Epidemiological studies on the association between adult height and cardiovascular disease (CVD) mortality have provided conflicting findings. We examined the association between adult height and the risk of CVD mortality.  We searched PubMed, Scopus, ISI Web of Knowledge, and Google Scholar for relevant studies published up to September 2021. Prospective cohort studies that reported the risk estimates for death from CVD, coronary heart disease (CHD), and stroke were included. The random-effects model was used to calculate summary relative risks (RRs) and 95% confidence intervals (CIs) for the highest vs. lowest categories of adult height. I2 = 59.4%, n = 15 studies) for CVD mortality, 0.82  for CHD mortality, 0.73  for stroke mortality, 0.70  for hemorrhagic stroke mortality, and 0.88  for ischemic stroke mortality.  In total, 20 prospective cohort publications were included in this systematic review and 17 in the meta-analysis. During 5 to 41 years of follow-up, the total number of deaths from CVD was 95,197  among 2,676,070 participants. The summary RR comparing the highest and lowest categories of height was 0.80 (95% CI: 0.74–0.87,  The present comprehensive meta-analysis provides evidence for an inverse association between adult height and the risk of CVD, CHD, and stroke mortality. Cardiovascular disease (CVD) is now a public health crisis, affecting millions of people in both developed and developing countries. It is one of the most common causes of death . AlthougTaller adult height was associated with a reduced risk of all-cause mortality and an increased risk of cancer mortality. However, epidemiological studies on the association between adult height and CVD mortality have provided conflicting findings. Higher height was associated with an increased risk of CVD mortality in a study among females , while oWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting the present meta-analysis.We carried out a systematic literature search using online databases, including PubMed, Scopus, ISI Web of Knowledge, and Google Scholar, to identify relevant papers published up to September 2021. No language or time limitations were performed. In the search strategy, a combination of MeSH  and non-MeSH terms was used (Supplementary Table Two of the authors (OF and ZK) screened the titles and abstracts of all studies found in the systematic search to identify studies that met our criteria for inclusion in the meta-analysis. Studies were selected if they (1) had a prospective observational design; (2) were conducted on the adult population; and (3) reported relative risks, including risk ratios (RRs), hazard ratios (HRs), and odds ratios (ORs) with 95% confidence intervals (CIs) to determine the association of height with the risk of CVD, coronary heart disease (CHD), and stroke mortality. If several publications were reported from a single cohort, the most comprehensive one was included.We excluded letters, comments, reviews, meta-analyses, and ecological studies. We also excluded studies that were conducted on children or adolescents and publications that reported RRs for cardiovascular and respiratory disorder mortality combined.After the study selection process, two reviewers (OF and SN) independently extracted data from the original cohort studies. The following items were extracted from each eligible study: the first author's name, publication year, cohort name, country, age range or mean age of study participants, gender, sample size, number of CVD deaths, follow-up duration, height assessment methods, comparison categories, adjusted RR with 95% CI for CVD mortality, and covariates adjusted in the statistical analysis. The greatest degree of adjustment from each study was considered and used for the meta-analysis. Any disagreements between the reviewers were discussed and resolved by the third reviewer (AE).The Newcastle-Ottawa scale was used to assess the quality of each study. This tool consists of several parts, including the selection of participants (4 scores), comparability (2 scores), and ascertainment of exposure or outcome (3 scores). The total score of NOS ranges between 0 and 9. Studies achieving nine points were considered to provide the highest quality.No patients were involved in the design, conduct, reporting, or dissemination plans of our research.χ2 test and quantified the inconsistencies using the I2 statistic. For the I2 statistic, we considered the I2 values of 25%, 50%, and 75% as low, moderate, and high between-study heterogeneity, respectively [ORs, RRs, and HRs (and 95% CIs) for comparison of the highest and lowest categories of adult height were used to calculate log RR, OR, and HR ± SE. The analyses were performed with the use of a random-effects model to account for between-study heterogeneity. We assessed heterogeneity between studies using Cochran's ectively . We alsoectively  to conveP values and effect estimates [P < 0.05 was considered statistically significant for all tests, including Cochran's Q test.Two studies , 16 repostimates . When ststimates . In caseThe flow diagram of study selection is shown in Characteristics of the 20 included articles are shown in Supplemental n = 16), smoking (n = 18), alcohol consumption (n = 11), and physical activity (n = 8). Based on the NOS score [Among the 20 included articles, six included only men , 24, oneOS score , all pubI2 = 59.4%; Pheterogeneity<0.001) (Fifteen cohort studies (14 publications) , 24, 27 y<0.001) . PublicaI2 = 70.6%; Pheterogeneity<0.001)  were included in this meta-analysis , 24–27. y<0.001)  There waI2 = 0%; Pheterogeneity = 0.80). We found no substantial publication bias by using Egger's test and Begg's test.Ten cohort studies (nine publications) , 24, 27 I2 = 0.0%; Pheterogeneity = 0.50). Publication bias tests were not performed (<10 studies).Four studies –6, 12 inI2 = 0.0%; Pheterogeneity = 0.61). Publication bias tests were not performed (<10 studies).Four studies –6, 12 exSupplemental Table The summary data from cohort studies indicated that adult height was inversely associated with the risk of cardiovascular mortality. Moreover, we found a significant inverse association between adult height and the risk of death from coronary disease and hemorrhagic stroke, while no clear association was seen with ischemic stroke mortality.CVD is a leading cause of death and a major global health threat. Although height attainment is generally not under individual control, it is a widely available index reflecting the interaction of genetics and various early life conditions. It may indicate underlying mechanistic pathways relevant to the risk of developing CVD. The current study provides up-to-date and reliable evidence on the association between adult height and CVD mortality.We found that adult height was inversely associated with CVD mortality. Consistent with our findings, a previously published meta-analysis reported that greater height was associated with a lower risk of all cardiovascular deaths . Our resThe present study has confirmed that taller individuals have a lower risk of death from coronary disease. In a multilocus Mendelian randomization meta-analysis, taller height was associated with a lower risk of CHD, with possible explanations such as better lung function, lower levels of adiposity, lipid profiles, and blood pressure . The finIn this meta-analysis, taller people had a lower risk of death from stroke, especially hemorrhagic stroke mortality. However, we failed to find an inverse association between adult height and ischemic stroke mortality. Unlike our findings, a meta-analysis of 121 prospective cohort studies showed that adult height was inversely associated with fatal and nonfatal ischemic stroke events. However, this study aligns with our findings reported an inverse relationship between height and hemorrhagic stroke events . The exaMultiple lines of evidence support mechanisms through which taller heights may decrease the risk of CVD mortality. Low socio-economic position in childhood might be considered a possible mechanism for an increased risk of CVD in later life , 38. TheThe large number of participants and deaths, prospective nature of included studies, and consideration of subtypes of CVD mortality are the major strengths of this study. Our meta-analysis also has some limitations that should be considered when interpreting the results. As a meta-analysis of cohort studies, confounding by unmeasured risk factors might have influenced our findings. We found significant heterogeneity in some analyses. The number of studies in stratified analyses was limited to fully explore between-study heterogeneity. Some included studies in the current meta-analysis used self-reported heights rather than measured ones, which might have biased our findings. However, most validation studies have found a strong correlation between self-reported and measured height; nevertheless, some over-reporting of height can occur. Although there was no evidence of publication bias in our analysis, it is still possible that some studies with null findings have remained unpublished. The data on covariates used in primary studies were assessed based on single measurement at the study baseline, and their changes throughout the follow-up were not considered in the original analyses.In conclusion, our results indicated that greater height was associated with a lower risk of death from CVD, CHD, and stroke. Well-designed, large prospective studies are required to obtain a better indication of the relationship.


Plant polyphenols have various health effects. Genistein, which is abundant in soybeans, and epigallocatechin-3-gallate, which is abundant in green tea, are major flavonoids, a subclass group of polyphenols. Several epidemiological studies have shown that these flavonoids have beneficial effects against cancer and cardiovascular diseases. However, other studies did not show such effects. Several confounding factors, including recall bias, are related to these inconsistent findings, and the determination of metabolites in the urine may be useful in reducing the number of confounding factors. Equipment, which can be used by research participants to collect samples from a portion of voided urine within 24 h without the help of medical workers, has been developed for epidemiological investigations. Previous studies, in which flavonoid metabolites in these urine samples were measured, revealed that soy intake was correlated with a reduced risk of certain types of cancer and cardiovascular diseases worldwide. Although soybeans and green tea consumption may have protective effects against cancer and cardiovascular diseases, further clinical studies that consider different confounding factors are required to provide evidence for the actual impact of dietary flavonoids on human diseases, including cancer and cardiovascular diseases. One possible mechanism involved is discussed in relation to the downregulation of reactive oxygen species and the upregulation of 5′-adenosine monophosphate-activated protein kinase elicited by these flavonoids. Plant polyphenols are found in foods including vegetables, fruits, legumes, nuts, and beverages. Genistein (GEN), which is abundant in soybeans, and epigallocatechin-3-gallate (EGCG), which is abundant in green tea, are major flavonoids, a subclass group of polyphenols  1]. In . In 1]. Several studies have shown a correlation between flavonoid-rich diets and a reduced risk of cancer, cardiovascular and neurodegenerative diseases, and other conditions ,3. For eTsugane et al.  emphasizHowever, several epidemiological studies did not show such beneficial effects on health. The inconsistent results may have been caused by recall bias and incomplete or inadequate adjustments of confounding factors, such as tobacco smoking, the use of different ingredients, cooking/brewing temperature, and genetic characteristics ,7,8,9. EThe measurements of flavonoids and/or their metabolites in the blood and urine can provide more accurate data on the consumption of flavonoids. We searched PubMed, Web of Science, and Google Scholar to collect human and cell-based studies about cancer and cardiovascular diseases (CVDs) from 1983 to 2022, and about 70% of the retrieved studies were from the last 10 years. We included studies with both positive and negative results on the preventive potential of soy isoflavones and green tea catechins against cancer and CVDs by focusing on human studies to examine the urinary metabolites of isoflavones and catechins to identify the beneficial effects of soy food and green tea consumption on these diseases.Several epidemiologic studies have found that a soy-rich diet reduces the risk of cancer, and isoflavones such as GEN and daidzein (DDZ) can have anticancer effects ,12,13. IA dose–response meta-analysis of prospective cohort studies, which included 23 studies with a sample size of 330,826 participants, revealed that soy/soy product consumption was inversely associated with cancer-related mortality (pooled relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.79–0.99) . The risGrosso et al.  conducteWang et al.  performeA population-based case–control study examined the association between dietary flavonoid consumption and the risk of esophageal squamous cell carcinoma (ESCC) among adults from a high-risk area in China. The results showed that when comparing the highest and lowest intake quartiles, an inverse association was observed between the risk of ESCC and the consumption of isoflavones , DDZ , and GEN  [A case–control study on 249 incident PCa cases and 404 matched controls found an inverse association for DDZ urinary excretion . Moreover, a weaker inverse association was found for GEN urinary excretion .In a prospective nested case–control study in Japan, an inverse association was noted between plasma GEN levels, but not DDZ, and the risk of BCa. However, nonsignificant inverse associations were found between the risk of BCa and GEN and DDZ consumption .A meta-analysis of two randomized controlled trials (RCTs) found a significant reduction in the diagnostic rate of PCa after the consumption of soy/soy isoflavones  . A meta-A meta-analysis of eight studies found that compared with the lowest level of soy food intake (≤5 mg isoflavones per day), the risk of BCa was reduced weakly among individuals with a modest intake of isoflavones (ca. 10 mg per day)  and strongly among those with a high intake of isoflavones (≥20 mg per day)  . HoweverA systematic review of 11 epidemiological studies showed that two cohort and two case–control studies indicated a moderate to strong and a weak inverse association, respectively, between soy consumption and the risk of BCa in postmenopausal Japanese women . SimilarPonte et al.  and the r = 0.40; p = 0.0001), O-desmethylangolensin (O-DMA) , and DDZ , and the sum of isoflavones  [Urinary isoflavonoid excretion is associated with soy consumption. The intake of soy foods was correlated with urinary concentrations of GEN ( 0.0001) . Equol i 0.0001) . A cross 0.0001)  showed a 0.0001) .Based on data from the US Department of Agriculture isoflavone database and dietary recalls of 2908 American adults with urinary isoflavone data in the 1999–2002 National Health and Nutrition Examination Survey, Chun et al.  found thThe urinary excretion rate of total isoflavonoids was significantly correlated with dietary soy food intake (a correlation coefficient of approximately 0.5). Hence, the urinary excretion rate of total isoflavonoids in overnight urine samples may reflect the usual intake of soy foods .In a case–control study, women with newly diagnosed early-stage BCa and controls were interviewed using questionnaires, and 72 h urine and blood samples were collected . In 144 In a study of 117 case–control pairs of postmenopausal women in Shanghai, Dai et al.  found a The urinary excretion rates of isoflavonoids, mammalian lignans, and citrus flavonoids were analyzed using overnight urine samples collected from 250 patients with incident BCa and matched controls. The results showed that patients with BCa had significantly lower urinary excretion of total isoflavonoids than controls . The risYamori et al. ,40 develAnalyses of urine samples collected from 251 women with BCa and 462 controls revealed that the risk of BCa was inversely associated with increased urinary excretion of total isoflavones  and GEN  . In Japap = 0.03) [A clinical study aimed to examine equol-producing status in relation to breast density in 224 women aged 36–58 years. The results showed that 30% were equol producers who had a significantly lower mean percentage of breast density than nonproducers  . The dieA prospective cohort study on 88 BCa cases and 268 controls in 14,697 postmenopausal women showed that a higher urinary GEN excretion was insignificantly associated with a reduced risk of BCa .Li et al.  performeA clinical study found that higher levels of urinary GEN and DDZ were associated with a reduced risk of advanced-stage endometriosis but not early endometriosis . For advA nested case–control study conducted in Shanghai, China, showed that the adjusted ORs of liver cancer across increasing quartiles of urinary GEN levels were 1.00 (reference), 0.55 (95% CI = 0.22–1.36), 0.57 (95% CI = 0.23–1.43), and 0.19 (95% CI = 0.06–0.59) in women and 1.00 (reference), 1.22 (95% CI = 0.52–2.86), 1.17 (95% CI = 0.47–2.90), and 1.23 (95% CI = 0.55–2.76) in men . These fIn a hospital-based case–control study in Jamaica that analyzed urine samples, men who produced equol had a decreased risk of total PCa   and high-grade disease   than those who are nonproducers (reference tertile) . No assoSong et al.  examinedA cross-sectional study evaluated participants aged 48–82 years. The results showed that equol producers (30% of participants) with weekly soy intake had a lower % mammographic density, an intermediate marker of BCa risk. Meanwhile, in nonproducers, weekly soy intake was associated with a higher % density . TherefoIn contrast, Seow et al.  found noIn a clinical study that evaluated serum and urine samples, Grace et al.  found thLarger clinical studies are necessary to determine the potential anticancer effects of isoflavones and the detection method associated with the prevention of cancer.Several epidemiological studies revealed that green tea consumption has beneficial effects against cancers ,9,15. ReZhao et al.  performeA pooled analysis based on the findings in 9438 cases and 20,451 controls from 22 studies worldwide found that the adjusted pooled OR of regular tea drinkers was 0.91 (95% CI = 0.85–0.97) . Stronge. In the subgroup analysis, the OR was 0.79 in women (95% CI = 0.68–0.91). Therefore, green tea has a protective effect in women [A dose–response analysis of the association between green tea consumption and esophageal cancer was performed. The results showed no association between esophageal cancer and one cup increase in the consumption of green tea per day in women .A comprehensive review by Abe and Inoue  showed tBased on a meta-analyses of 97 cohort studies on the association between dietary intake and the risk of ovarian cancer, the consumption of green tea was significantly associated with a reduced cancer risk  .However, several previous and recent studies did not show the anticancer effect of tea consumption. For example, in Asian populations, green tea consumption was not associated with lower risks of cancer-related mortality, although an association was found in mortality from all causes and coronary heart disease (CHD) . AccordiHuman studies on the absorption, distribution, metabolism, and excretion of tea catechins found that urinary excretion of metabolites during a 24 h period after green tea consumption corresponded to 28.5% of the ingested (epi)catechin (EC) and 11.4% of (epi)gallocatechin (EGC). Thus, it has a higher absorption than other flavonoids .An intervention study evaluated participants who consumed green tea polyphenol (GTP) capsules daily at doses of 500 and 1000 mg or a placebo for 3 months, and 24 h urine samples were examined. The results showed that the urinary excretions of EGC and EC can be practical biomarkers of green tea consumption in human studies .A clinical investigation evaluated the correlation between the dietary intake of polyphenol-rich foods and metabolites in 24 h urine samples collected from 419 participants. The results showed that urinary concentrations of (+)-catechin and EC are useful when used as short-term nutritional biomarkers of dietary catechin, EC, and total flavan-3-ol monomers .An intervention study evaluated healthy postmenopausal women who are at high risk of BCa and who received GTE corresponding to 843.0 ± 44.0 mg EGCG/day or a placebo for 1 year. The results showed that the urinary levels of catechins including EGC and EC were similar between the GTE and placebo groups at baseline. However, after treatment, the GTE group had significantly higher urinary catechin levels than the placebo group . The GTEYuan et al.  found thHelicobacter pylori infection [A nested case–control study aimed to investigate the association between urinary tea catechin markers and the risk of gastric and esophageal cancers on 190 incident cases of gastric cancer and 42 cases of esophageal cancer. The results showed that urinary EGC was significantly inversely associated with gastric cancer  after adjusting for confounders including nfection . SimilarO-methyltransferase (COMT), which may modulate the urinary excretion of tea catechins [Green tea may have a greater protective effect against the risk of BCa among women with the low-activity-associated genotype of the catechol-atechins . In 660 atechins . TherefoBased on a study of 353 patients with BCa and 701 matched controls in a cohort of women aged 40–70 years at baseline, the urinary excretion of EC was inversely associated with the risk of BCa  .GSTM1 and GSTT1.In the Shanghai Women’s Health Study on BCa, Luo et al.  found anIn contrast, a nested case–control study of hepatocellular carcinoma (HCC) (211 cases and 1067 matched controls) in the Shanghai Cohort Study found a statistically significant association between high urinary EGC levels and a high risk of HCC among participants who tested positive for the hepatitis B surface antigen . High leShirota et al.  recentlyA prospective cohort study of approximately 75,000 Chinese women found a dose–response relationship between soy food intake and the risk of CHD with an adjusted RR of 0.25 (95% CI = 0.10–0.63) in the highest versus the lowest quartile of total soy protein intake .A meta-analysis of cohort studies showed that soy/soy product consumption was inversely associated with CVD-related mortality  . HoweverIn a cohort study with 4,826,122 person years of follow-up, isoflavone intake was inversely associated with CHD (pooled hazard ratio (HR) = 0.87; 95% CI = 0.81–0.94) compared with the extreme quintiles . The conIn a review article, based on a series of evidence from observational studies and RCTs, Sekikawa et al.  revealedIn a cohort study with 503,998 person years of follow-up, Kokubo et al.  found thA prospective cohort study of approximately 75,000 Chinese women found a dose–response relationship between soy food intake and the risk of CHD, with an adjusted RR of 0.25 (95% CI = 0.10–0.63) in the highest versus the lowest quartile of total soy protein intake .A case–control study on 191 patients with ischemic stroke (IS) in eastern China found a significant inverse association between fruit consumption  and soy consumption  and IS .In a study of 890 Japanese men, a high total soy product intake within 12 weeks was associated with significantly lower levels of low-density lipoprotein cholesterol (LDL-C) .In a meta-analysis of randomized double-blind placebo-controlled trials, Mosallanezhad et al.  found a Based on a cross-sectional study on 10,536 children and adolescents aged 7–18 years in southern China, 39.5% of participants had a high soy food intake (more than three times per week), which was significantly associated with a lower prevalence of hypertension and a greater prevalence of obesity .In contrast, several studies did not show an inverse association between soy isoflavone intake and CVDs. For example, Yan et al.  performeA cross-sectional study was performed on 648 postmenopausal women who provided DDZ-challenged urine samples for determining the production of equol and O-DMA, another metabolite of DDZ. The results showed that soy isoflavone intake had minimal correlation with cardiovascular risk factors in producer phenotypes of these metabolites . Other sIn worldwide epidemiological surveys conducted on 61 populations in 25 countries, Yamori  showed tYamori et al.  performeIn a later study, the biomarkers of Japanese diets were analyzed in comparison with 24 h urine samples collected for grading Japanese diets by soy isoflavones and seafood taurine excretions . A higheA 2-year intervention study on 351 women showed that isoflavone supplementation reduced LDL-C levels by approximately 6% .A 6-month RCT on 270 eligible female equol producers showed that the serum LDL-Cs of the whole soy and DDZ groups decreased by 7.95% (95% CI = −15.09–−0.81%) and 6.32% (95% CI = −13.45–0.08%), respectively. Furthermore, their serum C-reactive protein decreased by 0.164 (95% CI = −0.309–−0.019) and 0.054 (95% CI = −0.199–0.012), respectively .In an intervention study in Scotland, 61 men aged 45–59 years with relatively high blood pressure (BP) and/or total cholesterol levels had diets containing at least 20 g of soy protein and 80 mg of isoflavones for 5 weeks . The resIn accordance with this finding, a study covering 60 populations in 25 countries showed that soy intake was significantly associated with decreased body mass index, BP, and serum cholesterol levels. Furthermore, the CHD mortality rates were inversely correlated with isoflavones in 24 h urine samples ,95.By reviewing 69 articles, Zhang et al.  found thA prospective cohort study on 66,832 Chinese women found that a regular high intake of soy isoflavones may be associated with an increased risk of IS. However, there was no association between this risk and urinary isoflavone concentrations . This diIn a cross-sectional study, the participants received supplementation with one soy bar per day for 3 days. A urine analysis revealed that 17.5% of participants were equol producers . The resAs previously mentioned, a recent meta-analysis of cohort studies revealed a mortality risk reduction in CVD, stroke, and/or heart disease with the intake of characteristic Japanese foods including green tea . In anotIn meta-analyses of prospective observational studies, a dose–response analysis indicated that tea consumption had protective effects against stroke , IS , and hemorrhagic stroke  . In the A meta-analysis of 22 prospective studies including 8459 CHD cases, 10,572 stroke cases, 5798 cardiac death cases, 2350 stroke death cases, and 13,722 total death cases found that increased tea consumption by three cups per day was associated with a reduced risk of CHD , cardiac-related mortality , stroke , total mortality rate , cerebral infarction , and intracerebral hemorrhage  . Howevern = 1115) and 24 trials (n = 1697).Grosso et al.  showed tA Japanese cohort study with an 18.5-year median follow-up showed that green tea consumption was inversely associated with all-cause mortality among CVD survivors. The multivariate HRs of stroke were 0.73 (95% CI = 0.42–1.27) for 1–6 cups/week, 0.65 (95% CI = 0.36–1.15) for 1–2 cups/day, 0.56 (95% CI = 0.34–0.92) for 3–4 cups/day, 0.52 (95% CI = 0.31–0.86) for 5–6 cups/day, and 0.38 (95% CI = 0.20–0.71) for ≥7 cups/day . A similSamavat et al.  conducteXu et al.  performeIn a meta-analysis of 24 trials with 1697 participants, the pooled results revealed that green tea significantly lowered systolic BP  and diastolic BP . However, significant heterogeneity was found in both SBP and DBP .A 5-year prospective cohort study of 3870 participants found that participants were less likely to be habitual tea drinkers if they were in the groups with an SBP of 144.4–149.9, 157.2–180.0, or 184.7–209.8 mmHg than those in the group with an SBP of 125.3–130.0 mm Hg. Thus, habitual tea consumption may give favorable effects on SBP .A population-based cohort of 38,913 Chinese participants with a median follow-up of 5.9 years found that habitual tea drinkers (≥3 times/week for at least 6 months) had a 17% lower risk of high BP progression  and a 14% decreased risk of incident hypertension  compared with nonhabitual tea drinkers .Yang et al.  conducteIn contrast, previous studies have reported several contrasting results. For example, in two large cohort studies, Feng et al.  found thThere are no epidemiological studies on the effect of tea consumption on CVDs based on urinary biomarker levels.The current review focuses on epidemiological evidence for the effects of soy/isoflavones and green tea/EGCG on cancer and CVDs. Accordingly, we briefly discuss the molecular mechanisms associated with these effects. Ponte et al.  summarizSeveral epidemiological studies have shown that isoflavone-rich diets have beneficial effects against several diseases such as cancer and CVDs.Animal and cell-based studies have supported these findings. However, other human studies did not show that isoflavone has such health benefits. As previously mentioned, the contrasting results might be attributed to recall bias and from incomplete or inadequate adjustments of various confounding factors ,7,9. VarSeveral studies have shown some confounding factors. Yan and Spitznagel  revealedIn a study conducted by Zhang et al. , an inveStudies on urinary biomarkers have contrasting results. Yu et al.  showed t


Obesity has been identified as an independent risk factor for cholelithiasis. As a treatment for obesity, bariatric surgery may increase the incidence of cholelithiasis. The risk factors for cholelithiasis after bariatric surgery remain uncertain. The purpose of this study was to explore the risk factors for postoperative cholelithiasis after weight-loss surgery and propose suggestions for clinical decision making.Four databases, PubMed, EMBASE, Web of Science and Cochrane, were systematically searched for all reports about cholelithiasis after bariatric surgery, and literature screening was performed following prespecified inclusion criteria. The included studies were all evaluated for quality according to the NOS scale. Data extraction was followed by analysis using Reviewer Manager 5.4 and StataSE 15.P < 0.00001] and race  were risk factors for cholelithiasis after bariatric surgery. Surgical procedure, preoperative BMI, weight-loss ratio, smoking, hypertension, diabetes mellitus, and dyslipidemia were neither protective nor risk factors for cholelithiasis after bariatric surgery.A total of 19 articles were included in this meta-analysis, and all studies were of high quality. A total of 20,553 patients were included in this study. Sex [OR = 0.62, 95% CI , Caucasian race and female sex are risk factors for developing cholelithiasis after bariatric surgery; surgical procedure, BMI, weight loss ratio, hypertension, diabetes mellitus, dyslipidemia, and smoking are not risk factors for cholelithiasis after bariatric surgery.The online version contains supplementary material available at 10.1186/s12944-023-01774-7. In addition, the sex sensitivity analysis and publication bias test can be found in the supplementary materials, and the results show that the combined effect size of sex was relatively stable and had no publication bias (P > 0.05).Defining men as exposed and women as nonexposed, 16 articles  evaluate2 = 0%, P = 0.84), so a fixed-effects model was used for the meta-analysis. The results showed that white race was a risk factor for cholelithiasis after bariatric surgery .Caucasians were defined as exposed, and other races were defined as nonexposed. Three articles evaluated whether race is a risk factor for cholelithiasis after bariatric surgery , 24, 30 2 = 0%, P = 0.82), so a fixed-effects model was used for the meta-analysis. As shown in Fig. P = 0.55].A meta-analysis was performed to determine whether smoking affects cholelithiasis after bariatric surgery and defined smoking as exposure and nonsmoking as nonexposure. A total of 3 articles , 27, 31 2 = 66%, P = 0.002), so a random-effect model was used for the meta-analysis. As shown in Fig. P = 0.36]. Due to the moderate heterogeneity among the studies, the literature was reviewed and eliminated one by one, and the heterogeneity was not significantly reduced, so sensitivity analysis and publication bias tests of the surgical method were carried out. The results were stable, and the funnel plot suggested that there may be publication bias. Therefore, Egger’s test was performed to determine whether there was publication bias. The Egger test showed P = 0.387, indicating no publication bias.This research examined two surgical procedures, RYGB and SG, and defined RYGB as exposure and SG as nonexposure. A total of 10 articles , 30–32 i2 = 0%, P = 0.88), so a fixed-effect model was used for pooling. As shown in Fig. P = 0.69].Many original studies have explored preoperative BMI as a risk factor. Except for Muriel Coupaye’s study , in whic2 = 83%, P = 0.003), so a random-effects model was used for pooling. As shown in Fig. P = 0.37]. There was high heterogeneity among studies, and the number of studies was too small to conduct subgroup analysis. After reviewing the literature, it was found that the article by Vicky Ka Ming Li . Due to the moderate heterogeneity among the studies, the literature was reviewed and checked one by one. The article by Mohammed A. Aldriweesh was removed, and the meta-analysis was performed again. The heterogeneity was reduced to I2 = 45%, P = 0.06 . If the article by Mohammed A. Aldriweesh and the article by Sabri Özdaş were removed and the meta-analysis was performed again, the heterogeneity was reduced to I2 = 18%, P = 0.28 . Therefore, a sensitivity analysis and publication bias test of hypertension were carried out. The results of the sensitivity analysis showed that the results were stable after excluding the studies one by one, and the funnel plot suggested that there might be publication bias. Therefore, Egger’s test was performed to determine whether there was publication bias. The Egger test showed that P = 0.718, with no publication bias.Hypertension was defined as exposure and nonexposure without hypertension. Eleven articles in total , 28, 31 2 = 21%, P = 0.24), so a fixed-effect model was used for the meta-analysis. As shown in Fig. P = 0.93]. In addition, the sensitivity analysis and publication bias test of diabetes supporting the findings. The results of the sensitivity analysis show that the combined effect size of diabetes was stable, and the funnel plot suggests that there may be publication bias. Therefore, Egger’s test was performed to determine whether there was publication bias. The Egger test determined that P = 0.141, with no publication bias.To explore the effect of diabetes on postoperative cholelithiasis, diabetes was defined as exposure, and the absence of diabetes was defined as nonexposure. A total of 11 articles , 27, 31 2 = 0%, P = 0.61), so a fixed-effects model was used for the meta-analysis. As shown in Fig. P = 0.54].Dyslipidemia was defined as exposure, and no hypertension was defined as nonexposure , 23, 31. on BMI, diabetes, hypertension, sex and surgical type. The results are the same as above.There are many original studies exploring the risk factors for cholelithiasis after bariatric surgery, but regarding conclusions, in addition to the current evidence suggesting that UDCA can prevent the occurrence of postoperative cholelithiasis –36, it iThe results of the present study show that Caucasian ethnicity is one of the risk factors, but data from East Asian populations were not taken into account in our meta-analysis due to the lack of original studies reporting from East Asian populations. More studies are needed in the future to provide a more comprehensive discussion of whether race is a risk factor.The surgical procedures in this meta-analysis included RYGB and SG because these two are highly practical, and other procedures, especially AGB, have serious adverse reactions , so theyPeople with obesity have a higher risk of developing cholelithiasis than nonobese people, and bariatric surgery, despite inducing rapid weight loss, can increase the chance of developing cholelithiasis , 44. TheFirst, two authors independently extracted data with %TWL,% TBMIL, %EWL, and %EBMIL as risk factors, but the original research data were too small to support the meta-analysis. In our meta-analysis, %TWL was not a risk factor, although two original studies , 23 suggThe pathophysiological process of gallstone formation involves abnormal cholesterol metabolism, and dyslipidemia is closely related to it. High levels of serum triglycerides and low-density lipoprotein have been reported by scholars as risk factors for gallstone formation . In addiWhether hypertension is a factor in postoperative cholelithiasis has been controversial. Aldriweesh and Guzmán suggested that hypertension is a protective factor , 19, butDiabetes is a risk factor for the formation of gallstones larger than 1 cm  and an iFinally, most studies controlled for age at baseline and were therefore not included in the meta-analysis. There were also many studies that explored sleep respiratory distress syndrome, pneumonia, renal failure, and liver cirrhosis as risk factors, but the number of studies was too small to be included in the meta-analysis.This meta-analysis is the first article to systematically summarize and scientifically describe risk factors for cholelithiasis after bariatric surgery. A total of 19 articles with 20,553 patients were included, covering all possible risk factors for meta-analysis.This study has the following limitations: there was heterogeneity in the proportion of postoperative weight loss, and the source of heterogeneity could not be identified based on current methods; the definitions of risk factors in many studies were not completely accurate, such as the definition of postoperative hypertension. But in this study, clinical diagnostic criteria were used to assign the pooled default definitions; the number of original studies was insufficient, and the risk factors included were not comprehensive due to incomplete data. Only three articles are included in TWL analysis. The above shortcomings need to be carefully considered when interpreting the conclusions of this study.In conclusion, Caucasian ethnicity and female sex are risk factors for cholelithiasis after bariatric surgery. For women and Caucasians, applying corresponding protective treatment after bariatric surgery is of higher priority in clinical decision making, such as UCDA. Surgical procedures, rapid weight loss, postoperative underlying diseases, and poor habits in the context of the occurrence of postoperative cholelithiasis still need more research for verification. There is no need to conduct protective methods routinely for these patients based on the current research conclusion.Additional file 1. Retrieval strategy.Additional file 2. Sensitivity analysis.Additional file 3. Funnel diagram.Additional file 4. PRISMA checklist.Additional file 5. publication bias test. (a) DM; (b) Dyslipidemia; (c) Gender; (d) Hypertension; (e) Surgical procedure.


Many packages for a meta-analysis of genome-wide association studies (GWAS) have been developed to discover genetic variants. Although variations across studies must be considered, there are not many currently-accessible packages that estimate between-study heterogeneity. Thus, we propose a python based application called Beta-Meta which can easily process a meta-analysis by automatically selecting between a fixed effects and a random effects model based on heterogeneity. Beta-Meta implements flexible input data manipulation to allow multiple meta-analyses of different genotype-phenotype associations in a single process. It provides a step-by-step meta-analysis of GWAS for each association in the following order: heterogeneity test, two different calculations of an effect size and a p-value based on heterogeneity, and the Benjamini-Hochberg p-value adjustment. These methods enable users to validate the results of individual studies with greater statistical power and better estimation precision. We elaborate on these and illustrate them with examples from several studies of infertility-related disorders. Genome-wide association studies (GWAS) of diseases and traits have increasingly been used to identify single nucleotide polymorphisms (SNPs). Although GWAS have tested hundreds of thousands of genetic variants to discover genotype-phenotype associations, they have a few limitations. Variants discovered in individual GWAS explain only a small proportion of heritability, and their genetic effect sizes are mostly small and require a substantial sample size to identify ,2. MoreoAs meta-analysis has become a popular tool for aggregating data from multiple sources, several studies have revised analytical strategies from previous well-known studies -9. A weiSince it is crucial to increase statistical power in order to identify significant variants, especially in studies with small sample sizes, we demonstrate Beta-Meta using studies of diseases related to infertility, most of which have relatively small sample sizes ,13-34.Meta-analysis can improve signal detection when we account for not only between-study heterogeneity but also differences in linkage disequilibrium (LD) between ethnicities ; in addiAfter surveying the studies of interest (infertility-related disorders in this paper), we created a table for input data in Excel . Beta-Methistudy, iβ is the logarithm of OR, where k is the number of individual studies, each of which is designed to examine the same SNP-phenotype association [When the OR and its confidence interval are used for input data, they are converted into the beta coefficient and the standard error, respectively. The normalized effect of the ociation .is is calculated from the 95% confidence interval of the OR.The standard error When synthesizing datasets for meta-analysis, it is important to ensure uniformity in allele labels and hence in the direction of the effect because alleles are typically called on only one of the two DNA strands in sequencing experiments . Beta-MeIn meta-analysis, datasets generated by multiple groups by different methods are likely to have any kind of variability, also known as heterogeneity. Heterogeneity indicates that the observed effects in datasets are more different from each other than would be expected by random error alone . To checfirst as :2I for the heterogeneity test [Then, we calculate the Cochran’s Q statistic, Q and Higgins’ heterogeneity metric, ity test .2I quantifies the degree of heterogeneity as a value between 0 and 100% [2I indicates stronger heterogeneity, the weighted average of the effect sizes is calculated, based on 2I, using two different models: the fixed effects model and the random effects model. A threshold value of 2I for the model selection is set to 50%.and 100% . As a gr2I<50, we use the fixed effects model to calculate the weighted average of the effect sizes and its standard error [For 0≤rd error .For 50≤I2≤100, we use the random effects model ,9.iRw are as follows [The weights for the random effect model  follows ,9:The integrated p-value through meta-analysis can be obtained as follows :Z-score, Z [where Φ is the cumulative distribution function of the standard normal distribution, and integrated score, Z  isp(1), p(2), ⋯,p(m) are the p-values of the SNPs sorted in ascending order (p(1) ≤ p(2) ≤ ⋯ ≤ p(m)), the adjusted p-values obtained through the BH procedure are as follows [Finally, to reduce the false-positive results, the integrated p-values are corrected by the BH adjustment method. When  follows :m is the number of different SNPs related to a specific phenotype, and j is the ranking in the ascending order of the p-values of SNPs related to the specific phenotype.where -8 was used to identify significant SNP markers. Of the total 26 SNP-phenotype associations from the 23 studies we investigated (-12 (Using Beta-Meta, we performed a sample test of integrating multiple studies of infertility and obtained a table containing all of the above calculated summary statistics values  and a fostigated , the onlted (-12 . After pIn order to check the accuracy of Beta-Meta, we compared the meta-analysis results of Beta-Meta  with thoBeta-Meta application can be utilized as an effortless meta-analysis tool for researchers with limited statistics backgrounds. It allows them to easily manipulate and analyze their own datasets on a personal computer as it is written in python and can be run with an executable file in MS Windows.As shown above, Beta-Meta increases the power to detect weak signals, identifying significant variants which was not significantly associated in single studies. Furthermore, it calculates the effect sizes and the p-values accurately by selecting the appropriate model based on heterogeneity and applying the BH adjustment. These can contribute to time-efficient management of the recent growth in aggregated GWAS especially for those involved in the field of genetic testing. Because it is difficult to obtain a large number of datasets and validate genotype-phenotype associations experimentally within a limited budget, meta-analysis is still in demand to discover SNP markers for genetic testing.In conclusion, the application presented here provides a conventional and yet convenient way to conduct a meta-analysis of GWAS. Beta-Meta is expected to facilitate various research projects, such as the discovery of novel SNP markers, the calculation of polygenic risk scores, and the acquisition of biological insights into complex diseases and traits.


The prevalence of allergic rhinitis (AR) has increased tremendously in the recent year in China. Evidence-based medicine to objectively evaluate the prevalence and risk factors for AR in China is urgently required. Toward this, we systematically searched four English and four Chinese databases to identify the literature on the same, from the year of website establishment until November 2021. A total of 51 studies were evaluated, and data were obtained through Stata 16 analysis. Overall pooled risk factors for adult AR were smoking , asthma , a family history of AR , a family history of asthma , drug allergy , food allergy , pollen allergy history , antibiotic use , occupational dust exposure , home renovation , and middle school education . Overall pooled risk factors for AR in children were passive smoking , asthma , a family history of AR , a family history of allergy , a history of allergic diseases , eczema, owning pets , eating seafood , boys , and breastfeeding . The results of our meta-analysis showed that the prevalence of allergy rhinitis was 19% (95% CI 14–25) among adults and 22% (95% CI 17–27) among children, with boys showing a higher prevalence than girls. The development of AR in China is associated with several factors, including allergic diseases , a family history of allergy , and dwelling and working environment ; conversely, breastfeeding can reduce the risk. Allergic rhinitis (AR) is induced by immunoglobulin E-mediated nasal infection leading to a series of nasal mucosa dysfunction of associated symptoms and concurrently affecting quality of life; the AR incidence has increased globally over time , 2. The With the acceleration of industrialization and urbanization, respiratory problems have increased and become a focus of concern in China . Cross-sAlthough the etiology of AR is not obvious, fungal spores, climate factors, indoor environment, ambient air pollution, and inherent characteristics may attribute to its occurrence –12. ExamWe searched the electronic databases such as PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure China Biology Medicine Disc, WANFANG database, and Chongqing VIP database from the year of website establishment until November 2021. The systematic review was conducted according to the observational study methodology of Cochrane recommendations and registered at PROSPERO under the registration number CRD42022299105. The search process was conducted using the terms: “Rhinitis, Allergic,” “Epidemiology,” and “Prevalence,” and the following keywords:  AND  AND “China.”The inclusion criteria were as follows: (1) all investigative studies or reports with a diagnosis of AR, (2) integrity and reproducible originality of data, (3) risk factors studies that calculated outcome with corresponding 95% confidence interval (CI) and adjusted odds ratio , and (4) language restricted to Chinese and English.C.The exclusion criteria were as follows: (1) duplicate, incomplete, incorrect, or unusable data, (2) comments, conferences, reports, and reviews, (3) non-up-to-date data and comprehensive data in the same region, (4) vague sample source, inclusion, and exclusion criteria, (5) special groups, such as officers, pilots, and nurses, and (6) the literature quality score of A is assigned a score of 6–7, B is assigned 4.0–5.5, and C is under 4 score.The parameters were extracted independently by two persons who conducted preliminary screening and cross-checking of data for quality control. When the results of both parties were inconsistent, a third party stepped in to help work out the problem. The extracted content of literature information included author, publication year, region, age, incidence and corresponding research results, case load, and risk factors. Depending on the methods of risk assessment criteria for cross-sectional study bias, outcome, comparability, and selection of study subjects, the study quality was evaluated independently by using the Combie checklist for the cross-sectional study. The seven terms are reassigned one point for each item, with a response of “yes” scoring 1 point, “no” scoring 0 points, and “not clear” scoring 0.5 points. X9 screening of the qualified literature, Excel 2019 extracting relational data, and Stata 16 analysis data. Heterogeneity between study results was determined by I2 when I2 >50% meant greater heterogeneity among the studies, using the random effects model. Risk factors sensitivity analysis was conducted using combined OR and 95% CI and compared using the fixed effects model and the random effects model to test for the results' robustness. Egger's test was used to evaluate publication bias wherein the conclusion was considered biased if p < 0.05.The data processing was conducted using the software Endnote Overall, 10,701 studies were initially identified from the databases according to the inclusion criteria. After excluding ineligible studies meeting the exclusion criteria such as duplicates, incomplete, incorrect, or unusable data, 51 studies were finally included in the review, and the flow diagram of the study design is shown in After Stata verification, the overall pooled prevalence of AR in adults was 19% (95% CI 14–25) , and theI2 <50% and combined effect size. Smoking, asthma, food allergy, antibiotic use, home renovation, and middle school education were chosen for the random effect analysis method to calculate on the basis of I2 >50% and combined effect size. The meta-analysis results revealed that the combined effect sizes of all other risk factors were statistically significant, except for the association between home decoration and adult AR , p=0.326), and a family history of allergy was the primary risk factor , p < 0.001) for AR in children . Egger's test of risk factors for adults showed no significant publication bias  showed that smoking was a significant risk factor for AR.Six studies on adult smoking , 43–45 aadult 3.30, 95% CI  and ORchildren 3.26, 95% CI ); thus, asthma was remarkably correlated with AR.Four studies , 18, 46 Three studies , 39, 54 Ten studies , 43–48 iThree studies , 43, 46 Four studies , 54, 60 Four studies , 58, 59 Three studies , 19, 46 Four studies , 45, 46 Three studies , 45, 49 Three studies , 19, 43 Eight studies , 59, 61 Three studies , 49, 50 Three studies , 55, 59 p=0.056).Three studies , 48, 51 Four studies , 35, 53 Five studies , 46, 52 p=0.326.Seven studies , 58, 59 The main purpose of this study was an assessment of the prevalence of AR and risk factors for AR among adults and children in China. The results of our meta-analysis showed that the prevalence of AR was 19% among adults and 22% among children in China. Regional differences have been observed in the prevalence of AR in China, with the lowest rate in the southern areas and the highest in northern China and high morbidity rates in cities with developed economies and industries, which is consistent with the incidence of AR in Europe , 63. ComAR, as a respiratory inflammatory disease, constitutes a complex immunological response in nasal mucous membranes and is closely related to environmental exposure. Allergies or a history of allergies and their incidence were determined by specific risk factors and intricate interplay of environmental exposures and genetic. Epigenetics have highlighted an association between subsequent risk and environmental exposures for AR and deserve further exploration in the pathogenesis of AR; these include a study of miRNA levels, histone acetylation, and alteration of DNA methylation , 69. MurT cells, and interleukin-1 family signaling in pathogenic diseases, confirming an essential role in lymphocyte-mediated immunity [Allergic diseases, AR, eczema, and asthma have close relationship due to overlapping genetic characteristics . Our resimmunity , 73, 74.immunity , 76. We Our results indicated that home renovation, occupational dust exposure, owning pets, and pollen allergy played a role in the development of AR, as well as some strong environmental factors, which ranged from personal living habits to many different exposures in both external environment and home. Although most of the factors studied were risk factors for AR, home renovation indicated no significant association in adults. Therefore, for high-risk patients, it is highly recommended that there should be no pets or plants, hygiene should be maintained, and indoor ventilation should be cleaned regularly to minimize the exposure to allergens.A, stimulates the immune response and modify the balance between the anti-inflammatory and proinflammatory status [Breastfeeding reduces the risk of AR disease because the breast milk constituent, including long chain fatty acids, cytokines, and immunoglobulin y status . The finDue to the biases in investigative studies, the conclusion of the review should contain consideration for different geographical regions and observation over time. The limitations of this study were as follows: (1) Geographic and demographic biases may exist. (2) Egger's test found that two factors, a history of allergic diseases and eating seafood, had a certain publication bias; therefore, these results need to be confirmed by further research, and (3) some risk factors could not be analyzed because of the limited available literature.In summary, the prevalence of AR was related to a variety of factors. Therefore, further studies in different geographical regions of China should be conducted with a focus on different risk factors. These studies may provide more information about the disorder and medical assistance using strategies to reduce the risk of AR among Chinese adults and children.


Leishmania genus. Mannose-binding lectin (MBL) is a serum complement protein and recognizes lipoprotein antigens in protozoa and the bacterial plasma membrane. Nucleotide variants in the promoter region and exon 1 of the MBL gene can influence its expression or change its molecular structure.Leishmaniasis is caused by an intracellular protozoan of the To evaluate, through a systematic review, case-control studies of the genetic association of variants in the MBL2 gene and the risk of developing leishmaniasis.vs. L), -221 (X vs. Y), +4 (Q vs. P), CD52 (A vs. D), CD54 (A vs. B), CD57 (A vs. C) and A/O genotype (A vs. O) was evaluated. International Prospective Register of Systematic Reviews (PROSPERO): CRD42020201755.This review carried out a search in PubMed, Science Direct, Cochrane Library, Scopus and Lilacs databases for case-control publications with six polymorphisms in the mannose-binding Lectin gene. The following strategy was used: P = Patients at risk of leishmaniasis; I = Presence of polymorphisms; C = Absence of polymorphisms; O = Occurrence of leishmaniasis. Four case/control studies consisting of 791 patients with leishmaniasis and 967 healthy subjects (Control) are included in this meta-analysis. The association of variants in the mannose-binding Lectin gene and leishmaniasis under the allelic genetic model, -550 (HThe meta-analysis results for any allelic genetic model showed no significant association for the variants within the promoter, the untranslated region, and exon 1, as well as for the wild-type A allele and mutant allele O with leishmaniasis.Caution should be exercised when interpreting these results, as they are based on a few studies, which show divergent results when analyzed separately.This meta-analysis showed a non-significant association between the rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, and rs1800451 polymorphisms of the Mannose-binding Lectin gene and leishmaniasis in any allelic and heterogeneous evaluation. Phlebotomus, is caused by intracellular parasitic protozoa belonging to the Leishmania genus.Leishmania spp., environmental and the immunological aspects.Leishmaniasis, a disease spread through bites by infected Phlebotomine sandflies of the genus Mannose-binding lectin (MBL) is a pathogen recognition receptor (PRR) and plays a critical role in host immunity. MBL leads to the activation of the complement system.Trypanosoma cruzi,Plasmodium falciparum,Mycobacterium tuberculosis.Leishmania (promastigote) is characterized by the presence of lipophosphoglycans (LPG) and other molecules such as mannose.18Across multiple lectin domains, carbohydrates such as mannose (six-carbon carbohydrates) are found on the surface of several pathogens, including The MBL2 gene is located on chromosome 10 10q11.2-q21)..21, 22 FConflicting results are observed between the MBL2 gene variants and susceptibility to leishmaniasis. Variants featuring high levels of the protein have been associated with susceptibility to VL in Africa,Some studies have been conducted previously to assess the effects of the MBL2 gene polymorphisms on the evolution of the infection in leishmaniasis, with contradictory results due to the small sample size, which lacks adequate power to detect the effects of MBL2 gene polymorphisms on leishmaniasis.To date, no systematic review has been performed on MBL2 gene variants and leishmaniasis. The use of a meta-analysis as a statistical tool to explore risk factors associated with different genetic diseases can provide a reliable conclusion. This systematic review included case-control studies of the genetic association of variants  in the MBL2 gene and the risk of developing leishmaniasis. This systematic review is in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42020201755.This systematic review was carried out in accordance with the recommendations of the PRISMA  protocol.  AND (“Mannose-binding Lectin” OR “Mannose-binding Lectin 2” OR “MBL” OR “MBL2”) AND (“Polymorphism” OR “Polymorphisms” OR “Single Nucleotide Polymorphism” OR “Single Nucleotide Polymorphisms”). The references cited in eligible articles were manually searched to identify additional publications. Ethical approval and informed consent were not required as this study was based on previously published studies, and there was no direct patient contact or influence on patient care.The following strategy was used: P = Patients at risk for leishmaniasis; I = Presence of polymorphisms; C = Absence of polymorphisms; O = Occurrence of leishmaniasis. The following terms were used in the search: Two researchers independently evaluated all search results. The inclusion criteria were as follows: 1) Case-control study, 2) rs11003125 (-550), rs7096206 (-221), rs7095891 (+4), rs5030737 (Codon 52), rs1800450 (CD54) and rs1800451 (CD57) polymorphisms, 3) Studies with sufficiently available genotyping data to calculate the Odds Ratios (OR) with 95% Confidence Intervals (95% CI) and 4) the Hardy-Weinberg Equilibrium (HWE). The exclusion criteria were: 1) Non-case-control study, 2) Case reports, 3) Reviews, 4) Animal studies, 5) Editorials, 6) Studies with no available data, 7) Studies with meta-analysis, 8) Other polymorphisms and 9) Duplicate data. Subsequently, all selected articles were verified by a third researcher, who resolved the divergences.Two researchers independently extracted the following data from the included studies: year of publication, first author, study region, ethnic group, clinical form, number of samples, age, and studied SNPs. Disagreements between the researchers were discussed and resolved by consulting a third researcher.The Newcastle-Ottawa scale  was usedvs. L), -221 (X vs. Y), +4 (Q vs. P), CD52 (A vs. D), CD54 (A vs. B), CD57 (A vs. C) and the A/O genotype (A vs. O). I2 was used to assess the heterogeneity between studies, where the values 25%, 50% and 75% corresponded to low, moderate, and high heterogeneity, respectively. The fixed model was used when I2 < 50%, and the random model was used when I2 > 50%. Pooled ORs were calculated using the Mantel-Haenszel method, and the statistical significance of OR was determined using Z statistics. In both models, p = 0.005 was considered statistically significant. The RStudio software (www.rstudio.com/products/rstudio/), version 1.3.1 for Windows was used for the statistical analysis of the study. Packages (“tidyverse”), (“meta”), (“metafor”).The meta-analysis evaluated the association of the MBL2 gene and leishmaniasis under the allelic genetic model, -550 , -221X allele: OR = 0.98; 95% CI = 0.45–2.13; p = 0.01; I2 = 91% and -221Y allele: OR = 1.02; 95% CI = 0.47–2.22; p = 0.01; I2 = 91%) and Q + 4 allele: OR = 0.85; 95% CI = 0.54–1.33; p = 0.03; I2 = 79% and P allele: OR = 1.17; 95% CI = 0.75–1.84; p = 0.03; I2 = 79%). Similar results were obtained for variants located on exon 1 CD52 , CD54  and CD57 . The presence of the wild-type A allele  and the mutant O allele  were also not associated with susceptibility or resistance.The results of the meta-analysis are shown in MBL recognizes the presence of mannose on the surface of pathogens to promote opsonization and activation of the complement system.The conflicting results generated by most studies had weak statistical power due to the small sample size included. To clarify conflicting results in genetic association studies, a meta-analysis offers a powerful method to synthesize data obtained from independent studies.In the present study, data from four studies were analyzed according to the low- and high- MBL producing alleles. However, the meta-analysis analyses showed no association between MBL2 gene alleles and susceptibility to leishmaniasis . High heHowever, caution should be exercised when interpreting these results, as they are based on a few studies, which show divergent results when analyzed separately. Therefore, further studies are needed to confirm whether the variants that determine low serum levels are susceptible or protective. The great importance of the association study involving genetic markers in leishmaniasis is emphasized, aiming at a new understandings of the molecular mechanisms of the disease. The variants can be used as molecular markers of the individual predisposition to certain types of diseases or as therapeutic targets in the development of new drugs.Overall, this meta-analysis showed no significant association between polymorphisms rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, and rs1800451 of the MBL2 gene and leishmaniasis.None declared.None declared.Wonei de Seixas Vital: Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing – review & editing.Felipe Jules de Araújo Santos: Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing – review & editing.Maurício Leandro Fernandes Gonçalves: Data curation, Formal analysis, Methodology, Writing – original draft.Claudia Dantas Comandolli Wyrepkowski: Data curation, Formal analysis, Methodology.Rajendranath Ramasawmy: Data curation, Formal analysis, Methodology, Writing – review & editing.Silvania da Conceição Furtado: Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing – review & editing.


GPX4 (rs713041) SNP and the risk of diseases in humans and its correlation with selenium status. Material and methods: A systematic search for English-language manuscripts published between January 1990 and November 2022 was carried out using six databases: CINAHL, Cochrane, Medline, PubMed, Scopus and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to assess a relationship between GPX4 (rs713041) SNP and the risk of different diseases based on three genetic models. Review Manager 5.4 and Comprehensive Meta-Analysis 4 software were used to perform the meta-analysis and carry out Egger’s test for publication bias. Results: Data from 21 articles were included in the systematic review. Diseases were clustered according to the physiological system affected to understand better the role of GPX4 (rs713041) SNP in developing different diseases. Carriers of the GPX4 (rs173041) T allele were associated with an increased risk of developing colorectal cancer in additive and dominant models . In addition, carriers of the T allele were associated with an increased risk of developing stroke and hypertension in the additive, dominant and recessive models . On the other hand, the GPX4 (rs713041) T allele was associated with a decreased risk of developing pre-eclampsia in the additive, dominant and recessive models . Moreover, selenium levels presented lower mean values in cancer patients relative to control groups . Conclusion: GPX4 (rs713041) T allele may influence colorectal cancer risk, stroke, hypertension and pre-eclampsia. In addition, low selenium levels may play a role in the increased risk of cancer.Aim: The single-nucleotide polymorphism (SNP) rs713041, located in the regulatory region, is required to incorporate selenium into the selenoprotein glutathione peroxidase 4 (GPX4) and has been found to have functional consequences. This systematic review aimed to conduct a meta-analysis to determine whether there is an association between  The dietary intake of selenium is essential for health. Severe deficiency, in combination with virus infection, was found to cause myocarditis in China, but more recently, various studies have indicated that a sub-optimal intake can increase the risk of diseases such as cancer ,2. GlutaGPX4 is vital for normal physiology, and its absence is incompatible with life due to its role in preserving mitochondrial function, inflammation, differentiation, immunity and cell death . InhibitDietary selenium influences the level of selenoproteins to different extents depending on the tissue and the specific selenoproteins. For example, low dietary selenium affects glutathione peroxidase 1 and selenoprotein W more than GPX4 , and it GPX4 mRNA in the 3′UTR, the regulatory region required for incorporation of selenium into selenoproteins  against its standard error (SE), and the degree of asymmetry was tested by Egger’s test (ion bias ). When pion bias .The risk of disease as a function of selenium levels and GPX3 activity (a commonly used marker of selenium status) in plasma/serum was also evaluated by continuous analysis, using mean and standard deviation for both selenium levels and GPX3 activity, reported in some of the studies. The standardized mean difference was used for this meta-analysis as the studies assessed selenium levels and measured GPX3 activity using different methods, allowing expression of the effect size between cases and controls relative to the variability observed in each study .Given the diversity of diseases considered in the selected studies, it was not possible to carry out the meta-analysis for all diseases. For meta-analysis purposes, according to Cochrane guidelines, at least two reports are required to perform statistical analysis . The sofGPX4 (rs713041) SNP and 9 for other reasons  SNP linked to nineteen diseases; these included breast cancer [The selected studies reported data related to t cancer ,17, colot cancer ,36, prost cancer ,37, laryt cancer , lung cat cancer , pre-eclt cancer ,39, hypet cancer , ischemiX4 rs7130 SNP linkt cancer , recurret cancer , pregnant cancer , Graves’t cancer , Hashimot cancer , acute pt cancer , Alzheimt cancer , depresst cancer , multiplt cancer , type 2 t cancer  and Kasht cancer . Regardit cancer , two rept cancer ,43, one t cancer , five ret cancer ,38,39,46t cancer ,41,44. Gt cancer , one KASt cancer , two rept cancer ,37, fourt cancer ,43,44,46t cancer ,41,45. TEvaluation using the Newcastle-Ottawa quality assessment scale for case-control studies revealed that ten selected studies were of high quality , whereas twelve were of moderate quality (score = 7), as indicated in GPX4 (rs713041) SNP on the development of different diseases, it was necessary to cluster diseases in groups according to body systems affected or disease characteristics. Three distinct groups with fourteen reports were created to evaluate the influence of GPX4 (rs713041) SNP in susceptibility to cancer, hypertension-related diseases, and reproduction.To better assess the influence of Selected studies reported data related to selenium levels in plasma or serum for only four types of cancer: breast cancer , prostatSeven reports regarding cancer were included: two for breast cancer ,17, one 2 < 50%). Using a fixed-effects model and all studies pooled into the meta-analysis, GPX4 (rs713041) SNP was not statistically related to cancer . Sensitivity analysis was performed to determine whether any study had a greater degree of influence between the association of GPX4 (rs713041) SNP and cancer risk. No single study had a larger influence over the other studies when assessing the association for the additive or recessive model. However, in the dominant model, a positive association was found between the rs713041 T allele and cancer risk when data for laryngeal cancer from Jaworska et al. study [p = 0.05), or when data for lung cancer from the same study were removed . No asymmetry was noted in the resultant funnel plots for the additive and recessive model , suggesting the lack of publication bias; whereas publication bias was present in the dominant model  SNP on the susceptibility of breast, colorectal and prostate cancer, separately, sub-group analysis was carried out, following Cochrane guidelines that define a minimum of two reports for meta-analysis [GPX4 (rs713041) SNP and breast or prostate cancer using a fixed-effects model and for each genetic model (GPX4 (rs713041) T allele were associated with an increased risk of developing colorectal cancer in comparison to those with the C allele in the additive model  and the dominant model   .GPX4 (rs713041) SNP with hypertension-related diseases was also tested. Four reports were included in this group: two evaluated pre-eclampsia [The association of clampsia ,39, one clampsia  and one X4 rs7130 SNP withclampsia ,39, wherclampsia ,41. All clampsia ,39,40,412 higher than 50% , indicating the presence of heterogeneity between the studies. For this reason, a random-effects model was used to investigate the association of rs713041 with hypertension-related diseases. Results show that GPX4 (rs713041) SNP did not increase the risk for hypertension-related diseases . Sensitivity analysis did not show any study having a greater degree of influence between the association of GPX4 (rs713041) SNP and risk of hypertension-related diseases. Publication bias was evident in the visual analysis of funnel plots . The trim and fill analysis identified one possible missing study. When the funnel distribution was rebalanced by including this putative additional study  SNP association with pre-eclampsia, separately from ischemic stroke and hypertension. After excluding pre-eclampsia papers from the meta-analysis, the rs713041 T allele was found to be associated with an increased risk of developing stroke and hypertension in comparison with the rs713041 C allele, in the additive model , in the dominant model  and also in the recessive model . On the other hand, when stroke and hypertension studies were excluded from the meta-analysis, the rs713041 T allele was associated with a decreased risk of developing pre-eclampsia in all three models  than those with the C allele.Sub-group analysis was carried out in all three models to assess GPX4 (rs713041) SNP with the exception of late-onset pre-eclampsia (dominant model) where there was no difference (p = 0.12)  .GPX4 (rs713041) SNP. The heterogeneity test was higher than 50% in the three genetic models , and random-effects analysis was used to explore the influence of rs713041 on reproductive disorders. No significant differences were observed in the additive model (p = 0.76), dominant model (p = 0.47) or recessive model (p = 0.79). By excluding one paper at a time to eliminate possible bias in the meta-analysis, no association between GPX4 (rs713041) SNP and reproductive disorders were observed in all genotype models. No asymmetry was noted in the resultant funnel plots for the additive, dominant and recessive model , suggesting the lack of publication bias.In an analysis of diseases related to the female reproductive system, 513 cases and 443 controls were included in the initial meta-analysis. Three studies were used: one report evaluated endometriosis , one misve model  and was GPX4 (rs713041) genotype has been investigated in other diseases, but the number of publications was limited and not sufficient to be included in a meta-analysis. The GPX4 (rs713041) SNP had been traced in autoimmune thyroid diseases in the Chinese population: Xiao et al. (2017) stated that the major C allele and CC genotype decreased in both types of autoimmune thyroid diseases (Graves’ diseases and Hashimoto’s thyroiditis) patients compared to controls, but no association of this SNP with both diseases was found [Previously, the as found .GPX4 (rs713041) genotype in acute pancreatitis patients in comparison to healthy control [Ściskalska et al. (2022) traced the  control . The fre control .GPX4 (rs713041) genotype has been investigated in neurological diseases such as Alzheimer’s disease and depression. Da Rocha et al. reported a significant association between GPX4 (rs713041) SNP and long-term visual memory in Alzheimer’s disease patients, as the T homozygote genotype was more frequent in subjects without long-term memory deficits [GPX4 (rs713041) SNP and depression as the TT genotype and the T allele increased the risk of depression, whereas CT heterozygous and C allele diminished its risk [Moreover, the deficits . Winger its risk .GPX4 (rs713041) SNP and type 2 diabetes mellitus and stated that there were no statistically significant differences in genotype distribution between type 2 diabetes mellitus patients and control, while higher levels of triglyceride were reported in GPX4 (rs713041) C/C cohorts, followed by C/T patients and T/T carriers [Gusti et al. (2021) investigated the association between carriers .GPX4 (rs713041) SNP in Kashin-Beck disease, an endemic joint disease mainly distributed in areas with low selenium intake, and stated that no significant differences were observed in either genotype or allele frequency between healthy and Kashin-Beck disease subjects [Du et al. (2012) investigated the association between subjects .GPX4 (rs713041) SNP and the development of multiple sclerosis (MS) in a Polish population [Wigner et al. (2022) assessed the association between pulation . They depulation .p = 0.002). Sensitivity analysis showed that none of the studies reversed the association between cancer risk and lower selenium status. Publication bias was assessed by visual examination of the funnel plot (p = 0.34).Lower selenium levels in plasma or serum have been reported to be closely related to the development of various cancers . Data fonel plot , and Eggp = 0.25).Another marker of selenium status is the level of glutathione peroxidase 3 (GPX3) activity in plasma or serum, which is crucial to maintain redox status. Reduced levels in plasma have been associated with increased oxidative stress. Data for GPX3 activity were available in only two reports ,37, inclGPX4 (rs713041) SNP on susceptibility to several human diseases. This meta-analysis showed a statistically significant relationship between GPX4 (rs713041) SNP and susceptibility to colorectal cancer and hypertension-related diseases (stroke and hypertension), with carriage of the T allele giving increased susceptibility. On the other hand, the T allele was associated with a decrease in the risk of pre-eclampsia.A systematic review and meta-analysis were conducted to investigate the influence of GPX4 (rs713041) SNP in human endothelial cells affected cell function—homologous TT cells were more susceptible to oxidative stress and monocyte adhesion in comparison to CC cells [The selenoprotein GPX4 contains selenium as part of the active centre and catalyzes the conversion of lipid peroxides from the oxidation of glutathione, which is constantly reused by glutathione reductase (GR) . It has CC cells .GPX4 (rs713041) T/C variation with several diseases. Genotype and allele frequencies in case and control groups were investigated in three different genetic models: the additive model, which assumes a linear and uniform increase based on the number of each copy of the disease-causing allele (T) (the risk for CT is k then the risk for TT is 2k); the dominant model which assumes that having one or more copies of the disease allele (in this study considered as T) increases the risk compared to C (TT or CT genotypes have higher risk); and the recessive model which assumes that two copies of T allele are required to alter the risk  [Due to the potential importance of GPX4 function in several molecular pathways, as recently reviewed by Ursini and colleagues , this sy and CC) .GPX4 (rs713041) genotype T allele was associated with an increased risk of developing colorectal cancer in both additive and dominant models, as well as an increased risk of developing stroke and hypertension in additive, dominant and recessive models. The increased risk for colorectal cancer, stroke and hypertension in the rs713041 allele T genotype may be the result of an effect of the SNP on mRNA translation and, consequently, GPX4 activity and increases in oxidative stress, ferroptosis, and inflammation. Such changes could be expected to impact cancer risk. The data analysis indicates associations between colorectal cancer risk and rs713041 genotype and suboptimal selenium status. This is compatible with increased colorectal cancer risk with lower selenium status in a large pan-European population [GPX4 (rs713041) genotype and selenium status is important in determining disease risk.pulation . Unfortupulation . HoweverGPX4 (rs713041) SNP has been associated with the hyperactivation of signaling pathways that generate oxidative stress and inflammation mediators, such as adhesion molecules [GPX4 (rs713041) T allele was associated with a decreased risk of developing pre-eclampsia in all the genotype models. It is important to highlight that all the studies reporting pre-eclampsia data are by Chen et al. and Peng et al., which relate to the Chinese Han population, and all cases and controls were recruited from Shandong Province in China [GPX4 (rs713041) SNP, selenium status and pre-eclampsia needs more studies from different geographic areas to provide a clear understanding.The olecules . TT genoolecules . Pre-eclolecules . Surprisin China ,39. Therin China . AltogetThis study had some limitations which should be considered. In general, diseases with similar characteristics were clustered for meta-analysis, but not all selected studies were included as they did not fit in a specific disease group or there was only one study per disease, which prevented meta-analysis . Another limitation of the study is that the effect of ethnicity on disease risk could not be assessed due to the small number of included studies on different ethnic groups. Finally, a thorough analysis of a combination of genotype and selenium status was not possible. Despite the small number of studies per disease group, the quality of the studies included was high, and publication bias was not present , providing strength to the conclusions.GPX4 (rs713041) SNP with a variety of diseases. Overall, our findings suggest that GPX4 (rs713041) SNP influences colorectal cancer development and progression with low selenium status playing also a role in different cancers, and that GPX4 (rs713041) SNP influences the risk of stroke and hypertension. This study, taken together with animal and cell culture work [This is the first meta-analysis to assess the association of GPX4 rs7041 SNP wure work ,51,57, h


Regarding dietary components, the following were assessed: total fruit (n = 2), citrus fruit (n = 1), total vegetables (n = 2), cruciferous vegetables (n = 1), red meat (n = 6), processed meat (n = 4), poultry (n = 2), eggs (n = 1), fish (n = 5), whole grain (n = 2), potato (n = 1), and nuts (n = 2). The methodological quality of the included meta-analyses was generally low or critically low. Although the strength of evidence was generally weak, convincing or suggestive evidence was found for a healthy/prudent, plant-based diet, fruit and vegetables, and lower risk of PC, whereas a high intake of red meat was associated with a higher risk of PC at a convincing level of evidence. Further studies are needed to confirm the role of the other dietary patterns/food components and the risk of PC.Pancreatic cancer (PC) represents the third leading cause of cancer death in 2020. Despite the fact that, in 2018, the World Cancer Research Fund report concluded that there is still a lack of evidence on the role of foods or diets and risk for PC, a flourishing body of evidence has been published and needs to be analyzed. For this reason, we conducted an umbrella review on the association between different dietary patterns/food components and PC. Data sources PubMed/MEDLINE, Scopus, Web of Science, EMBASE, and the Cochrane Collaboration were searched. The Joanna Briggs Institute Umbrella Review Methodology was used. The protocol was registered in PROSPERO. A total of 23 articles were included, covering a wide range of dietary patterns/food components: healthy/prudent dietary patterns ( Pancreatic cancer (PC) is the 12th most common cancer type in the world, with 495.773 new cases in 2020. Although the incidence rate is not very high, PC is almost always intractable, and it represents the third leading cause of cancer death in high-income countries  and the eighth worldwide with 466.003 deaths  in 2020  . HoweverWeak strength of evidence or no evidence was found when considering western, unhealthy, and Mediterranean diets. However, in the last-mentioned case, only one meta-analysis , with twConsidering the dietary components, higher consumption of vegetables was associated with a lower risk of PC; similarly, higher consumption of red meat was associated with a higher risk of PC with the highest strength of evidence. Looking at vegetable consumption, a total of two meta-analyses were retrieved ,53 Figu. One metHighly suggestive evidence was identified in two meta-analyses assessing the association between higher consumption of fruit and lower risk of PC ,53. The The association between higher consumption of citrus fruit and lower risk of PC was assessed by one meta-analysis with a weak strength of evidence [random effect size: 0.85 ]  Figure . SimilarNo evidence was detected for the association between higher consumption of poultry, eggs, fish, and risk of PC, assessed by two ,50, one Detailed information on the assessment of the strength of evidence is reported in To our knowledge, this is the first umbrella review evaluating the quality and strength of evidence from meta-analyses on dietary risk factors for PC in adults. After a careful selection of studies according to eligibility criteria, we found 23 different systematic reviews with meta-analyses of observational studies that displayed the effect of a healthy diet, Mediterranean diet, plant-based diet, DII, western diet, unhealthy diet, and food components . Overall, assessment through the AMSTAR-2 tool found that the quality of these meta-analyses ranged from critically low to moderate, with issues mainly related to the research question and inclusion criteria, as well as the search strategy for literature finding. As regards dietary patterns, this umbrella review found a higher number of meta-analyses for healthy/prudent diets, whose definitions varied greatly across the included reports. Therein, convincing evidence that health/prudent diets protect against PC was reported in the studies by Lu et al.  and GrosGrosso et al. also speculated that the geographical differences across the original studies might account for the amount and proportion of individual unhealthy food consumption, which may have affected the results of their meta-analysis . It is wWhen the number of individuals studied in the meta-analysis increased (particularly those enrolled in primary cohort studies), the difference according to the design was attenuated, as seen with regard to the risk according to the adherence to plant-based diets in the meta-analysis by Zhao (2022) et al. , which rIn this respect, several studies have found possible mechanisms through which bioactive compounds could affect cancer risk. These include epigenetic mechanisms (such as downregulation of oncogenes and upregulation of tumor-suppressor genes and regulation of telomerase activity), immunoregulation, suppression of cancer cells proliferation, migration and invasion, and antioxidant and anti-inflammatory activity ,64,65,66As for DII, it is well known that the pro-inflammatory potential of the diet can be a causative factor in cancer development and progression ,68, and Weak or no evidence of an increased risk of PC was reported for western and unhealthy diets, with two studies for each analysis. Both dietary patterns are high in red and processed meat, high-fat and high-sugar dairy products, and low intakes of fruits, vegetables, and whole grains , which cAs known, MedDiet may have a role in cancer prevention, although, in our umbrella review, it displayed no evidence for PC. Worth noting is that the role of MedDiet was evaluated only in one retrieved study  on the oWhen exploring the association of group or single dietary components, the literature search found meta-analyses with very large populations, up to around three million people included therein. With regard to fruit consumption, the analyses found highly suggestive evidence for diets with higher total fruit consumption  and weak evidence for citrus fruit. Similarly to fruit, diets rich in vegetables showed highly suggestive-to-convincing evidence  or weak evidence . As briefly said before, fruits and vegetables are rich in vitamins, carotenoids, and other phytochemicals that have been associated with reduced risk of PC, also through a protective effect on type 2 diabetes mellitus, a well-recognized risk factor for PC ,76.Several overlapping biological mechanisms have been extensively suggested to shed light on the inverse relationship between the intake of whole grain foods and PC risk ,77: the Meta-analyses investigating red and processed meat consumption and the risk of PC showed great variability of evidence strength and quality. Convincing evidence was reported in the study by Paluszkiewicz et al., which included quantitative analyses of PC risk in relation to main dietary compounds . ConversThe evidence for the other dietary components analyzed  were less or not at all consistent, and the supporting literature was of low methodological quality. The slight but significantly increased PC risk associated with potato consumption has been related mainly to substances formed during its preparation and cooking. For example, fried potatoes are characterized by a high content of trans fatty acids, salt, and acrylamide. While acrylamide may exert a mutagenic effect due to the capacity of glycidamide to form DNA adducts, trans fatty acids and salt intake induce chronic inflammation, which may be related to carcinogenesis . Boiled Altogether, the results from this umbrella review corroborate observational findings indicating that dietary patterns emphasizing healthy/prudent diets, vegetables, fruits, whole grains, nuts, and plant-based compounds, and limiting foods with pro-inflammatory potential, red and processed meat, are associated with lower risk of PC. However, the methodological quality of the meta-analyses included in this umbrella review appears to be mainly low or critically low, fostering further research on the effect of dietary components and patterns on the risk of PC in order to draw firmer conclusions with a view to informing evidence-based practice and decision-making ,82. In tTo comprehensively appreciate the results of this umbrella review, some limitations must be acknowledged. First, as an umbrella review is a systematic review of meta-analyses, it depends on the quality of the included meta-analyses and does not take into account potential omissions or overlaps of original studies. Second, the retrieved evidence showed heterogeneity in terms of populations, methodologies, duration of interventions, study quality, the definition of intervention, and control diets. In particular, regardless of the type of diet, dietary pattern, and single foods within a population, dietary habits may be influenced by sociodemographic characteristics and cultural habits, which may represent potential sources of heterogeneity within the same group of dietary habits. In this sense, this umbrella review offers room for further investigating whether sociodemographic drivers may have an extent on the association between diets and PC risk. Furthermore, it highlights the lack of clinical studies on this topic. In fact, while a substantial amount of secondary research included observational studies, no analyses of RCTs on the association between diet and the risk of PC were available. Although interesting, the pooled results of observational studies are less strong due to uncontrolled multiplicity in statistical comparisons, with differences in the final results mainly due to the framing of study questions and differences in the inclusion criteria, comparisons, populations, and statistical methods used. Based on these findings, we can state that future studies need a more consistent and uniform methodology , with a detailed account of the methods used, participant sociodemographic and clinical characteristics, and outcome data. This approach would allow more precise quantification of the association between dietary patterns and PC.. In this umbrella review, a systematic and comprehensive literature search synthetizes meta-analyses that assessed the effects of different popular diets, dietary patterns, and food components on the risk of PC. Plant-based diets, as well as the consumption of higher fruits and vegetables, whole grains, and nuts, have been linked to the strongest and most consistent evidence, with no meta-analyses reporting negative effects. Convincing evidence of reduced risk was also reported for healthy/prudent diets, albeit not confirmed in all the found meta-analyses. DII, western patterns, and unhealthy diets reported a tendency towards detrimental effects on PC risk but showed relevant differences in terms of quality and strength of evidence. Spare meta-analyses showed weak evidence of potential risk from red and processed meat and potato. The strength of evidence for the other diet components and patterns evaluated was not statistically significant. Overall, the results from this umbrella review depict the strengths and limitations of evidence on PC risk according to the most popular diets, highlighting the need for a robust understanding of healthy eating guidance for PC prevention. There is a growing body of evidence regarding the association between numerous diets/dietary patterns and several cancers; however, they have different strengths of association, even if the certainty around the direction of the association is well established. More in detail, and considering results shown in the last edition of the WCRF/AICR report, evidence on dietary intake  and pancreatic cancer risk reached a limited level of evidence. Similar data are also reported, for instance, for cancer of the gallbladder, ovary, and esophagus (adenocarcinoma). On the contrary, a strong level of evidence has been reached for certain dietary factors and both the increase  and the reduction  of colorectal cancer risk. Based on the above-mentioned limited certainty around the association between dietary intake and pancreatic cancer risk, we developed the current umbrella review