such as formaldehyde, acrolein and other irritating compounds can directly stimulate the respiratory mucosa and cause vasospasm and contraction of the nasal mucosa. Long-term effect will lead to damage to the ciliary cells of the nasal mucosa, becoming the inducement of allergic rhinitis and aggravating the condition.Tobacco exposure is a common environmental factor. It had been reported as an important factor involving in allergic rhinitis. One meta-analysis has recovered that not active smoking, but passive smoking Many studies have demonstrated that prenatal and neonatal factors, such as pregnancy diseases, delivery mode and feeding type may influence the risks of allergic rhinitis in offspring.,10 Tobacco exposure is also the most important toxic exposures in utero and in early life, which has been implicated in the aetiology of asthma and some allergic disease in offspring. However, the aforementioned meta-analysis showed that maternal smoking exposure during pregnancy is not associated with the risk of allergic rhinitis in the offspring. But active smoking during pregnancy vs passive smoking during pregnancy or other subgroup analysis had not been considered in the analysis. Furthermore, more and more studies still further focus on this topic and have assessed the association between smoking exposure during pregnancy and allergic rhinitis in the following years. Some studies showed that not only maternal active smoking–14 but also maternal passive smoking–17 could increase the risk of AR in offspring. However, others have showed conflicting evidence suggesting that both maternal active smoking–16,18–25and maternal passive smoking have no effect on the risk of allergic rhinitis in offspring. Hence, published studies have shown conflicting results. Whether smoke exposure in utero is causally linked to the development of offspring allergic rhinitis or not is an unsettled matter. Therefore, it is necessary to summarize all of available evidence and carry out meta-analysis on tobacco exposure during pregnancy, the critical time window, on the risk of allergic rhinitis in offspring. We aim to provide more reference for clinical work of allergic rhinitis management and ensure public health safety.Substantial evidence suggests that detrimental environmental factors exposure in early life not only influence prenatal development, but also may produce structural and functional alteration, leading to increased risks of metabolic, cardiovascular, and neuroendocrine disorders in offspring. “Fetal origin theory of adult disease” or “Developmental Origins of Health and Diseases (DOHaD)” theory, has become the foundation for this increasingly popular scientific field.22.1Comprehensive literatures were searched in CNKI , Wanfang Data, VIP , SinoMed, PubMed, Web of science and Embase. We have applied the following algorithm both in medical subject heading and in free text words: AND  AND (“offspring” OR “children” OR “child”) AND (“risk factors” OR “risk factor” OR “influence factors” OR “influence factor” OR “relative” AND “risk” OR “relative risk” OR “risks”). To identify all potentially eligible studies, the references lists of all comprised studies were examined. We searched from the beginning of databases up to September 30, 2020. No language restriction of publication was applied.2.2Studies were selected when:1.the study type was cohort, case-control or cross-sectional study.2.the outcome of interest was offspring's allergic rhinitis defined by physician diagnosis, skin prick test (SPT) or international study of asthma and allergies in childhood (ISAAC) questionnaires or questionnaires.3.the exposure factor was maternal smoking during pregnancy including maternal active smoking and maternal passive smoking.4.studies offered available data on the relevant risk estimates including odds ratio (OR) and their confidence intervals (CI), or enough data to compute them.2.3The information of each eligible study was extracted: study design, the name of the first author, year of publication, population origin, diagnostic mode, sample size, children age when investigated, maternal active or passive smoking. was used. There were 8 items in the NOS and the total score was 9 points, including 4 items (4 points) in the study population selection, 1 item (2 points) in the inter-group comparability and 3 items (3 points) in the measurement of the results. The literature with score ≥ 6 is considered to be high quality and was included Two researchers read through the articles to selected relevant studies, abstracted data and evaluated methodological quality of included studies independently. If no agreement was reached, then a third researcher would help to decide.2.42statistics. When P > .1 and I2 < 50%, it shows that the heterogeneity of the studies is not significant, and the fixed effect model is used, whereas the random effect model is used. In addition, subgroup analyses were conducted to explore reasons for heterogeneity based on exposure type (active or passive smoking), study design, population origin, maternal complications. Publication bias was assessed using funnel plot and Begg's rank correlation. Sensitivity analysis was performed by exclude the study one by one. P < .05 was deemed statistically significant.The statistical analysis was performed using Stata version 15.1 (StataCorp) and Review Manager 5.3 (Cochrane). The odds ratio (OR) and its 95%CI were transformed to natural logarithms to normalize their distribution, stabilize variances, and it's convenient to compute standard errors. The pooled odds ratio (OR) and its 95%CI for each outcome of interest were calculated by weighting the inverse of variance. Preference should be given to estimates adjusted for potential confounding factors rather than rough estimates. The study heterogeneity was tested by using Cochrane Q test and I3 Finally,16 articles–26 that met the inclusion criteria and with high quality were included.The flow diagram of the review process is presented in Figure 3.1,19,22,23 were cohort studies and 2 studies,21 was case-control study. All cohort and case-control studies scored well using the NOS achieving scores between 6 and 9  Critical Appraisal tool .Study characteristics of the 16 included studies are presented in Tables 3.2P = .978 (>.05), indicating no publication bias in this meta-analysis. Heterogeneity test showed significant heterogeneity among 16 studies , so the random effect model was used for all studies including subgroup analysis.The funnel diagram showed that the left and right distribution of each study is basically symmetrical Fig.  and the P = .02)  in case control studies and cohort studies, while maternal smoking during pregnancy was significantly correlated with offspring allergic rhinitis  in the cross section study and in Oceania study , while there was a significant correlation between maternal smoking during pregnancy and offspring allergic rhinitis in Asia  and in America study  , while maternal passive smoking was significantly associated with offspring allergic rhinitis  , sub-group analyses in this condition was carried out in further, and the results showed that in the cohort study there was no significant correlation between maternal active smoking during pregnancy and offspring allergic rhinitis , while in cross-sectional study there was a significant correlation  , while no significant correlation in Asia study , Europe study and Oceania study  , and increased asthma risk in children ≥6years old by 22% . Chunhong Duan's meta-analysis indicated that maternal smoking during pregnancy could increase the risk of recurrent wheezing in infancy. It is concluded that environmental tobacco smoke exposure increases the risk of wheeze or asthma in children by at least 20%. Smoking during pregnancy and exposure to environmental tobacco smoke in childhood may be non-allergic factors associated with increased risk and incidence of persistent asthma or rhinitis. The result of our meta-analysis and systematic review displayed that active and passive smoking exposure during pregnancy could increase the offspring allergic rhinitis risk by at least 13%. With the previous meta-analysis, which showed that allergic rhinitis was not significantly associated with active smoking , but was significantly associated with passive smoking  in the non-pregnant state. Taken together, it is clear that environmental tobacco smoke at anytime would play an important role in the development of allergic rhinitis.Exposure to environmental tobacco smoke at critical times (i.e. during pregnancy and early life) has been identified as a potential cause of allergic disease in children.,38 A number of animal studies have been implemented to uncover the mechanism. Rhesus monkeys studies have suggested nicotine exposure during pregnancy as the key factor causing alterations in pulmonary function, possibly because nicotine is transported across the placenta and directly interacts with nicotinic acetylcholine receptors in pulmonary vessels to alter connective tissue expression and cause vascular structural alterations.,40 Ferrini's study has revealed that prenatal exposure to environmental tobacco smoke predisposes offspring to an exacerbated allergic airway inflammation, which is associated with a reduction in pulmonary NK cell function. Environmental tobacco smoke exposure during pregnancy is considered as possible factor of the development of childhood allergic diseases through epigenetic mechanisms,–45 mainly including histone acetylation, microRNA (miRNA) expression, and DNA methylation. However, the causal relationship between smoking during pregnancy and offspring allergic rhinitis is not well defined.Epidemiological studies have demonstrated that perinatal environmental smoking exposures have adverse effects and are important contributors in the development of offspring asthma or allergic disease. Clinic studies disclosed that fetal exposure to maternal active or passive smoking was related to lower birth weight, which increased the risk for reduced lung function, respiratory tract infections and asthma or wheeze.P = .29), but only significantly associated with allergic rhinitis in their offspring in cross-sectional studies and studies in Asia and America, possibly due to the limitations of the types of included literature and the diversity of the distribution area of the study population. And that many studies have defined allergic rhinitis by questionnaire, which has inherent limitations based on the design, such as the respondents may have memory bias. Therefore, future studies should use more objective methods to diagnose allergic rhinitis, make objective measurements of environmental tobacco smoke, such as measuring nicotine in hair and design more cohort study.The strength of our study is that we comprehensively analyzed the relationship between maternal exposure to smoking during pregnancy and the risk of allergic rhinitis in offspring so far. We estimated aggregate data from 22 independent datasets, including 1,149,879 participants. Moreover, the quality of the included literature was generally good. However, the results of this study are subject to several limitations. Firstly, we can’t exclude literatures that may not contain potential confounding factors, such as maternal factors, fetal factors, intrauterine environmental exposure and postnatal environmental exposure that are all directly or indirectly related to the results. Secondly, we found a significant association between smoking during pregnancy and allergic rhinitis in offspring in cross-sectional studies, but not in cohort studies, possibly due to the few cohort studies included. Thirdly, maternal active smoking during pregnancy was not significantly associated with offspring allergic rhinitis in all of included studies  for their help in the codification process of this studyConceptualization: Yaqian Zhou, Yunpeng Dong.Data curation: Yaqian Zhou, Junrong Chen, Jinhua Shen, Yide Yang.Formal analysis: Yaqian Zhou.Funding acquisition: Jian Li.Investigation: Yaqian Zhou.Methodology: Yaqian Zhou, Yide Yang.Supervision: Jian Li, Yunpeng Dong.Validation: Yunpeng Dong.Visualization: Yunpeng Dong.Writing – original draft: Yaqian Zhou.Writing – review & editing: Mei Tian, Liujiang Song, Jian Li.


It is well-established that the association between atherosclerotic cardiovascular diseases (ASCVD) and connective tissue diseases (CTDs), but the relationship between coronary heart disease (CHD) and idiopathic inflammatory myopathies (IIMs) remains controversial yet. The aim of this meta-analysis is to systematically evaluate the risk of CHD in IIMs patients. In addition, we explore differences in traditional cardiovascular risk factors between IIMs patients and controls.We searched Pubmed, EMBASE and Cochrane databases to identify relevant observational studies published in English up to August 2021. Pooled relative risk (RR) and 95% confidence interval (CI) was calculated using the generic inverse variance method for the risk of CHD. A meta-proportion analysis was conducted to assess differences in cardiovascular risk factors between two groups.A total of 15 studies met inclusion criteria: seven studies focused on CHD and nine studies focused on traditional cardiovascular risk factors. The results demonstrated that IIMs patients had a higher risk of CHD . Hypertension , diabetes mellitus  and dyslipidemia  were more prevalent in IIMs patients compared with controls. However, there was a significant heterogeneity among studies assessing the risk of CHD and hypertension. Subgroup analysis demonstrated that definition of CHD, country and sample size may be potential sources of heterogeneity.IIMs patients were at increased risk of CHD, and traditional cardiovascular risk factors appeared more prevalent in IIMs patients. This systemic review offers the proof that early appropriate interventions could reduce cardiovascular-associated morbidity and mortality in IIMs patients. Idiopathic inflammatory myopathies (IIMs), also referred to generally as myositis, are a group of rare, chronic inflammatory autoimmune disorders, with the annual incidence and prevalence rate of 5.8–7.9 per 100,000 person-years, 14.0–17.4 per 100,000 person-years, respectively . DM and It is worth mentioning that multiple studies have exhibited a strict association between connective tissue diseases (CTDs) and CHD risk, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), but the risk of CHD in IIMs patients is still inconclusive due to the conflicting epidemiological studies –10. SomeThis systemic review and meta-analysis was conducted according to the recommendation of Meta-Analyses of Observational Studies in Epidemiology group (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement , 20. TwoThe inclusion criteria of this review were as follows: (1) Although it is currently recommended to use the new EULAR/ACR classification criteria for adult and juvenile IIMs and their major subgroups , studiesRelevant data of the eligible studies were independently collected by two reviewers. The following information was extracted from each study: last name of the first author, year of publication, country, study design, sample size, demographic characteristics of the study population, and study results. The quality of included studies was assessed according to the Newcastle-Ottawa Scale (NOS), which mainly included three domains  with eight items . The higOur primary outcomes of interest were CHD, hypertension, diabetes mellitus and dyslipidemia, and these end points were treated as dichotomous variables. CHD included angina pectoris, myocardial infraction (MI) and unstable angina, which diagnosis was based on patients' medical charts, registry databases, or self-reports. Hypertension was defined as blood pressure consistently above 140/90 mmHg, or antihypertensive drugs use, or diagnosis of hypertension in medical charts, registry databases, or self-reports. Diabetes mellitus was defined as fasting blood glucose ≥7.0 mmol/L, or typical symptoms of diabetes mellitus with random blood glucose ≥11.1 mmol/L, or glycosylated hemoglobin (HbA1c) ≥6.5%, or intake of hypoglycemic medications, or diagnosis of diabetes in medical records, registry databases, or self-reports. Dyslipidemia was defined as triglyceride (TG) level ≥150 mg/dL, total cholesterol (TC) level ≥220 mg/dL, low-density lipoprotein cholesterol (LDL-C) level ≥140 mg/dL, high-density lipoprotein cholesterol (HDL-C) level ≤ 40 mg/dL, or use of lipid-lowering medications, or diagnosis of dyslipidemia in medical charts, registry databases, or self-reports.I2 statistics were applied to evaluate statistical heterogeneity among studies, and a higher I2 value indicating a higher level of heterogeneity. An I2 value of 0–25, 25–50, 50–75, and 75–100%, was considered as insignificant, low, moderate, and high heterogeneity, respectively , subgroup analysis or sensitivity analysis was conducted to explore the potential source of heterogeneity. In the current study, funnel plot analysis could not be conducted as <10 studies were included in each meta-analysis. All tests were two-tailed, and P < 0.05 was considered to be statistically significant except for assessing the presence of heterogeneity.All statistical analyses were performed using Review Manager 5.4 software  and Stata 16.0 software . As the outcome of interest (CHD risk) was relatively uncommon, and only one case-control study reported the estimate as OR, thus we use OR as an estimate for RR to calculate the pooled effect estimates. Moreover, adjusted point estimates and standard errors were collected from individual studies and were combined by using the generic inverse variance method of DerSimonian and Laird . The metOur search strategy yielded a total of 1,451 and 5,040 potentially relevant articles associated with CHD risk and cardiovascular risk factors, respectively. After eliminating duplicate articles, the remaining 1,330 and 4,605 articles were screened based on titles and abstracts, respectively. At this stage, 1,317 and 4,585 studies were excluded as they were unrelated to the current study, and the remaining 13 and 20 articles were subjected to full-text review. Of them, nine articles  were excluded due to lacking available data, and 8 articles  were also excluded as they utilized the same database. For example, the study by Antovic et al.  and the In all eligible studies, seven studies (six cohort studies and one case-control study) were relevant to CHD risk and nine studies (five cohort studies and four case-control studies) were relevant to traditional cardiovascular risk factors. Among the studies on the risk of CHD, the number of IIMs patients ranged from 350 to 10,156, with the mean age of IIMs patients ranging from 46.1 to 62.4 years, and the proportion of females in the case group ranged between 45 and 73.2%. Moreover, five of these studies strictly defined CHD as MI or acute coronary syndrome (ACS) –14, 16, P = 0.0006), but the heterogeneity was high among the studies . Therefore, we conducted the subgroup analysis and sensitivity analysis. Subgroup analysis categorized by the country and the definition of CHD, and the results were summarized in I2 statistics of 60 and 75%, respectively. What's more, the pooled RR of subgroup in MI and ACS was 2.27 and 2.30, indicating that MI and ACS were indeed more prevalent in patients with IIMs compared with non-IIMs population. Besides, sensitivity analysis was conducted by sequentially omitting each individual study to assess the stability of the results. The pooled estimates did not significantly change at each step, suggesting that the results of this meta-analysis were relatively robust. Notably, all cohort studies presented that there was an increased risk of CHD in IIMs patients, but the only case-control study did not show an increased risk. When excluding this case-control study, the pooled RR of all cohort studies was 2.44 (95% CI: 1.86–3.21), with a relatively low heterogeneity (I2 = 73%).The forest plots of the meta-analysis were presented in P < 0.00001), but the statistical heterogeneity was significant among these studies, with an I2 of 58% (P = 0.01). Notably, these seven studies were conducted in six different countries, and the number of IIMs patients ranged from 28 to 4,958 among these studies. We assumed that the different geographic regions of the country and sample size may be the potential source of heterogeneity, so we performed a subgroup analysis according to the above variables. In our study, a large sample study was defined as the number of case groups >500, otherwise, the study was categorized as a small sample study. The results of our subgroup analysis were listed in I2 = 68%).As shown in P < 0.00001), as presented in I2 = 29%, P = 0.19).We identified seven studies with 7,385 IIMs patients that assessed the prevalence of diabetes mellitus –32, 34. P = 0.0004), implying that dyslipidemia was more prevalent in IIMs patients .A total of three studies including 905 IIMs patients and 7,409 controls that evaluated the prevalence of dyslipidemia in patients with IIMs , 31, 33,patients . What's To our knowledge, the current study included the largest study population and provided the latest meta-analysis of the risk of CHD and the prevalence of cardiovascular risk factors  in IIMs patients. The results of our study demonstrated an increased risk of CHD in patients with IIMs in comparison with the non-IIMs subjects. Meanwhile, cardiovascular risk factors were more prevalent in IIMs patients. There was a significant heterogeneity among studies assessing the risk of CHD and the prevalence of hypertension.I2 statistics among Canada and Sweden subgroups had significant changes. However, the heterogeneity was still high in other countries subgroups, and the possible reasons were as follows. Firstly, these three studies were conducted in three different countries. Indeed, people living in different countries may have different life and eating habits, genetic and environmental characteristics, all of which may affect the risk of CHD. Nevertheless, there was only one article assessing the risk of CHD in these counties, so we were not able to draw a clear conclusion for these regions. Secondly, the sample sizes of the case group changed greatly, ranging from 655 to 10,156. Thirdly, the definitions of CHD and population selection of these studies were inconsistent. Two population-based studies defined CHD as ACS, while another hospital-based study used a broad definition. Besides, our subgroup analysis also showed a higher risk of MI and ACS in IIMs patients, which was similar to the results of previous studies (I2 = 0%), thus we speculated that the definition of CHD may be the main source of heterogeneity.This meta-analysis revealed a significant association between IIMs patients and CHD risk, and the risk of CHD in IIMs patients was 2.19 times higher than that in non-IIMs subjects, which was consistent with the results of the previous studies , 18, 35. studies –14, 16. I2 value reduced to 0 and 13%, respectively. Based on these results, we think that geographic regions of the country and sample size may be the main source of heterogeneity among the studies focused on hypertension. In the future, more prospective multicenter studies with large sample sizes are required to be conducted to confirm these results.This meta-analysis also indicated that IIMs patients were 1.44, 1.67, and 1.48 times more likely to be complicated with hypertension, diabetes mellitus, and dyslipidemia compared with non-IIMs individuals, respectively. However, significant heterogeneity among studies on hypertension in IIMs patients was present. We performed subgroup analysis stratified by geographic regions of the country and sample size of case group. The results indicated that the prevalence of hypertension in IIMs patients was greatly higher than that in the control group of all subgroups, with lower statistical heterogeneity. In addition, sensitivity analyses suggested that the results were convincing and robust, but the heterogeneity among cohort studies was still relatively higher. In order to investigate the source of heterogeneity among the cohort studies, we conducted further subgroup analysis based on sample size. The findings demonstrated that there was no obvious change in the pooled OR between the total and the two subgroups, but the heterogeneity among the large sample studies and small sample studies decreased significantly; P = 0.004)  . In addi= 0.004) , 43, 44.= 0.004)  demonstrIt is worth noting that it remains questionable whether the high prevalence of cardiovascular risk factors can be attributed to IIMs itself or pharmacotherapy. IIMs are long-term and chronic autoimmune diseases in nature that require long-term treatment with medication, and GC are considered as first-line therapy in patients with IIMs , 44. NumEven though this meta-analysis included relatively high-quality studies, there were still some limitations. First, considerable statistical heterogeneity was observed among the studies on CHD and hypertension, thus interpretation of the results should be cautious. Second, the majority of included studies were performed using medical registry-based databases, which cannot completely guarantee the accuracy of the data. Third, as the included studies were all observational studies, it was difficult to draw a causal relationship. Therefore, it was not clear whether IIMs itself or other potential confounding factors work together to increase the risk of CHD or the prevalence of traditional cardiovascular risk factors. Fourth, a subgroup analysis evaluating all the different subtypes of PM or DM that cannot be performed, which may limit the power of the analysis. In addition, due to few studies, we cannot assess the publication bias, but there may be some inevitable publication biases, as only published English studies were used. Overall, further prospective studies with larger sample sizes should be carried out to verify our findings.In conclusion, this meta-analysis revealed an increased risk of CHD in patients with IIMs compared with age- and gender-matched non-IIMs subjects. Meanwhile, traditional cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, were more prevalent in IIMs patients. Besides, chronic inflammation, traditional cardiovascular risk factors and some therapeutic drugs of IIMs were associated with the increased risk of CHD. Therefore, clinicians ought to realize those associations, and adopt appropriate measures to reduce the risk of CVD in patients with IIMs.The original contributions presented in the study are included in the article/LQ and HW: conception and design of the study. QL and XY: literature search and data collection. FL and LC: data analysis and interpretation. LQ, FL, and HW: supervision. All authors contributed to the article and approved the submitted version.This study was supported by the National Nature Science Foundation (grant number 81300243).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This meta-analysis suggests that consumption of oat could reduce the risk for T2D and all-cause mortality, while no significant association was found for CVD. Future studies should address a lack of standardized methods in assessing overall oat intake and type of oat products, and investigate a dose-dependent response of oat products on cardiometabolic outcomes in order to introduce oat as preventive and treatment options for the public.Cardiovascular disease (CVD) and type 2 diabetes (T2D) remain the top disease and mortality burdens worldwide. Oats have been shown to benefit cardiovascular health and improve insulin resistance. However, the evidence linking oat consumption with CVD, T2D and all-cause mortality remains inconclusive. We conducted a comprehensive systematic review and meta-analysis of prospective cohort studies to evaluate the associations between oat consumption and risks of T2D, CVD and all-cause mortality in the general population. Five electronic databases were searched until September, 2020. Study specific relative risks (RR) were meta-analyzed using random effect models. Of 4686 relevant references, we included 9 articles, based on 8 unique studies and 471,157 participants. Comparing oat consumers versus non-consumers, RRs were 0.86 (95% CI 0.72–1.03) for T2D incidence and 0.73 (95% CI 0.5–1.07) for combined CVD incidence. Comparing participants with highest versus lowest oat intake, RRs were 0.78 (95% CI 0.74–0.82) for T2D incidence, 0.81 (95% CI 0.61–1.08) for CHD incidence and 0.79 (95% CI 0.59–1.07) for stroke. For all-cause mortality one study based on three cohorts found RR for men and women were 0.76 (95% CI 0.69–0.85) and 0.78 (95% CI 0.70–0.87), respectively. Most studies ( Oats (Avena sativa) are a whole-grain cereal predominantly grown in Europe and the Americas . They arTo find a consensus, a comprehensive analysis of the literature is needed. We, therefore, undertook a systematic review and meta-analysis of prospective studies to explore the associations of oat consumption with the risk of T2D, CVD and all-cause mortality in the general population.We performed a systematic review and meta-analysis in accordance with a recently published guideline on conducting a systematic review and meta-analysis, as well as the PRISMA guidelines ,18. The We searched MEDLINE via Ovid, EMBASE, Web of Science Core Collection, Cochrane Library, and Google Scholar to identify relevant articles. Search terms included subject headings and free text words related to oat consumption  and adverse outcomes including incident CVD , incident T2D and all-cause mortality. We searched the databases from inception until 18th September 2020. We limited our search to human studies. No limitations on publication date or language were used. We additionally searched the references of eligible articles and studies that have cited those articles. The complete search strategy is outlined in the Studies were included if they (i) were of prospective design ; (ii) had reported on oat intake as part of the diet or as supplements, and (iii) had provided information on the association between oat intake/supplementation with risk of T2D, CVD and/or all-cause mortality. We excluded abstracts, cost-effectiveness studies, letters to the editor, conference proceedings, cross-sectional studies, case-control studies other than those of prospective design , systematic reviews, and meta-analyses. Studies, among adults, examining the association between oat consumption  and outcomes of interest were included.The titles and abstracts were screened by two independent reviewers in accordance with the selection criteria (FW and PET). A data extraction form was used to record information such as the author’s name, study location, study design, sample size, baseline age, follow-up time, methods used to assess oat intake, outcome definition, number of events, measures of associations, and level of adjustment. Before beginning the full data extraction, the form was developed, piloted, and discussed within the review group. When multiple publications were assessed, the most recent or comprehensive information was used. Extracted data are summarized in The quality of included studies was independently assessed by two authors (FW and PET) using the Newcastle–Ottawa Scale for cohort studies ; a thirdWe calculated pooled relative risks (RR) and 95% confidence intervals (CI) for incident CVD, incident T2D, and all-cause mortality between oat consumers and non-consumers, and highest vs. lowest oat intake based on the extracted data from each study. Odds ratios reported by Xu X. et al., 2019 were converted to relative risks using the method described by Grant R, 2014 .p-value <0.05 was considered significant.The inverse variance weighted method was used to combine RR to produce a pooled RR using random-effects models to account for between-study heterogeneity; as a sensitivity analysis, we reported the estimates derived from fixed effect models. Fixed effect models, on the other hand, were used to pool results from different groups in the same study, which were then included in our meta-analyses. For meta-analyses including 4 or more studies, we also assessed publication bias by funnel plot, and Egger’s test was used to assess asymmetry. All analyses were conducted with STATA 16.1 . We calculated 2-tailed tests and a n = 6) were of fair to good quality (score ≥ 7), while 2 studies were of poor quality (score < 5). The assessed oat intake varied between the studies: 3 studies analyzed oatmeal consumption, 1 investigated oatmeal and whole grain oat intake, 1 article assessed the effects of oat fiber from various oat containing products [A total of 4686 citations were identified, of which 30 were chosen for full-text evaluation . Of thosproducts , 1 studyproducts , and 2 lproducts . No studFive studies ,26,28,292 = 47%, p = 0.129) (Higher oat intake (more than 5.7 g/day) was significantly associated with lower risk of T2D when compared to lower consumption (less than 1.3g/day), with a relative risk of 0.78  .2 = 97.6%, p < 0.001)  . There wn = 1) cohort and the Nurses’ Health Study cohort (n = 2), were excluded since new studies on the same cohorts analyzing the same outcomes were included in the analysis  and 0.79 , respectively . We p > 0.05, For risk of T2D and CVD, the results were of low and very low certainty. The evidence was based solely on the observational data. Despite the fact that the study population and each outcome showed good generalizability, we found some heterogeneity. We were unable to investigate the publication bias for other outcomes due to the small number of studies. There was no evidence of publication bias in the study of oat intake and CVD risk (The fixed effects models showed significant associations of oat intake (high vs. low) with incidence of type 2 diabetes, composite cardiovascular disease and stroke  a,b. UndeWe conducted a systematic review and meta-analysis using data from approximately 471,157 participants from 8 studies to help clarify available evidence on the associations of oat intake with the risk of type 2 diabetes, cardiovascular disease, and all-cause mortality. Overall, our findings show that a high oat consumption is associated with a lower risk of T2D and all-cause mortality, but not consistently with CVD.To date, this is the first meta-analysis to investigate the association between oat intake and risk of type 2 diabetes, cardiovascular disease and all-cause mortality. Our findings are in agreement with multiple published meta-analyses, reporting positive effects of oat intake on T2D risk factors, such as lowering HbA1c, fasting and postprandial glucose and fasting insulin . Since oOats deliver high amounts of valuable nutrients, including proteins, minerals, B vitamins, and iron, but a substantial amount of the beneficial effect is attributed to the fiber content. Fiber intake in general has been found to be associated with reduced risks of all-cause mortality, CVD and all cancers . In multThis work’s strengths and weaknesses deserve careful consideration. This is the first comprehensive meta-analysis using a predefined protocol, investigating the associations of oat consumption with risk of T2D, CVD and all-cause mortality. The quality of included studies was good to moderate and the numbers of participants and the analyzed events were high. Several limitations also warrant mentioning. Because only 9 articles met our search criteria, we may not have enough power to detect a definite effect in the case of cardiovascular disease risk. Due to the limited number of studies included in each analysis, it was also not possible to define the sources of heterogeneity observed in our meta-analyses. The possible reasons for the null association with CVD could be the difference in assessed oat intake in different populations: 8 articles analyzed oatmeal consumption, 3 assessed oatmeal and whole grain oat intake, one article assessed the effects of oat fiber from various oat containing products , one stuOur findings could have significant policy and scientific ramifications. These findings emphasize the importance of including oats and/or oat products in the diet to reduce the risk of T2D and possibly CVD (as suggested by the results of fixed effects models) two of the most common noncommunicable diseases worldwide. Cardiovascular diseases together with type 2 diabetes cause 19.5 million deaths annually (WHO noncommunicable disease report 2018). Most of these deaths are premature and could be prevented by educating health care providers as well as the public about the benefits of a healthy life style such as a healthy diet. Given that current global noncommunicable disease prevention strategies  recommend an increase in fruit and vegetable consumption, our findings may have important policy implications. Despite recommendations from several health organizations to increase consumption of fiber-rich foods, fiber intake worldwide remains well below recommended levels . RecogniResults of this meta-analysis indicate a potential beneficial role of oat consumption in type 2 diabetes and mortality. However, the evidence is limited and mainly from observational data, making it difficult to draw firm conclusions. Further detailed work with large studies and clinical trials is needed to better characterize these associations and to assess causality.