Background: Numerous data show a role for genetic polymorphisms in the development of epilepsy. Previously, the TT genotype of the MTHFR 677C>T polymorphism was found to be associated with a decreased leucocyte DNA methylation status. Polymorphisms in the MTHFR gene could modify the pharmacodynamics of many drugs. This meta-analysis aimed to assess the relationship between MTHFR 677C>T polymorphism and susceptibility to epilepsy in young patients. Methods: Available databases  were searched using specific keywords. Eight studies, published between 1999 and 2019, with 1678 young patients with epilepsy and 1784 controls, met the inclusion criteria. Apart from the total groups, additional analyses in age subgroups  were conducted. Statistical analyses were conducted using the RevMan 5.4 and MedCalc software. The pooled odds ratio (OR) was estimated with a random- or fixed-effects model depending on the heterogeneity. Analyses were performed for five genetic models, i.e., dominant (CT + TT vs. CC), recessive (TT vs. CC + CT), additive (TT vs. CC), heterozygous (CT vs. CC), and allelic (T vs. C). The publication bias was assessed with the use of Egger’s and Begg’s tests. Results: Both the MTHFR TT genotype (in the additive model) and the T allele  significantly increased the risk of epilepsy when the total groups were compared . The sensitivity analysis for these models indicated the stability of the results. Similarly, significant results were obtained among young adults for all the genetic models . Those results were also stable and reliable. In the group of children, no relation between 677C>T polymorphism and epilepsy was observed; however, the analysis was based only on three studies, and one study also comprised young adults. No publication bias was demonstrated. Conclusions: The meta-analysis revealed that the carrier state for the T allele as well as the TT genotype of the MTHFR 677C>T polymorphism increases the risk of epilepsy in young adults but not in children. The pathogenesis of epilepsy, which is one of the most common neurological disorders worldwide, is heterogeneous but still not fully known. Epileptogenesis is a dynamic process that begins with the action of one or several damaging factors . In response to the damage factor within the latent period, the changes begin at the molecular level in gene expression and protein synthesis, and then, disturbances in the functioning of ion channels and neurons begin. The consequence of these changes is epileptic seizure as a clinical manifestation . Based oThe first remarks on the hereditary component in epilepsy were emphasized in 400 years BC by Hippocrates, who was also the first one who suggested a possible etiology and therapy for the disease . Due to In experimental animal models, the genome-wide alteration of DNA methylation signatures was demonstrated as a general pathomechanism associated with epileptogenesis and epilepsy . The autMTHFR gene was found to be related to the thermolability of the enzyme, which, in consequence, leads to an elevated level of homocysteine. Previously, it was observed that a disturbance in homocysteine metabolism may influence cellular methylation processes, including DNA methylation [MTHFR TT genotype was associated with a decreased leucocyte DNA methylation status. Polymorphisms within the MTHFR gene could modify the pharmacodynamics of many drugs that require methylation reactions during metabolism or their biochemical effects [MTHFR TT genotype. On the other hand, the authors reported no genotype-dependent effect of carbamazepine treatment on the levels of the B6 and B12 vitamins. Additionally, the effect of valproic acid on the levels of vitamins was not related to MTHFR genotypes [MTHFR 677C>T polymorphism and epilepsy, while others have not [Methylenetetrahydrofolate reductase  is an enzyme involved in the remethylation process. MTHFR catalyzes the reduction of 5,10-methyltetrahydrofolate to 5-methyltetrahydrofolate, the dominant form of folate and carbon donor in the remethylation of homocysteine to methionine. The gene encoding MTHFR is located on chromosome 1, in the p36.3 region. The common 677C>T polymorphism within the hylation . In the hylation , the MTH effects  observedenotypes . Some sthave not ,12,13,14MTHFR gene and susceptibility to epilepsy. The attention was focused on young patients, who included children and young adults up to 45 years old. In young people, the involvement of genes in the development of the disease may be of greater importance than in older patients.To overcome the discrepancies of the results published, a meta-analysis was conducted to assess the relationship between 677C>T polymorphism in the MTHFR polymorphism” or “677C>T polymorphism”) and (“epilepsy” or “antiepileptic drugs”) and (“young adults” or “adolescents” or “children” or “infants”). The studies searched were included in the meta-analysis when the following criteria were met: (a) confirmed epilepsy, (b) patients and control groups, (c) ages of the patients younger than 45 years old, (d) access to data on genotypes, (e) full-length paper or brief communication, and (f) article written in English. In turn, publications were excluded for the following reasons: (a) unavailability of genotyping results; (b) lack of a reference (control) group; (c) mean ages of the epilepsy patients above 45 years; (d) conference proceedings, review articles, case reports, meta-analyses or animal studies as article types; and (e) language of the article other than English. Eventually, 8 case–control studies [Databases  were searched for relevant papers (the last search was performed in late August 2021) using the following keywords:  for case–control studies was performed [The following data were extracted from each study included in the present meta-analysis: the first author’s name, year of publication, population, ages of cases and control subjects, and sizes of the analyzed groups, as well as the number with a particular genotype of the erformed . Using t2 was calculated. It describes the proportion of variance (from 0% to 100%) that is due to variance in the true effect sizes rather than sampling error. The selection of the statistical model for the analyses was performed on the basis of heterogeneity. I2 at 25%, 50%, and 75% suggested low, intermediate, and high inconsistency, respectively. In the case of significant heterogeneity between studies, the random-effects method  was used to calculate the pooled OR with the 95% CI, whereas in the case of nonsignificant heterogeneity, the calculation was performed with the fixed-effects method . The strength of the correlation between the MTHFR 677C>T polymorphism and epilepsy was assessed in the following models: dominant (CT + TT vs. CC), recessive (TT vs. CC + CT), additive (TT vs. CC), heterozygote (CT vs. CC), and allelic (T vs. C).Statistical analyses were conducted twice with the use of the Review Manager software  and MedCalc software , and an experienced biostatistician served to solve doubts. To determine the strength of association between the selected genetic model and the disease, the pooled odds ratio (OR) with 95% confidence intervals (CIs) was assessed. To assess the degree of heterogeneity between the studies included, the Ip value was below 0.05.To assess the potential publication bias, both Egger’s regression and Begg’s rank correlation tests were performed. In addition, to evaluate the stability of the results, sensitivity analyses were performed by the sequential exclusion of each study. The result was considered to be statistically significant when the The crucial data extracted from the studies included in the present meta-analysis  are shown in In general, the studies were performed in different racial populations, whereas Caucasians were the most numerous. In the case of the age of the studied patients and controls, two studies analyzed only children ,11. In tMTHFR gene was observed in three studies [MTHFR genotypes with symptomatic or cryptogenic epilepsy but not with idiopathic epilepsy was reported. In turn, Aydin et al. [The correlation between 677C>T polymorphism in the  studies ,14,15. I studies , the reln et al.  and Vilan et al.  observedn et al. .MTHFR 677C>T polymorphism, together with the results of the HWE in the controls and quality assessment for each study, is shown in The distribution of the genotypes and alleles of the One study  demonstrMTHFR gene was present in over 12% of the total group of epileptic young patients compared to almost 10% of the healthy controls. Additionally, carriers of the T allele (subjects with CT or TT genotypes) were more frequent in the epilepsy group than in the controls (55% vs. 51%).The TT genotype of the MTHFR CT + TT vs. CC) for the total groups ; thus, the pooled OR was calculated using the REM  (p = 0.01).Significant heterogeneity between the analyzed studies was observed only in the case of the dominant model  . The recp = 0.002). A weaker relation, but again significant, was observed for the allelic model , whereas a lack of relation was demonstrated for the heterozygous model .Similarly, in the additive model , the results were statistically significant . In turn, omitting the study by Scher et al. [p = 0.09). Thus, the results in the dominant and recessive model should be treated with caution.In the sensitivity analysis, no change in the OR value was demonstrated in the case of additive, heterozygous, and allelic models after excluding subsequent studies. Therefore, these analyses were considered stable. However, in the dominant model after omitting both the study by Scher et al.  and the r et al.  also chaIn the total group, no publication bias was observed since the shapes of the funnel plots of all the genetic models analyzed were roughly symmetrical. Due to the wide range of the ages of the epileptic patients from the studies included, two analyses in age subgroups were additionally performed, i.e., in the group of young adults (age over 18 years but below 45 years) and in the group of children.MTHFR T allele in the young adults with epilepsy and controls was similar to that observed in the total group .In this meta-analysis, five studies were included ,14,15,17In all the analyzed genetic models for young adults, nonsignificant heterogeneity between the analyzed studies was observed; thus, FEM was used to calculate the OR .MTHFR 677T allele may be a risk factor for epilepsy . A higher OR was found in the case of the recessive model in young adults , while the highest OR was shown for the additive model . In turn, comparable values of pooled OR were demonstrated for both heterozygous as well as allelic models in young adults .In young adults, the carrier state for the The sequential exclusion of each study included in the meta-analysis in the subgroup of young adults revealed no change in the OR value in the case of any of the genetic models. Thus, the results are stable and reliable.Similarly to in the total groups, in the subgroup of young adults, no publication bias was demonstrated .MTHFR T allele carriers in children with epilepsy was comparable to that observed in the controls .This meta-analysis contained three studies ,11,16 wiSignificant heterogeneity between the analyzed studies was observed for the dominant as well as heterozygous model; thus, the random-effects model was used to calculate the pooled OR. In the children subgroup, none of the analyzed genetic models showed significance .The sequential exclusion of each study included in the meta-analysis in the subgroup of children demonstrated that the values of the OR in the case of any of the genetic models did not change. Thus, the results are stable and reliable.In the subgroup of children, no publication bias was demonstrated, which was consistent with the results in the total groups and in the subgroup of young adults .MTHFR TT genotype may be related to epilepsy in comparison to the CC genotype . The sensitivity analysis indicated the results were stable and therefore reliable. The updated meta-analysis revealed that, in the total groups, the The results of the dominant (CT + TT vs. CC) and recessive (TT vs. CT + CC) models were not stable; therefore, despite the fact of significance, they should be treated with caution.MTHFR gene and epilepsy were published [MTHFR gene had elevated plasma levels of homocysteine. Earlier data demonstrated that the inhibitory effect of homocysteine thiolactone on Na+/K ATPase activity in the hippocampus cells of male rats can cause seizures [MTHFR gene may affect different transcriptomes and proteomes, it may influence the clinical response to various drugs, e.g., antiepileptic drugs [MTHFR gene had poor seizure control. In the study by Kini et al. [MTHFR 677C>T polymorphism and epilepsy itself was established since the authors analyzed the impact of the MTHFR genotype on the rate of major malformations in the offspring of women taking antiepileptic drugs as a secondary outcome. The study demonstrated that neither controls carrying the T allele (CT+TT genotypes) nor cases exposed to antiepileptic drugs having the CC genotype had a higher risk of major malformations [Previously, two meta-analyses analyzing the relation between 677C>T polymorphism in the ublished ,22. The ublished  from 201ublished  and two ublished ,24. Bothublished  was not ublished ,26,27,28ublished  observedseizures . Since tic drugs . In the ic drugs , epilepsi et al. , no relarmations .MTHFR 677C>T polymorphism and epilepsy among young adults were demonstrated within all the analyzed genetic models, especially for the recessive model  and additive model . The results were stable and reliable. The present meta-analysis is the first one to include a children subgroup. However, no relation between 677C>T polymorphism and epilepsy in the children groups was observed. The analysis should be treated with caution since it was based on only three studies, and one study also comprised young adults. The study by Ono et al. [MTHFR gene had no impact on elevated levels of homocysteine in epileptic children receiving carbamazepine or valproic acid. In addition, a recent study by Zhu et al. [MTHFR polymorphism in epileptic patients and controls aged 15–55 years old but in reference to its impact on homocysteine levels. The authors did not demonstrate genotype distributions. However, in the study, the MTHFR TT genotype was observed to increase patients’ susceptibility to the effect of oxcarbazepine in disrupting homocysteine homeostasis [After dividing the studies involved in the present paper according to age, greater odds for the correlation between o et al.  was inclo et al. ,32. Vuruu et al.  analyzedeostasis .MTHFR gene should be carried out in strictly defined age groups, so that the results are not underestimated or overestimated.The strength of the present study is the analysis within age subgroups, which was performed for the first time. This approach showed that the 677C>T polymorphism may be related to epilepsy in young adults, whereas including children in the overall analysis lowered the results. Therefore, it can be assumed that the analyses regarding the relationship of the 677C> T polymorphism in the MTHFR polymorphism in the development of epilepsy. Performing meta-analyses of interactions between particular genes and factors that are simultaneously present in the patients would be more accurate for understanding the role of the polymorphism in the pathogenesis of the disease. In the case of MTHFR polymorphism, the level of homocysteine should be especially considered, as the presence of a particular MTHFR genotype without elevated levels of homocysteine may have no impact on the pathogenesis of epilepsy.In the present study, some limitations should be addressed. The first one is the small number of studies included in the meta-analysis. Secondly, the analysis was generally conducted for epilepsy; there was no possibility to perform analyses in specific epilepsy subgroups. In addition, there were also no additional data on other factors that could possibly interact with the MTHFR 677T allele as well as the TT genotype in comparison with both the CC genotype and CC + CT genotypes is related to epilepsy in young adults, but no such correlations were observed for the pediatric population.Performing research to identify possible genetic biomarkers that will be clinically useful may be of great importance from the point of view of the diagnosis and treatment of epilepsy. The present meta-analysis revealed that the carrier state for the


Vitamin D has been extensively studied in relation to cancer risk at several body sites, but its relationship with non-melanoma skin cancer (NMSC), the most frequent malignancy in humans, is still unclear. Here, we performed a systematic literature search and meta-analysis of published studies and did not find convincing evidence that a causal association exists between vitamin D intake (from foods and supplements), vitamin D blood concentration, or polymorphisms of the genes coding for the vitamin D receptor and binding protein, and NMSC risk.VDR) and vitamin D binding protein (VDBP) genes, and the risk of NMSC. Random effects meta-analysis models were fitted to merge study-specific risk estimates into summary relative risk (SRR) and corresponding 95% confidence intervals (CI). Twenty-four studies altogether were included. There was a suggestive association between increasing serum/plasma vitamin D concentration and NMSC risk , although with large heterogeneity across studies (I2 = 91%). NMSC risk was associated with highest vitamin D intake in observational studies but not in clinical trials. Finally, there was no significant association between any polymorphism of the VDR and VDBP genes and NMSC risk. In conclusion, no strong relationship between vitamin D metabolism and NMSC risk appears to exist according to our systematic review and meta-analysis, although some findings are worthy of further investigation.We aimed to provide a comprehensive overview of the link between vitamin D and non-melanoma skin cancer (NMSC). For this purpose, we conducted a systematic literature review (updated to 3 February 2021) and meta-analysis of the studies reporting on the association between vitamin D intake (from diet and supplements) and blood concentration, polymorphisms of the vitamin D receptor ( Non-melanoma skin cancers (NMSC) are the most common type of skin malignancies among humans (particularly fair-skinned populations of European descent) and its incidence rates have been on the rise globally for decades . The neaVDR gene lead to an altered functionality of the VDR protein, and have been investigated in association with the occurrence of several diseases.Vitamin D is produced in human skin and is also found naturally in some foods . In addiVDR and VDBP genes, and NMSC risk.The best defined role of vitamin D in humans is in supporting the normal development and maintenance of bone tissues and in regulating calcium metabolism ,8. FurthThe literature search yielded 4232 non-duplicate entries, of which 4026 were removed based on title . The rem2 = 91%). No indication for publication bias was found (p = 0.11) and meta-regression did not indicate any significant factor associated with heterogeneity .Ten studies reported a RR estimate comparing NMSC risk among those in the highest vs. lowest category of serum/plasma 25(OH)D concentration  10,11,1,17,18,19Two other studies were not included in the meta-analysis because they were based on populations composed of patients. Gruijl et al. detected no association between serum 25(OH)D concentration and SCC risk in a cohort of 1192 kidney transplant patients . InsteadSix independent studies provided a RR estimate for the increase in NMSC risk associated with a linear increment in serum 25(OH)D concentrations . Of thesFive studies reported on the association between vitamin D intake  and NMSC risk ,26,27,28VDR gene  and NMSC risk [Apa1, Bsm1, and Taq1: no association with NMSC risk emerged for any of these three polymorphisms, either in the Hom vs. WT or in the Het vs. WT models  genotype was reported to significantly increase BCC risk  in the study by Lesiak et al. [Five papers reported on the association between any of five polymorphisms of the MSC risk ,30,31,32T models . The hetk et al. .VDBP gene and NMSC risk [VDBP gene (rs7041 and rs4588) that were investigated, despite some limited evidence of an age-specific effect.Finally, we found a single study that considered polymorphisms in the MSC risk . The stuVDR or VDBP genes. We included 24 papers published between 2010 and 2020. There was some evidence that individuals with higher measured plasma or serum 25(OH)D concentration were at increased NMSC risk. However, studies were greatly heterogeneous, which suggests caution in drawing conclusions, particularly regarding the magnitude of the possible association. Vitamin D intake was associated with a mild increase in BCC risk in the large observational study by Park et al.; however, this finding was not confirmed in another four studies, two of which had a RCT design. Finally, NMSC risk was not associated with any single polymorphism of the VDR or VDBP genes.We conducted a systematic literature review of studies that examined whether NMSC risk was associated with vitamin D serum or plasma concentration, vitamin D intake (from diet or supplements), or polymorphisms at the The association between serum/plasma 25(OH)D concentration and NMSC risk is most likely due to UV radiation exposure being causally linked to both vitamin D concentration in the blood and NMSC risk. The mild, yet significantly increased BCC risk observed among individuals with higher vitamin D intake in the large study by Park et al. is difficult to explain, particularly in light of the growing evidence in favour of a protective effect played by vitamin D supplementation against cancer at several body sites ,35,36. HVDR or VDBP genes do not seem to suffer from an increased NMSC risk based on the results of the present meta-analysis, with the possible exception of the VDR TaqI gene polymorphism. However, the number of studies eligible for inclusion in each gene polymorphism-specific meta-analysis model was limited, which prevents drawing firm conclusions. The studied polymorphisms of the VDR gene are known to impair the functionality of the receptor and eventually disrupt several vitamin D-linked biological pathways [VDR polymorphisms may affect the risk of cancer at multiple body sites [Individuals carrying polymorphisms at the pathways . Considedy sites  and thatVDR and VDBP gene with NMSC risk, thus allowing us to obtain a comprehensive picture of all the existing scientific literature on the topic. Despite this unprecedented breadth in its aims, the present work is not without some of the limitations that also flawed previously published systematic reviews and meta-analysis [This is the first systematic review and meta-analysis that simultaneously considered the link between vitamin D intake and blood concentration and the presence of polymorphisms at the analysis ,38, inclVDR) or in the vitamin D binding protein (VDBP) genes. A first screening of all retrieved items was conducted by discarding those papers that were deemed as surely not eligible for inclusion based on their title . All papers that were not discarded during this initial screening were read in full to check if they met all the following inclusion criteria: studies with a case-control (CC), nested case-control (NCC), cohort, or randomised clinical trial (RCT) design that reported  a measure of relative risk (RR) and 95% confidence intervals (CI) or another measure of statistical uncertainty for the association between at least one exposure of interest  and the risk of developing NMSC as a whole or either of its main subtypes (BCC and SCC). Risk estimates assessing the association between VDR polymorphisms and cancer risk comparing heterozygous carriers (Het) and homozygous carriers (Hom) with wild-type (WT) subjects were retrieved from all included studies. The corresponding authors of potentially eligible articles were contacted twice when deemed necessary, e.g., in order to obtain additional data or to ensure that the study really met all inclusion criteria (the article was discarded if no reply was received after the second attempt). The reference lists of all eligible papers as well as previously published reviews and meta-analyses were inspected to find additional publications. When there were two or more articles relying on fully or partially overlapping study populations, data were extracted from that with the largest study size. No language restriction was applied as long as an abstract was available in English. Two members of the writing group (SC and SR) independently decided on the inclusion of each paper, and any disagreement was resolved by consensus. The protocol of the present review was not registered; all the material prepared in the process of planning, literature search and articles selection, data extraction, data analysis, and text writing, is available from the corresponding author on reasonable request.The present literature search and quantitative meta-analysis was planned, conducted and reported according to the MOOSE guidelines . On 3 FeThe following information was extracted from each eligible article: publication year, country of study, study design, source and number of study participants, number of NMSC cases , sex and age distribution, follow-up length, details of matching (if any was applied) in CC studies, procedures and methods used to assess the exposure, and what variables were used for statistical adjustment of RR estimates.RR estimates and corresponding 95% CI were transformed into logRR and corresponding variance using the formula proposed by Greenland . When no2, which represents the percentage of total variation across studies that is attributable to heterogeneity rather than chance [We used random effects models with maximum likelihood estimation (PROC MIXED in SAS software), taking into account between-study and within-study variability when more than one estimate from a single study was used, to calculate summary RR. Homogeneity of effects across studies was quantified by In chance . A funnen chance .To assess the influence of possible sources of bias, we considered the STROBE  checklist proposed for observational epidemiologic studies . Accordihttp://www.r-project.org). The statistical significance threshold was set at p = 0.05, and all tests were two-sided.All the statistical analyses were conducted using using SAS software  and R software, version 2.12.2  are worthy of further investigation, for instance within existing large-scale RCTs including vitamin D supplementation as an experimental arm. The cornerstone of NMSC prevention must remain limiting exposure of the skin to UV light, and vitamin D supplementation may be recommended as the preferred method to secure the multiple health benefits of adequate vitamin D concentration (which extends far beyond the possible effects on the skin) while avoiding the health risks associated with an excessive exposure of the skin to the UV radiation.


Research is still required to establish the relationship between family history (FH) and gastric cancer (GC) in relation to different histological types and anatomical sites. The present work aimed to examine the influence of first-degree FH on the risk of GC, also according to the GC location and histological type, including 5946 cases and 12,776 controls from 17 studies of 11 countries in three continents participating in the Stomach Cancer Pooling (StoP) Project consortium. This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype.Although there is a clear relationship between family history (FH) and the risk of gastric cancer (GC), quantification is still needed in relation to different histological types and anatomical sites, and in strata of covariates. The objective was to analyze the risk of GC according to first-degree FH in a uniquely large epidemiological consortium of GC. This investigation includes 5946 cases and 12,776 controls from 17 studies of the Stomach Cancer Pooling (StoP) Project consortium. Summary odds ratios (OR) and the corresponding 95% confidence intervals (CIs) were calculated by pooling study-specific ORs using fixed-effect model meta-analysis techniques. Stratified analyses were carried out by sex, age, tumor location and histological type, smoking habit, socioeconomic status, alcohol intake and fruit consumption. The pooled OR for GC was 1.84  in subjects with vs. those without first-degree relatives with GC. No significant differences were observed among subgroups of sex, age, geographic area or study period. Associations tended to be stronger for non-cardia  than for cardia GC , and for the intestinal  than for the diffuse histotype . This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype. Considering these findings, accounting for the presence of FH to carry out correct prevention and diagnosis measures is of the utmost importance. Gastric cancer (GC) is the fifth leading cause of cancer by incidence and the third leading cause of cancer death in both sexes worldwide. In 2018, there were an estimated one million new GC cases and nearly 800 thousand deaths [Helicobacter pylori infection—shared by family members. Still, an unexplained large variability between risk estimates has been reported according to geographic area, ethnic group and sex, as well as the histological type and location of GC [The most accepted model of human gastric carcinogenesis is a multistage model in which both environmental and genetic factors are involved . This inon of GC . Given tFive-year GC survival in most countries is less than 30% . TherefoThe StoP Project is a consortium of epidemiological studies on gastric cancer. A detailed description of its aims and methods has been provided elsewhere . InclusiH. pylori infection and consumption of fruit and vegetables; (iii) specific cancer-related variables (for cases only), including cancer subsite and histotype; (iv) FH of GC among first-degree relatives . All of the above variables were harmonized centrally according to a pre-specified format. Furthermore, any additional information related to the FH of GC available in each study  was considered.For this analysis, the studies were selected from the StoP consortium studies that had both the family history information and the covariates that we used in the models. This work is based on the second data release of the StoP Project, where 17 studies ,23,24,25The StoP Project received ethical approval from the University of Milan Review Board (reference 19/15 on 1 April 2015).2—that is, the proportion of total variation contributed by between-study variance [To estimate the association between FH and GC, a two-stage modeling approach was used . First, variance .H. pylori infection were carried out. Additional analyses were carried out according to type of study, control selection system (matched or by frequency), source of controls  and study period (XX or XXI century).To investigate whether the role of FH was heterogeneous across strata of selected covariates, analyses stratified by sex, age, socioeconomic status, GC location (cardias/non cardias), histological subtype , tobacco smoking, socioeconomic status, alcohol intake, fruit consumption and n = 942) and 7.7% of the controls (n = 979) had an FH of stomach cancer in first-degree relatives, ranging from 4.4 to 23.0% among cases, and from 1.0 to 16.8% among controls.The main characteristics of the StoP Project studies included in the present analysis are shown in 2 = 6.1%, Pheterogeneity = 0.383). In all studies, first-degree FH was positively related to GC, with ORs ranging between 1.46 and 11.26 . The difRegarding the analysis of the type of family member affected, H. pylori infection. Furthermore, no significant differences were observed according to whether the studies were performed in European  or non-European populations ; were matched  or not-matched ; and were multicentric  or not . Modest differences were observed according to the type of controls , and to the study period before the year 2000  or after the year 2000 .The results of this uniquely large collaborative study confirm and quantify the influence of FH on the development of GC better than previously available studies. History of GC in a first-degree relative has been found to increase the risk of GC by about 85%. In this pooled investigation, results were suggestive of a possible higher risk of non-cardia than of cardia GC in subjects with a positive FH of gastric cancer, whereas no relevant differences were observed in strata of sex, in the histological type of GC or in the characteristics analyzed in epidemiological studies. The family aggregation of GC is due to a complex interaction between genetic inheritance and environmental and lifestyle factors . It is kH. pylori infection and, therefore, are more likely associated with family transmission [Our results do not show relevant differences according to sex. Though findings of different studies have varied, with some of them reporting a stronger risk related to FH among women , our finsmission . On the smission ,35,36, gsmission ,37 and tsmission .The results of the present study show a higher risk of GC when the affected relatives were siblings rather than parents, which is in line with previous studies reporting that the association tends to be stronger among siblings than between parents and offspring ,28,39,40Regarding the histological type of GC, our results show that a FH of GC is associated with both intestinal and diffuse subtypes, which is consistent with findings from the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study , which sH. pylori infection is the major environmental factor in gastric carcinogenesis. As in our study, another investigation [H. pylori infection had a slightly higher risk of GC than those without H. pylori infection. However, these differences were not significant.tigation  showed tNo significant differences were found when the geographical origin of the samples of the studies included (European vs. non-European populations) was analyzed. Most previous studies on FH and GC were conducted in Asian countries, in North America and in Northern Europe , and thiH. pylori infection and tobacco smoking, with respect to FH [Only moderate differences were observed in relation to studies based on hospital- and population-based controls. A higher risk of GC related to FH emerged for studies conducted after the year 2000, as compared to those conducted earlier. This may be due to a decrease in the weight of environmental factors, particularly ct to FH ,43.As strengths of the study, there are 5946 cases and 12,776 controls available for the analysis, accompanied by a wide variety of predictor variables, providing an adequate statistical power. Furthermore, this project is a collaborative framework, contributing with varied geographical origins. In addition, we assessed the relationship between FH and GC by location and histological types. The most important difference between our work and the rest of the studies and meta-analyses is that, in our case, we worked with a consortium of studies, meaning we directly used the study data instead of the ORs of the published articles. This allows us to adjust all studies for the same variables and to have more homogeneity in the results.Our results confirm and further quantify the effect of FH on the development of GC. Subjects with an FH of GC among first-degree relatives have an approximately doubled risk of GC occurrence. It is important to take into account the presence of an FH to carry out GC prevention measures, both primary and secondary, i.e., early diagnosis.


Background: Recent studies have reported that homocysteine (Hcy) may play a vital role in the pathogenesis of vascular dementia (VaD) and Alzheimer's disease (AD). Our study explored the relationship between the plasma Hcy and folate levels and the risk of dementia.Methods: We searched Embase, PubMed, and Web of Science for published literature, including case-control studies and prospective cohort studies, and performed a systematic analysis.Results: The results of our meta-analysis, consisting of case-control studies, showed higher levels of Hcy and lower levels of folate in dementia, AD, and VaD patients than those in non-demented controls . AD patients showed significantly lower plasma Hcy levels compared to VaD patients . Subgroup analysis revealed that ethnicity, average age, and dementia type had no significant effect on this association. Furthermore, from the analysis of prospective cohort studies, we identified that elevated plasma Hcy levels were associated with an increased risk of dementia, AD, and VaD . In addition, every 5 μmol/L increase in the plasma Hcy level was associated with a 9% increased risk of dementia and a 12% increased risk of AD.Conclusion: Hcy and folic acid are potential predictors of the occurrence and development of AD. A better understanding of their function in dementia could provide evidence for clinicians to rationalize clinical intervention strategies. Dementia is a severe threat to the health of older people and places a heavy burden on their families and society  Homocysteine OR “Hcy” OR Hyperhomocysteinemia OR Folate OR Folic acid and (2) Dementia OR Cognitive OR Cognition OR Alzheimer OR Vascular dementia. Some articles were identified via manual screening of relevant references from other studies on the subject.The inclusion criteria for the meta-analysis of case-control studies were that the studies must provide the number of dementia patients and controls and clearly present means and standard deviations (SD) of Hcy and/or folic acid levels for both patients and controls. For the meta-analysis of prospective cohort studies, studies must present blood Hcy concentration levels, adjusted relative risk (RR), and 95% confidence intervals (CI) for dementia or AD occurrence.The exclusion criteria were as follows: (1) we selected population-based case-control studies and cohort studies to extract raw data, case report, review, letters were all excluded; (2) we designated two independent reviewers to scrutinize the manuscripts of retrieval, irrelevant titles and abstracts were excluded; and (3) studies with incomplete data were excluded such as undefined included cohorts and imprecise level of Hcy and folic acid.Two reviewers independently assessed the included studies. The extracted data included the name of the first author, publication year, the ethnicity of samples, the number of subjects, gender distribution, mean age, mean follow-up duration, mean and SD of Hcy and folate levels for patients and controls, source and detection method used for Hcy and folate analyses, categories of plasma Hcy, and multivariable-adjusted effects (RR and 95% CI for each exposure category). Different Hcy and folate concentration measurement units were converted to a standard format (μmol/L for Hcy and nmol/L for folate).The Newcastle-Ottawa Scale (NOS) Stang,  was usedAll the included studies were approved by ethics committees and conducted according to the Code of Ethics of the World Medical Association (Declaration of Helsinki). All the participants of the included studies provided written informed consent.Q-test and the I2-test. I2 > 50% represented high heterogeneity. Thus, the random-effects model was applicable. Subgroup analyses—stratified by dementia type (AD and VaD), geographical ethnicity (Caucasian or Asian), average age , and gender distribution —were also conducted. A dose-response meta-analysis was used to assess the potential linear and non-linear dose-response relationships between blood Hcy levels and the risk of dementia. Sensitivity analysis was used to assess the results after removing any of the studies one at a time. The risk of publication bias was assessed using Egger's test and Begg's test. A value of p ≥ 0.05 indicated no publication bias. If publication bias was observed, we applied the trim and fill method to recalculate the results. All meta-analyses were performed using Stata version 15.1.The standard mean differences (SMD) with a 95% confidence interval (CI) were calculated to explore the differences in Hcy and folate levels between the dementia and control groups. The pooled RR with 95% CI was used to evaluate the relationship between the Hcy and folate levels and the risk of dementia. Heterogeneity was evaluated using the We initially identified 1,746 relevant articles from available databases, including Embase, Pubmed, and Web of Science, and 1,078 of the articles were left after removing duplications and reviews. We excluded 927 articles after reading titles or abstracts and selected 151 full-text articles for eligibility. Subsequently, 70 articles were removed on account of failing to data extraction after careful perusal, thus 81 articles were included in this meta-analysis eventually. Thereinto, 55 and 37 articles were retrospective researches relevant to Hcy and folic acid, and 13 articles and 5 articles were prospective aiming at Hcy and folic acid, respectively. A flow diagram of the retrieval process is illustrated in P < 0.05) (p = 0.000) (p = 0.000) . Therefore, we used the trim and fill method to recalculate the pooled effect size, and the results were slightly altered but still similar to our original risk estimate   . Further= 0.000) . Our stu= 0.000) . Begg's  folate) . Sensiti folate) .p < 0.05), and higher Hcy levels in AD patients, with an SMD of 0.689 , than in the controls. This indicated significant differences in plasma Hcy and folate levels between AD patients and controls. Further, we also found that Hcy levels were higher and folate levels were lower in VaD patients than in the controls. Additionally, high Hcy and low folic acid levels in dementia patients were found in the Caucasian and Asian cohorts. Ethnicity also exhibited no significant effect on this association. Further subgroup analysis based on age  showed higher levels of Hcy in dementia patients than in healthy controls. In both male and female subgroups, higher Hcy and lower folic acid levels were observed in dementia patients than in controls. Plasma folate levels were significantly lower in dementia patients with a mean age of 70–80 and 80–90 years than in controls. However, dementia patients with an average age of 60–70 years had marginally lower folic acid levels . The above results are shown in To further explore the effect of geographical ethnicity, average age, gender, and dementia type on plasma Hcy and folate levels in dementia patients and controls, subgroup analyses were performed. The 55 studies for Hcy and 37 studies for folate levels were divided into two subgroups based on the dementia type. Subgroup analysis showed lower folic acid levels in AD patients, with an SMD of −0.503  (p = 0.703).A significant reduction in the plasma Hcy level was observed in AD patients compared to VaD patients  . AdditioIn total, 13 prospective studies on Hcy levels and risk of dementia were included in our study. A summary of these studies is shown in Begg's and Egger's tests indicated no publication bias. For further linear dose–response analysis, eight studies about Hcy with more than two categories were included, with a total of 15,134 participants and 1,627 all-cause dementia cases. There was no significance for non-linear dose-response analysis (p-non-linear = 0.801). The summary RR of dementia was 1.09 (95% CI [1.057–1.131]) per 5 μmol/L of increased Hcy . In otheOur meta-analysis included 81 articles, and 15 of these were prospective cohort studies. Drawing on this, we systematically analyzed the association between the Hcy and folate levels and the risk of dementia. The results of the meta-analysis not only confirmed that dementia patients had higher Hcy and lower folic acid levels than the controls but also suggested that subjects with high Hcy levels and low folic acid levels might be susceptible to AD. We found a linear trend that for every 5 μmol/L increase in Hcy levels, the risk of dementia and AD increased by 9 and 12%, respectively. To our knowledge, the present meta-analysis is the largest and most comprehensive evaluation of the correlation between Hcy and folate levels and the risk of dementia.A recent meta-analysis of retrospective studies by Shen et al. demonstrated that AD was significantly associated with high Hcy levels and low serum folate levels. They also suggested that high Hcy and low folate levels may be associated with an increased risk of occurrence of AD  have reported the beneficial effects of Hcy-lowering interventions  category in the strict sense. Randomized placebo-controlled trials of Hcy-lowering treatment are needed to determine the effect of such treatment on the progression of dementia. In addition, although the RR with fully adjusted models was used in our study, different adjustments for confound risk among the different studies could potentially influence the results. Not all the included studies took account of the adjustment for cardiovascular risk factors, MMSE score, vitamin B, duration of follow-up, and other factors. Lastly, only studies with full texts and published papers were included in our meta-analysis; therefore, publication bias may have affected our findings.In conclusion, our meta-analysis is the first to report that patients with dementia, including AD and VaD, show higher levels of Hcy and lower levels of folic acid compared to non-demented controls. We also revealed a possible influence of elevated plasma Hcy levels and reduced folate levels on the risk of dementia. Moreover, every 5 μmol/L increase in the plasma Hcy level was associated with a 12% increase in the risk of AD. The above findings indicate that Hcy and folic acid may contribute to the incidence of dementia. Our study provides vital evidence for clinicians to rationalize clinical intervention strategies. Moreover, longitudinal studies are needed to further elucidate the relationship between Hcy, folic acid, and dementia.The original contributions presented in the study are included in the article/RZ and XL: designed the experiments. RZ, XL, and JZ: performed the experiments. XL, QW, and HC: analyzed the data. RZ and QW: wrote the paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Femoral head osteonecrosis (FHON) is a worldwide challenging clinical topic. Steroid use is one of the main etiologies of FHON. There are several genetic variants associated with FHON. Therefore, the purpose of this umbrella review was to provide a comprehensive summary of a meta-analysis and systematic review of genetic variations associated with nonsteroidal and steroid-induced FHON.The eligible studies were selected from the PubMed and MEDLINE databases for the collection of diverse systematic meta-analyses and reviews. The genetic main effect score was assigned using the Human Genome Epidemiology Network’s Venice criteria to assess the cumulative evidence on the effects of a single nucleotide polymorphism (SNP) on FHON.Eight articles reported the meta-analysis of candidate SNP-based studies covering eight genes and 13 genetic variants. In the nonsteroid-induced FHON genetic variants including rs2012390 and rs11225394 in MMP8, rs1800629 and rs361525 in tumor necrosis factor (TNF)-α, VNTR in intron 4, rs1799983 and rs2070744 in endothelial nitric oxide synthase (eNOS), rs2010963 in vascular endothelial growth factor (VEGF), and rs6025 in factor V showed significance in each reference. The steroid-induced FHON genetic variants including rs693 and rs1042031 in apolipoprotein (Apo)B, rs1045642 in ABCB1, and rs1799889 in PAI-1 showed significance in each reference.Based on the systematic review conducted in this study, we organized the genomes associated with FHON and looked at each contribution. Our results could give an integrative approach for understanding the mechanism of FHON etiology. It is expected that these results could contribute to the strategy of prediagnosis, evaluating the individual risk of nonsteroid-induced and steroid-induced FHON.Level of Evidence: Level I.The online version contains supplementary material available at 10.1186/s13018-022-03079-4. Femoral head osteonecrosis (FHON) is a worldwide challenging clinical topic. FHON was described as hip trauma with late complications by Jean Cruveilhier, a French anatomist and pathologist . Since tSteroid use is one of the main etiologies of FHON. Steroids are dose-dependent etiologic agents of FHON . Long-teSo far, several genetic factors associated with FHON have been reported including apolipoprotein (Apo)A, which is involved in lipid metabolism and the coagulation system , 18; VEGTherefore, the purpose of this umbrella review was to provide a comprehensive summary of a meta-analysis and systematic review of genetic variations associated with nonsteroidal and steroid-induced FHON.The eligible studies were selected from the PubMed and MEDLINE databases for the collection of diverse systematic meta-analyses and reviews in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines . The seap values.The eligible studies included meta-analyses of four types: (i) SNP-based systematic reviews and gene meta-analyses related to femoral neck head necrosis, (ii) studies providing definite information on the statistical processes and results, and (iii) studies written in English and published after January 1, 2012. Only studies in adult populations were included, and gender differences were not considered because general SNP-based meta-analyses associated with FHON were performed regardless of sex. The following types of studies were excluded: (i) systematic meta-analyses without a quantitative synthesis of the evidence, (ii) non-human studies, (iii) having huge errors or poor quality, and (iv) studies with no specific statistical results including heterogeneity tests, the examined risk factors, and the overall p values, and heterogeneity estimates.Two independent authors were included in the data extraction stage. One author extracted the data and then it was checked by a second author. For selecting the eligible articles, the following information was included: (i) the first author’s name; (ii) year of publication; (iii) the genetic variants of each study and effect size (ES); (iv) the number of studies included in each article; and (v) sample size, Methodological quality was rated by the Assessment of Multiple Systematic Reviews (AMSTAR) instrument . This vep values of at least < 0.005 to be considered for strong candidacy. A specific description of the application of the guidelines is provided in Table The genetic main effect score was assigned using the Human Genome Epidemiology Network’s Venice criteria to assess the cumulative evidence of SNP effects on FHON . BrieflyFor the systematic reviews, 24 unique references were identified from the databases. After excluding the duplicates and articles that were not on the main topics, 13 articles remained. Three additional articles were excluded as ineligible studies because they provided inadequate data. Two other articles with no significant results were excluded. Finally, eight eligible publications –37 were Eight articles reported the meta-analyses of candidate SNP-based studies covering eight genes and 13 genetic variants.p value of under 0.00001 for the genetic main effect. The rs11225394 SNP showed a strong evidence class according to the Venice criteria. Peng et al. [p value was under 0.001 in the allele genetic model and recessive genetic model, respectively. This result of rs361525 showed extremely significant and strong evidence with a score of AAB in the Venice criteria. Song and Lee et al. [p value of under 0.001 in the allele genetic model and the dominant genetic model. The evidence class was moderate. Rs1799983 and rs2070744 also showed barely significant results and excessive heterogeneity with I2 values of 80.20% and 90%, respectively. Rs2010963 of the VEGF gene in Asians also showed significant results in the homozygote model and the dominant model with strong evidence [p value of < 0.001 with strong evidence was recorded in rs6025, which is a genetic variant of factor. Shang et al. demonstrated that rs6025 in a mixed ethnicity population showed a high possibility of disease occurrence with an odds ratio of 4.55 , TNF-α (rs1800629 and rs361525), eNOS , VEGF (rs2010963), and factor V (rs6025). Among them, the variants in MMP8, TNF-α, eNOS, and factor V showed high significance, and particularly the variants in TNF-α (rs361525) and eNOS (VNTR in intron 4) had more than two types of model significance. Meanwhile, the genes with genetic variants in steroid-induced FHON were ApoB (rs693 and rs1042031), ABCB1 (rs1045642), and PAI-1 (rs1799889). Among them, the variants included in ApoB and PAI-1 showed high significance and particularly the variant in PAI-1 (rs1799889) had more than two types of model significance.The PAI-1 gene is an important regulator of fibrinolysis because it plays a role as an inhibitor of plasminogen activators . Rs17998p value < 0.00001 and a mean OR of 0.63 in nonsteroid-induced FHON. It is supposed that MMP-8 has a protective effect in nonsteroid-induced FHON.MMP-8, which is usually expressed in neutrophils but also in chondrocytes and synovial fibroblasts , is locaIt is known that TNF-α promotor polymorphisms like TNF-α gene-308 or -238 affect transcriptional activity , 45. SomThe ABCB1 gene encodes the transport protein, p-glycoprotein (P-gp), which has crucial functions in pumping foreign substances out of cells . In the The eNOS gene which is located on chromosome 7q35-q36 is known to increase NO . NO is kVEGF is known to be highly expressed in the necrotic area of FHON. Its major role is in angiogenesis and osteogenesis . The VEGFactor V (FV) is well known as a component involved in the blood coagulation process . The facAPO is the main blood plasma protein mediating normal lipid metabolism by interacting with cellular receptors . It has In brief, the nonsteroid-induced associated genes were MMP-8, TNF-α, eNOS, VEGF, and factor V, and the steroid-induced associated genes were ApoB, ABCB1, and PAI-1. The overall gene mechanisms of FHON are presented in Fig. The present study had several limitations. First, our study excluded gender factors in the data collection. Second, classifications of ethnicity were not specified. Third, further validation of the study results was not conducted. Fourth, although this study included many SNP results from various papers, it was limited by the studies available at the time. Fifth, this study contains a significant amount of meta-analyses derived from various references. Therefore, results might lead to an over-estimation of one or the other genes’ actual significance. Finally, most genetic variations reported in meta-analyses only appear once when searching meta-analyses containing genetic variations to collect only reliable data related to steroid-induced FHON and nonsteroid-induced FHON. This result is thought to be because there were not many meta-analyses selected for the subject of this study, and the genetic variation that each study focuses on is different.Based on a systematic review of published papers, we organized the genomes associated with FHON and examined each contribution. Our results could give an integrative approach for understanding the mechanism of FHON etiology. It is expected that these results could contribute to the strategy of prediagnosis and evaluating the individual risk of nonsteroid-induced and steroid-induced FHON.Additional file 1. Table S1: Excluded publications with reasons.


Findings regarding the association of body mass index (BMI) with pulmonary hypertension (PH) are conflicting, and there is no systematic review and meta-analysis to summarize the results. Therefore, the purpose of this systematic review and meta-analysis is to assess this relationship.Q-test and I2-test was applied to assess between-study heterogeneity.To detect the relevant articles, PubMed, Scopus, and Google Scholar were searched until February 2021. Included essays were pooled using a random-effect model. Cochrane 2 = 92.3). Furthermore, The summary risk estimate for a one-unit increment in BMI was 1.01 , with high heterogeneity, I2 = 73.5 %, P heterogeneity <0.001). Subgroup analysis showed significant positive association between BMI and the risk of PH in studies controlled for cofounders, and studies with higher sample sizes .Fourteen articles  were included in the meta-analysis. The meta-analysis of comparing highest vs. lowest BMI categories did not indicate a significant association between BMI and PH (Summary Effect Estimate: 1.59 (95% CI: 0.50, 5.07, IThere is no significant association between BMI and risk of pulmonary hypertension. Further studies are required to confirm these findings. Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, which leads to an elevation in pulmonary vascular resistance (PVR), potentially eventuating in right heart failure and mortality , 2. The The prevalence of overweight and obesity has considerably increased in recent years . The bodAnimal studies showed that metabolic disease due to obesity might lead to pulmonary vascular remodeling and precapillary PH . EpidemiGiven that PH is one of the causes of mortality and morbidity worldwide and the growing prevalence of obesity, clarifying the association between body mass index (BMI) would be of critical importance in providing more particular guidelines for prevention of PH. Based on our knowledge, there is no systematic review and meta-analysis to summarize the data regarding the association of BMI with PH. Therefore, this systematic review and meta-analysis has been formed to assess the association of BMI with PH in adults.The framework of the present study was designed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .PubMed, Scopus, and Google Scholar were explored using relevant keywords in order to discover the related articles published up to February 2021. The search term was obtained from Medical subject headings (MESH) and related keywords as follows: [(Obesity OR “body mass index” [Mesh] OR Obesity/complications [Mesh] OR overweight [Mesh] OR adiposity [Mesh] OR “body mass index” [Title/Abstract] OR BMI [Title/Abstract] OR “fatness” [Title/Abstract] OR “Obesity/complications” [Title/Abstract] OR overweight [Title/Abstract] OR adiposity [Title/Abstract]) AND ]. No filters were applied when searching the databases. To prevent missing any articles, the reference lists of the included articles and relevant reviews were manually inspected.Two investigators assessed the titles, abstracts, and, when necessary, the full texts of the articles using the following inclusion criteria: (1) observational studies ; (2) studies that reported the association of BMI with the risk of PH; (3) studies conducted on adults; (4) studies that reported the hazard ratio (HR), rate ratio (RR), or odds ratio (OR) and the corresponding 95% confidence interval (CI) in a linear or categorical manner; (5) studies published in the English language. If the two investigators encountered any paradoxes, they reached a solution through a discussion with the principal investigator.Studies that did not report HRs, RRs, or ORs with the corresponding 95% CI, those used International Classification of Diseases (ICD) for obesity definition, studies with insufficient data, those conducted on children, and studies with similar populations were excluded. In the case the authors could not access the full text of a paper, they sought it by contacting the corresponding author. However, no responses were received.Two independent authors read each paper carefully to extract the following information: first author's name, publication year, country, study design, the participants' age (mean/range), gender, health condition, total sample size, number of PH patients, the cut-off points for defining PH, PH assessment approach, duration of follow-up for cohort studies, continuous or categorical values, and the adjustments made. When two authors could not reach an agreement on an issue, the corresponding author resolved it.We evaluated the quality of each eligible study using the Newcastle-Ottawa Scale (NOS) . This scQ-test and I2 test was applied to assess heterogeneity among included studies. Cochrane Q-test, with P < 0.1 expressing significant between-study heterogeneity. The I2 values of 25-50, 50-75, and >75% were considered as low, moderate, and high heterogeneity, respectively (P < 0.10) were implemented to identify publication bias , insufficient data (n = 7), review article (n = 1). Furthermore, studies that defined obesity with ICD instead of BMI (n = 1), those conducted on children (n = 1), and studies with similar population (n = 1) were also removed. Finally, six cohorts  (n = 3) (n = 1) (n = 1) (n = 1) (n = 6) (n = 8) (The demographic information of the eligible studies is presented in n = 8) , 25, 29, (n = 3) –28, Port (n = 1) , Taiwan  (n = 1) , and Ira (n = 1) . The stu (n = 6) , 25, 28  (n = 8) , 27, 29. (n = 8) , 27, whi (n = 8) . Based oI2 = 92.3) (I2 = 73.5%) The meta-analysis of the five observational studies , 24, 27  = 92.3) . Further = 92.3) , 28, 29 In the analysis of comparing highest vs. lowest BMI categories, subgroup analysis showed PH assessment tool and adjustment were the source of heterogeneity. Furthermore, a significant positive association was observed between BMI and the risk of PH in the studies that assessed PH with RHC, were conducted in the United States, included adjustments, had larger sample sizes , and had a greater number of cases (≥200) .Only the sample size was identified as the source of heterogeneity through subgroup analysis of the relationship between a one-unit increment in BMI and PH risk. Besides, subgroup analysis presented that a one-unit increment in BMI could elevate the risk of PH in adjusted studies, and studies with higher sample sizes  .Sensitivity analysis demonstrated that in either categorical or continuous analysis, no study significantly affected the overall effect size.P = 0.565) or highest vs. lowest BMI (P = 0.989) with the risk of PH.No evidence of publication bias was identified through both Egger's test and observation of the funnel plot regarding the association of a one-unit increment in BMI  had pulmonary artery systolic pressures of more than 50 mmHg (2 was the main predictor of high pulmonary artery pulse wave velocity (PA-PWV) (Pulmonary hypertension is identified by elevated PAPs as well as increased pulmonary vascular resistance resulting in right ventricular failure . This st 50 mmHg . Tarasev 50 mmHg  demonstr 50 mmHg . A cohor 50 mmHg . Another 50 mmHg . A syste 50 mmHg . However 50 mmHg . In anot(PA-PWV) . VaryingRight heart catheterization (RHC) is the gold standard diagnostic tool for confirming the echocardiographic findings pertaining to PH . Our stuSeveral mechanisms can be considered when assessing the association of high BMI with PH. Firstly, hypoxemia, hypercapnia, acidosis, wide swings of intrathoracic pressure, elevated sympathetic tone, and diminished endothelial function are conditions in obstructive sleep apnea and obesity hypoventilation syndrome that lead to pulmonary artery vasoconstriction and subsequent endothelial dysfunction . SecondlThis study has some strengths. Based on our knowledge, this study is the first systematic review and meta-analysis evaluating the association of BMI with the risk of PH in adults. Moreover, we did not identify any evidence of publication bias.This study has several limitations. Firstly, the main limitation is a small sample size. Secondly, although all included studies controlled different types of relevant confounders, it may be necessary to consider other residual confounding factors. Furthermore, because most studies failed to report the confounding factors, we could not perform subgroup analysis according to adjusted factors. Thirdly, the heterogeneity among the studies was extreme, though we tried to minimize it via subgroup analysis. Fourth, the number of studies that provided adequate data for non-linear dose-response analysis was so low that we could not perform this analysis. Fifth, since different form of PH are more likely to be affected by BMI or insulin resistance , combining all forms of PH may have error. However, very limited number of articles reported specific form of PH and we could not perform subgroup analysis based on this factor. Finally, combining echocardiogram and RHC derived-definitions of PH is problematic, because, echocardiogram studies used different cut offs, and they do not allow for differentiation of the proper phenotype of PH. However, after excluding studies assessed PH with echocardiogram, small number of studies were remained. Therefore, we included studies assessed PH with either RHC or echocardiogram and performed subgroup analysis for this factor.In conclusion, we found no significant association between BMI and risk of PH. Further studies are required to confirm these findings.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.SP, LY, and JH designed the work. SP and LY extracted the data and wrote the manuscript. BW analyzed the data. JH supervised the work. All authors critically revised and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: The main aim of this study was to test whether the use of mouthwash is associated with subtypes of squamous cell carcinoma of the head and neck (SCCHN) and to test the potential risk of SCCHN depending on the mouthwash use duration, frequency, or alcoholic content. Materials and methods: We performed a meta-analysis using Web of Science and Scopus databases to detect the risk change associated with mouthwash use depending on the alcohol content, duration and frequency of use, and anatomical location. We used a random-effects model with the Sidik–Jonkman estimator for effect size model measures. Results: We included 17 studies in the meta-analysis containing 17,085 cases and 20,032 controls. The risk difference for SCCHN between mouthwash users and non-users was minimal, with a value of −0.02 . Alcoholic mouthwash use was associated with a minimal decrease in risk . Frequent usage of mouthwash was associated with a statistically significant risk increase for SCCHN but the risk increase was marginal . Conclusions: Overall, our study failed to show a statistically significant correlation between mouthwash use and the risk of SCCHN. The only statistically significant correlation that we could identify was between frequent usage and SCCHN, potentially caused by prolonged contact between some constituents of mouthwash  and the oral epithelium. Squamous cell carcinoma of the head and neck  is one of the most common tumor types, causing significant morbidity and mortality, especially in the Middle East, Asia, and Africa ,2.The most important risk factors for SCCHN, namely tobacco, alcohol, and HPV infection , can be Mouthwashes are liquid antiseptic solutions that decrease the microbial load in the oral cavity, although there are unique formulations for other uses as well, including analgesic, anti-inflammatory, anti-fibrinolytic, antifungal, or cosmetic. Alcohol is often used in mouthwashes for its antiseptic functions and as a carrier for some active ingredients, including menthol or thymol, helping them penetrate the plaque ,10. The A potential association between the usage of mouthwashes and an increased risk of oral cancer was initially hypothesized by Weaver et al. in 1979 , who shoFurther studies evaluating this association had contradictory results, with some supporting and others contradicting it. Gandini et al., in 2012, performed a meta-analysis that showed no statistically significant association between mouthwash use and the risk of oral cancer . Aceves This meta-analysis was performed based upon the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines ,19.We analyzed articles extracted from Scopus and Web of Science  from the first year of each database up to February 2021 using the following keywords: “mouthwash” AND “oral cancer,” “mouthwash” AND “head cancer,” “mouthwash” AND “pharyngeal cancer”, and “mouthwash” AND “laryngeal cancer”. To add data from gray literature, we searched on all databases in Web of Science , analyzed books by using the Google Books website , and performed searches with the same keywords in ResearchGate and Google Scholar. We downloaded relevant articles, checked their references, and downloaded additional articles that we considered appropriate from the reference list. All downloaded articles were included in a Paperpile database.Two authors performed each search; the differences were noted, and a third reviewer reevaluated the studies for which differences were found when comparing the two lists before including them in the final analysis.We used the following inclusion criteria: (1) studies containing information about the numbers of cases and controls that were mouthwash users/non-users, or which had data that allowed us to determine these values; (2) studies published in English and present in major online databases. The following exclusion criteria were employed: (1) the absence of relevant data; (2) case reports or case series; (3) less than 100 cases. Cases were considered subjects with SCCHN and controls were subjects without SCCHN.For each study, two reviewers extracted the data separately and included it in an Excel 365 database. A third reviewer combined the databases and checked the results for inconsistencies. We used the following information: study name, country of origin, type of study, inclusion and exclusion criteria; we also included the number of cases and controls, use of mouthwash in cases and controls—overall, gender-based (if given), the alcohol content of the mouthwash, usage interval (short/long term), frequency (less/more than once daily)—and the location of cancer—oral, pharyngeal, or laryngeal. We considered high alcohol-content mouthwashes to contain over 25% alcohol and low alcohol-content mouthwashes to contain less than 25% alcohol .We used the Newcastle Ottawa Scale for case-control studies, which yields scores from 0 to 9, to assess the quality of the articles included in our analysis .2 was used to test the presence heterogeneity between studies with the following thresholds: 0–35%—most likely not significant, 36–55%—moderate heterogeneity, 56–85%—most likely substantial heterogeneity, and 86–100%—significant heterogeneity . We useInitially, we obtained 1001 articles in Scopus and 606 in Web of Science. After removing duplicates and reviewing the abstracts, we selected 56 to be further analyzed. We added one other article from the other resources mentioned above.From the 57 articles, 17 were finally included in the meta-analysis. Fifteen studies were identified by both reviewers and two additional ones by reviewer 2 (HS). The inter-evaluation similarity was 88%. Details about the search synthesis are presented in The included studies had quality scores ranging from 3 to 8 out of 9, with an average value of 6.24. The quality score for each study is given in 2 = 92.07%). Publication bias was not statistically significant . Five studies contained distinct datasets for women. In this group, the risk difference was 0.06 , which was also not statistically significant. The heterogeneity of the studies was lower (I2 = 75.86%). Three studies contained distinct datasets for men. In this group, the risk difference was 0.00 . The heterogeneity of the studies was lower (I2 = 64.12%).We included 17 studies in the analysis, containing 17,085 cases and 20,032 controls. Overall, mouthwash usage was 37.88% in the cases group and 47.06% in the control group. The risk difference between the cases and controls was minimal at −0.02  and not statistically significant . The het2 = 84.25%). Publication bias was statistically significant . Four studies contained specific data about the use of non-alcoholic/low-alcohol mouthwash  . The het2 = 82.97%). Publication bias was not statistically significant .Seven studies included data allowing us to establish the risk of SCCHN associated with a shorter duration of mouthwash use ,37,38,392 = 81.99%). Publication bias was not statistically significant .The same studies evaluated the risk of SCCHN associated with more extended usage . These studies included 6825 cases (of which 1443 were mouthwash users) and 8555 controls (1634 were mouthwash users). The risk associated with regular mouthwash use was 0.01, with a 95%CI between −0.04 and 0.05. The heterogeneity of the studies was high (I2 = 59.35%). Publication bias was not statistically significant .Six studies contained data that allowed us to establish the risk of oral cancers associated with mouthwash use ,30,33,382 = 86.33%). Publication bias was not statistically significant .Six studies contained data that allowed us to establish the risk of pharyngeal cancers associated with mouthwash use ,30,33,382 = 91.33%). Publication bias was not statistically significant .Four studies contained data that allowed us to establish the risk of laryngeal cancers associated with mouthwash use ,26,28,30Overall, our study failed to show a statistically significant correlation between mouthwash use and the risk of SCCHN. The risk difference between mouthwash users and non-users was minimal , suggesting a minimal  protective effect of mouthwash use. Gender differences were also minimal, with a 6% risk increase for women and a 0% risk increase for men . The result was similar to other meta-analyses in the field: Aceves Argemi et al. found an OR of 1.057  , while GIn the next step of our analysis, we tested whether alcohol usage affects the SCCHN risk. Both subgroups  showed similar results, well within the margin of error. This result was similar to that of Aceves Argemi et al., who found an OR of 1.48  for users of high-alcohol mouthwashes . DuratioThe last part of our analysis tested whether mouthwash use can be explicitly linked to oral, pharyngeal, or laryngeal cancer. As their anatomical location predisposes tissues of the upper aerodigestive tract to numerous potential carcinogens, there is increased tissular vulnerability to cancers . As discFirst, the results presented in various articles were inconstant, especially regarding subgroups . This caused us to use approximations in determining which studies should be included in which group, leading to increased heterogeneity in the results. Second, we preferred to use the Sidik–Jonkman estimator, which produces more robust results than DerSimonian–Laird but tends to increase the confidence intervals and potentially misses some marginally statistically significant results. Third, SCCHNs are not the only types of cancers in this region. Even if some studies analyzed this type of cancer explicitly, others were not specifically focused on it or did not specify exactly what subtypes of cancer they had analyzed. Overall, our study failed to show a statistically significant correlation between mouthwash use and the risk of SCCHN. The only statistically significant correlation that we could identify was between frequent usage and SCCHN, potentially caused by prolonged contact between some constituents of mouthwash  and the oral epithelium. We preferred not to separate these types of studies, as most oral and neck cavity cancers were of the squamous cell carcinoma type.Overall, our study failed to show a statistically significant correlation between mouthwash use and the risk of SCCHN. The only statistically significant correlation that we could identify was between frequent usage and SCCHN, potentially caused by prolonged contact between some constituents of mouthwash  and the oral epithelium. However, the results were inconclusive, as actual patterns of mouthwash use may be very inconsistent  and cannot be easily quantified using retrospective studies. Better results could be obtained during prospective studies with strictly controlled variables; however, such studies are difficult to design due to the relative rarity of SCCHNs and the need for an increased timespan to properly identify relevant trends.


CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC . Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank . Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g.,  Major risk factors for OC/OPC include alcohol consumption, tobacco use and human papillomavirus infection  summary data. We then evaluated the association between the nsCL/P PRSs and OC/OPC using individual participant data on OC/OPC cases and controls using data from the largest OC/OPC GWAS , which were split into two subsamples, based on the continent of the study centre (North America and Europe).2.1.3UK Biobank is a large‐scale cohort study of 502,655 participants aged between 40 and 69 years, who were recruited from 22 recruitment centres across the United Kingdom between 2006 and 2010. In UK Biobank, we identified OC/OPC cases and controls using secondary care data from Hospital Episode Statistics (HES) as well as the death and cancer registers. For secondary analyses, we used data on self‐reported alcohol consumption and tobacco smoking which were collected at baseline using a questionnaire. More information on the study design, genotyping and phenotyping is contained in the Supporting Information Methods.For analyses, we used a subset of the study of 750 OC/OPC cases and 336,319 controls, after restricting to individuals of self‐reported “White British” descent and using kinship coefficients to remove individuals related to the greatest number of other individuals.2.22.2.1r2 < .1 and 250 kb) at 11 different p value inclusion thresholds  to generate sets of independent (in terms of LD) variants in each score. The PRS was then constructed using effect alleles and weightings based on the magnitude of effect on nsCL/P of each genetic variant taken from the meta‐analysis GWAS summary statistics. LD clumping was performed using PLINK  in our sample meant that it was not possible to stratify by OC/OPC subtype, so all cases were analysed together. All analyses were adjusted for the first 10 genetic principal components, age, and sex.The UK Biobank data set was used as a follow‐up data set for analyses in the OC/OPC GWAS data set. For the analyses in UK Biobank, we used the nsCL/P PRS most strongly associated with OC/OPC in the OC/OPC GWAS data set, tested the association of this PRS with OC/OPC. The limited number of OC/OPC cases , as in a previous study  and UK Biobank  for association with alcoholic units consumed per week and tobacco smoking pack years. All analyses were adjusted for sex, age and the first 10 genetic principal components.We tested the nsCL/P PRS  increase in nsCL/P PRS was associated with increased odds of PC/OPC . PRS with more liberal inclusion thresholds , which included thousands of SNPs, were more strongly associated with risk of OC/OPC than more conservative inclusion thresholds  was associated with increased odds of both oropharyngeal cancer  and OC cancer .Similarly, there was strong evidence for an association between the nsCL/P PRS and the primary OC/OPC subtypes, oropharyngeal and OC cancer. A 1 3.2p value inclusion threshold < .1). Here, we found no clear evidence that this PRS is associated with increased risk of OC/OPC . However, confidence intervals overlapped with the IARC sample estimate  and the meta‐analysis of the two estimates suggested evidence for an association .In the UK Biobank sample of 750 cases and 336,319 controls, we attempted to replicate the association between the nsCL/P PRS most strongly associated with OC/OPC in the IARC sample (3.3p = .84). Mendelian randomization sensitivity analyses generated consistent effect estimates . We did not find strong evidence that the nsCL/P PRS was associated with any of the measures tested. A 1 SD increase in nsCL/P PRS corresponded to a −0.02 pack year decrease in lifetime smoking  and a −0.05 units per week decrease in alcohol use .To evaluate whether shared genetic effects could relate to interactions of the nsCL/P PRS with shared environmental risk factors we investigated the genetic overlap between the PRS and measures of alcohol consumption and tobacco smoking in UK Biobank. Again, we used the nsCL/P PRS most strongly associated with OC/OPC in the IARC sample . Therefore, it is possible that allele frequency differences between cases and controls relating to population differences could result in spurious associations with the nsCL/P PRS, although this is unlikely given the number of SNPs in the PRS. Third, with insufficient genetic instruments for OC/OPC, we did not perform a bidirectional Mendelian randomization analysis so cannot rule out the possibility that OC/OPC variants consistently affect nsCL/P risk. Fourth, we were unable to run stratified analysis investigating the possibility of heterogeneity between HPV and non‐HPV driven tumours. Fifth, in this study we treated nsCL/P subtypes  homogeneously despite growing evidence that they are aetiologically distinct , are required to investigate the possible common biological pathways between nsCL/P and OC/OPC, and to evaluate possible mechanistic relationships between nsCL/P and cancer subtypes affecting distinct areas to orofacial clefts.To conclude, we found some evidence of shared genetic influences on nsCL/P and OC/OPC unrelated to alcohol or tobacco intake. Follow‐up analyses, potentially using additional datasets such as the Cleft Collective (L. J. H., A. R. N., and S. J. L. conceptualised and designed the project. L. J. H. and C. L. performed statistical analyses. A. R. N., E. M., K. L., V. G., and P. B. were involved in data acquisition. L. J. H. drafted the manuscript and interpreted results under the supervision of G. H., G. D. S., B. S. P., and S. J. L. All authors contributed to critically revising the manuscript. All authors gave their final approval and agree to be accountable for all aspects of the work. All authors declare no relevant conflicts of interest to the publication of this manuscript.Supporting informationClick here for additional data file.


Conversely, there was no association between MUFA intake and measures of renal function . In multivariable models, the top quartile of PUFA intake had a 21% lower risk for CKD, but there was no significant association between CKD risk and MUFA intake. Genetically determined serum MUFA (heptadecenoate (17:1), myristoleic acid (14:1), and palmitoleic acid (16:1)) and PUFA (α-linolenic acid and eicosapentaenoic acid) concentrations had no significant association with eGFR and CKD risk. Additionally, no association was found in the analyses stratified by diabetes status. Higher dietary PUFA intake is associated with lower risk of CKD, while there was no association with serum levels of MUFAs or PUFAs. Additional studies including clinical trials are warranted.Polyunsaturated fatty acid (PUFA) intake is generally associated with better renal function, while the association of monounsaturated fatty acids (MUFAs) remains unconfirmed. Mendelian randomization (MR) analysis was used to obtain unconfounded estimates of the causal association of dietary intake and genetically determined serum PUFA and MUFA levels with measures of renal function. Data from participants of the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2010 were used. Data from the largest genome-wide association studies (GWAS) on MUFAs, PUFAs, eGFR, and chronic kidney disease (CKD) were analysed for the entire sample. A total of 16,025 participants were included. eGFR improved across increasing quartiles of total PUFA intake from 86.3 ± 0.5 (Q1) to 96.2 ± 0.5 mL/min/1.73 m² (Q4), ( Chronic kidney disease (CKD) is defined as significantly impaired kidney function, identified by a reduced glomerular filtration rate (GFR) or increased urinary albumin excretion  that are confirmed on two or more occasions at least 3 months apart . The gloBoth low plasma concentrations and dietary intakes of n-3 and n-6 polyunsaturated fatty acids (PUFA) have previously been associated with impaired renal function ,16,17, wMendelian randomization (MR) analysis using functional single nucleotide polymorphisms (SNPs) associated with specific changes in physiological exposures (such as serum MUFAs and PUFAs) as genetic instruments of analysis are capable of providing unbiased and robust evidence on the mechanisms of the pathogenesis of disease and the efficacy of treatments. Compared with conventional risk-factor epidemiology, these studies are considerably less prone to confounding, residual bias, and reverse causation . While rTherefore, national survey data ) and Mendelian randomization (MR) analysis were used to determine unbiased estimates of the casual association of genetically determined serum levels and dietary intake of MUFAs and PUFAs with renal function.We used data from the NHANES, which were previously published in detail . In brieThe methods for the specific analyses can be found in the NHANES Laboratory/Medical Technologists Procedures Manual ,25,26,27Dietary intake was assessed though 24 h recall, obtained with the assistance of a trained interviewer, through the use of the United States Department of Agriculture Automated Multiple-Pass Method (AMPM), which is an interview system with standardized probes that is aided by a computerized system ,31. Brie2), diabetes (DM) (self-reported history of DM or fasting plasma glucose ≥126 mg/dL), and hypertension (HTN), diagnosed in individuals with systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or in those on antihypertensive drugs [p-value of less than 0.05 characterized significant results.CDC guidelines for the analysis of complex NHANES data, using the appropriate weighting methods and accounting for the masked variance, were employed . Mean anve drugs . Log trave drugs . Multi-cve drugs . All of This study employed a two-sample MR study design. Briefly, summary statistics from different genome wide association studies (GWAS) were analyzed for the exposures (serum MUFAs and PUFAs) and outcomes  of interest, to estimate the effects of the former on the latter . That isn = 8866 adults, European descent) [2 = 0.8 was required for such proxy SNPs. Bias in effect estimates can induced by correlation between SNPs, and in order to minimize this bias, our genetic instruments were limited to independent SNPs not in linkage disequilibrium (p = 0.0001). We refer to a set of SNPs that proxy serum MUFAs and PUFAs as “genetic instruments”.We retrieved summary data for the association between SNPs and four circulating MUFAs (myristoleic acid (14:1 (tetradecenoic)), palmitoleic acid (16:1 (hexadecenoic)), 10-heptadecenoate (17:1), oleic acid (18:1 (octadecenoic))) from the GWAS (7824 adults of European ancestry) . Genotypdescent) . In instn = 133,413 with replication in up to 42,166 participants) was used to obtain genetic associations with eGFR [2 and that of type 2 diabetes (T2 D) was fasting glucose ≥126 mg/dL, antidiabetic drug treatment, or self-reported. Kidney function and T2 D were assessed simultaneously. For the GWAS analysis, a centralized analysis plan was applied with each study regressing sex- and age-adjusted residuals of the logarithm of eGFR on the SNP dosage levels. Furthermore, logistic regression of CKD was performed on SNP dosage levels, adjusting for sex and age. For all traits, adjustment for appropriate study-specific features, such as study site and genetic principal components, was included in the regression, and family-based studies appropriately accounted for relatedness.A meta-analysis consisting of the largest genotyped study sample  method. The Q value for IVW was used to determine heterogeneity. As the final effect estimate may be potentially affected by pleiotropic variants, a sensitivity analysis including weighted median (WM) and MR-Egger and using the leave-one-out method, was performed . Causal http://useast.ensembl.org/index.html, accessed on 2 April 2020) and PhenoScanner (SNP phenotypes are provided by Ensembl and the phenotypes of correlated SNPs are provided by PhenoScanner).The Q′ heterogeneity statistic was used to determine the heterogeneity between individual genetic variant estimates . FurtherSensitivity analysis was performed using MR-Egger and the MR pleiotropy residual sum and outlier (MR-PRESSO) test . Outlierp = 0.412). Compared with those without CKD, participants with CKD were more likely to be non-Hispanic Whites (82.9 vs. 68.4%), and less likely Mexican-Americans (2.5 vs. 9.0%), non-Hispanic Black (8.1 vs. 11.2%), other Hispanic (3.0 vs. 5.4%); p < 0.001 for differences in the distribution of ethnicity by CKD status. The mean age was 45.8 years; participants with CKD were older than those without . Those presenting with CKD had a higher BMI (p < 0.001) and higher serum CRP, TG, and fasting glucose , as well as being more likely to have DM and HTN . Across increasing the total MUFA quartiles, the mean urine albumin, log ACR, and eGFR did not change significantly . Multiple potential confounders, arranged into three separate models, were used to evaluate the odds of CKD across the quartiles of the total MUFAs and PUFAs  mean levels of kidney function by quartiles of total MUFAs and PUFAs are shown in nd PUFAs . In the Employing the expanded models and following adjustment for age, sex, race, poverty to income ratio, fasting blood glucose, systolic and diastolic blood pressure, HTN, DM, TG, HDL, and CRP the top quartile of total PUFA intake had a 21% lower likelihood of CKD (OR = 0.79 (0.68–0.88)). With regard to MUFA intake, in three different models with range-varied confounders , we found no association between intake of MUFA and prevalent CKD .The instrument associations for serum MUFA and PUFA levels are shown in p > 0.5888, p > 0.6569, p > 0.9542, p > 0.937, Genetically higher serum heptadecenoate (17:1), myristoleic acid (14:1), oleic acid (18:1), and palmitoleic acid (16:1) levels had no significant effect on risk of CKD , nor the level of eGFR . Genetically determined levels of serum ALA and EPA had no significant impact on either diabetic subjects . Furthermore, the results of the MR-PRESSO did not indicate outliers for all of the estimates. The horizontal pleiotropy test, with very negligible Egger regression intercept, also indicated a low likelihood of pleiotropy for all of our estimations . The results of the MR-RAPS were identical with the IVW estimates, again highlighting a low likelihood of pleiotropy  is believed to be bidirectional  and highWe found no significant association between different dietary intakes of total and individual MUFAs and CKD. The addition of MR analysis makes our study superior to simple observational studies, as MR is a powerful tool for the detection of causation , and ourOur study has some limitations. Firstly, the inability of the NHANES database to distinguish between MUFAs of an animal and plant origin, which could potentially contribute to the lack of association in this and other observational studies of CKD. In the “Western diet” pattern, MUFAs are predominantly supplied by foods of an animal origin, while in countries that typically follow a Mediterranean diet for example, extra virgin olive oil is the major source of these fatty acids . AccordiIn conclusion, we found no evidence to support an association between the intake of total or individual MUFAs, nor a causal effect of serum MUFAs on CKD. While no causal effect of genetically determined serum PUFAs on prevalent CKD could be determined, a clear inverse association was observed between the dietary intake of PUFAs and CKD. While further investigation is required into the role of PUFAs in the development of CKD, these findings do not contradict the current evidence-base for the benefit of replacing dietary SFAs with MUFAs and, preferentially, PUFAs .