Fermented foods represent a significant fraction of human diets. Although their impact on health is positively perceived, an objective evaluation is still missing. We have, therefore, reviewed meta-analyses of randomized controlled trials (RCT) investigating the relationship between fermented foods and non-transmissible chronic diseases. Overall, after summarizing 25 prospective studies on dairy products, the association of fermented dairy with cancer was found to be neutral, whereas it was weakly beneficial, though inconsistent, for specific aspects of cardio-metabolic health, in particular stroke and cheese intake. The strongest evidence for a beneficial effect was for yoghurt on risk factors of type 2 diabetes. Although mechanisms explaining this association have not been validated, an increased bioavailability of insulinotropic amino acids and peptides as well as the bacterial biosynthesis of vitamins, in particular vitamin K2, might contribute to this beneficial effect. However, the heterogeneity in the design of the studies and the investigated foods impedes a definitive assessment of these associations. The literature on fermented plants is characterized by a wealth of in vitro data, whose positive results are not corroborated in humans due to the absence of RCTs. Finally, none of the RCTs were specifically designed to address the impact of food fermentation on health. This question should be addressed in future human studies. Acetobacter), lactic acid (lactic acid bacteria (LAB)), propionic acid (Propionibacterium), and ammonia and fatty acids  [Fermented foods and beverages are generally defined as products made by microbial organisms and enzymatic conversions of major and minor food components. These products have been produced and consumed since the development of human civilization by all cultures around the world covering all types of food groups, including dairy, vegetables, legumes, cereals, starchy roots and fruits as well as meat and fish. Basically, fermentative processes can be categorized by the microorganisms and primary metabolites involved: alcohol and carbon dioxide (yeast), acetic acid  . The rea, molds) , (ii) im, molds)  and  . The hea, molds) ,5.Amongst fermented foods, the effects of fermented dairy products on health and disease, in particular, have been the focus of research in the past. Multiple benefits against non-communicable diseases and metabolic impairments have been attributed to this food group, such as weight maintenance, reductions in risks of cardiovascular diseases, diabetes type 2 and overall mortality, and improved glucose metabolism ,7,8,9,10The proposed modes of action that make fermented foods attractive for consumption regarding potential health effects are manifold. One example is the simple, but effective, way of helping lactose intolerant persons to digest lactose by utilizing microbial organisms and their galactosidases that start to cleave the milk sugar during fermentation and continue with this activity in the gastrointestinal tract (GIT) of humans. This process allows affected people to ingest dairy products (cheese and yoghurt) without experiencing any symptoms of lactose intolerance . AnotherFermentation can also lead to the enrichment of new compounds in food products, such as some B vitamins, including folate, riboflavin, B12, as well as vitamin K2 (menaquinones), which are synthesized from various non-vitamin precursors by certain bacteria in plants and dairy foods ,18. LastDespite the many potential benefits of fermented foods, their recommended consumption has not been widely translated to global inclusion in food guides.The food guides of Canada and the USA recommend the intake of yoghurt and kefir as items listed under the dairy products section, but, in general, there is no inclusion of fermented products as a healthy food category. Japan highlights the importance of consuming foods from every food group in order to achieve a well-balanced diet but does not specifically mention fermented foods. Almost the same pattern appears in the Chinese recommendations with the exception that the Chinese Nutrition Society highlights the use of yoghurt for people suffering from lactose malabsorption. Fermented foods have a long history in Asia, where the earliest records of fermenting processes can be traced back to 300 BC in China, and the third century in Japan . China iAlso, European food guides lack recommendations for fermented foods. For example, the UK puts emphasis on carbohydrates, fruits and vegetables but does not mention fermented foods as a special category. The Swedish model for healthy eating has no particular section regarding dairy products or any other fermented food.However, the consumption of fermented milks, in particular, is very common in Europe. Fermented milks have been found to be beneficial for lactose maldigesting persons  and are In Switzerland, the fermented products food group is not explicitly mentioned, though individual food items are—for example, cheese and yoghurt are part of the recommendation to consume three portions of dairy products per day. Also, coffee is part of the national food pyramid, though it is promoted to the public based on its capability to contribute to humans’ liquid supply, rather than its potential beneficial characteristics as a fermented food. Other fermented foods of plant origin, such as pickles and sauerkraut or fermented soya, are not explicitly mentioned in the food pyramid . A few pThe aim of this review was to give an overview on the present knowledge and gaps regarding the association of fermented foods and non-communicable chronic diseases.The PubMed database was searched at the end of March 2017, by combining various search terms for dairy foods (“milk” or ”dairy” or “dairy products” or “yoghurt” or “yogurt” or “yoghourt” or “cheese” or “cultured milk products”) with search terms for non-communicable diseases . The search was limited to the last five years (January 2012–March 2017) and to human studies. Only meta-analyses and systematic reviews were taken into consideration. Search results were evaluated, and studies in children, or those that focused on single nutrients or individual microorganisms only, were excluded.The identified references were analyzed by specifically focusing on fermented dairy products, including yoghurt, cheese, and fermented milk and comparing the outcomes of these analyses with milk (as a reference for non-fermented dairy) and total dairy . Consequently, physiological effects of fermented dairy products which are mediated by the fermentation process, as assessed by one of the clinical indications investigated in this report, should be observed with fermented milk, yoghurt and cheese but not with milk. Such effects could also be observed with total dairy intake, provided fermented products contribute significantly to the total intake of dairy products. Finally, one should note that effects observed with the consumption of cheese, but not milk, might not be uniquely attributed to the impact of milk fermentation since cheese making also involves the removal of whey.For probiotics, the same search was conducted as on dairy products, except that the key words “devoted to dairy products” were replaced by the key word “probiotic*”(the asterisk being the PubMed truncation symbol).For fermented foods of plant origin, the same search strategy was used that is described above, except the key words “devoted to dairy products” were replaced by the key words “plant or soy*” or “sauerkraut or olive*” or “coffee” or “wine” or “fermented plant food*”. As the outcome of this search strategy was not satisfactory, a manual search was subsequently performed.To rate the results of meta-analyses summarizing observational studies, the characterization of an effect as ‘beneficial’ or ‘detrimental’ was based on the direction of the effect and on the statistical significance of the dataset provided by each meta-analysis. Non-significant effects were characterized as ‘neutral’. The size of the effect was qualified as ‘weak’ for a risk reduction of ≤10% and ‘moderate’ for a risk reduction >10%. For meta-analyses summarizing three or more prospective cohort studies (grade IIa), the quality of the evidence was rated as ‘moderate’ without consideration of other important parameters of relevance to an estimation of the evidence, such as the heterogeneity of the studies, the relevance of the population studied, or the qualities of the investigated foods or probiotics tested. For meta-analyses summarizing less than three prospective cohort studies or summarizing case-control studies (grade IIIa) or retrospective studies (IIIb) the evidence was rated as ‘weak’ see also .To rate the results of meta-analyses summarizing randomized controlled intervention studies, the characterization of an effect as ‘beneficial’ or ‘detrimental’ was based on the direction of the effect and on the statistical significance of the dataset provided by each meta-analysis. Non-significant effects were characterized as ‘neutral’. The size of the effect was qualified as ‘weak’ for a risk reduction of ≤10% and ‘moderate’ for a risk reduction >10% compared to normal range values. All meta-analyses were summarizing three or more controlled randomized trials (grade Ia), and the quality of the evidence was therefore rated as ‘moderate’ without consideration of other important parameters of relevance to an estimation of the evidence, such as the heterogeneity of the studies, the relevance of the population studied, or the qualities of the investigated foods or probiotics tested.The data from all meta-analyses presented in this report are summarized in This report does not focus on particular brands of products , particular bacterial strains, probiotic products, or nutraceuticals. As such, the products described in this report  are to be considered from a generic point of view.To answer the question of how fermented dairy products affect the development of cardio-metabolic diseases, 16 meta-analyses published in the last five years were identified and taken into consideration for this evaluation. In order to assess the associations of dairy products with cardio-metabolic diseases, we consequently focused on meta-analyses that combined the results of either observational studies ,39,40,41The major outcomes from this analysis are summarized in Five meta-analyses have investigated the association between dairy product intake and CVD risk in the last five years ,37,38,45The meta-analysis by Qin et al.  indicateIn their systematic review, Drouin-Chartier et al.  concludeTaken together, none of the meta-analyses reported a detrimental effect of dairy products, including all fermented dairy products investigated. A neutral effect of yoghurt was demonstrated in all four meta-analyses in which this product was investigated, whereas one out of five meta-analyses reported a beneficial effect of cheese consumption. On the other hand, the data from two meta-analyses on fermented dairy provided evidence for a beneficial effect of this product category. In conclusion, these meta-analyses provide weak evidence that fermented foods may have a beneficial effect on CVD, although the data remain weak and inconsistent.Four meta-analyses have investigated the association between dairy products and CHD/CAD risk in the last five years ,32,35,38In their systematic review, Drouin-Chartier et al.  concludeTaken together, moderate evidence for a moderate reduction of risk of CHD was associated with the consumption of cheese in three out of four meta-analyses, whereas the other analyses, including yoghurt, milk and dairy, indicated a neutral effect.Four meta-analyses have investigated the association between dairy product consumption and stroke risk in the last five years ,34,36,38In their systematic review, Drouin-Chartier et al.  suggesteTaken together, none of the dairy products, including fermented dairy products, are associated with a detrimental effect on stroke. Moderate evidence for a weak to moderate effect of fermented dairy products, in particular, cheese, is indicated by these meta-analyses, although these effects are inconsistently associated with the fermentation process—yoghurt was found to have a neutral effect when investigated in the product-specific study.Two meta-analyses have investigated the association between dairy products and hypertension risk in the last five years ,40. In aThe study by Soedamah-Muthu et al.  suggesteIn the review of RCTs on the impact of fermented milk on hypertension, Usinger et al.  suggesteThe included studies were of variable quality as well as heterogeneous, and the findings do not support the use of fermented milk as an anti-hypertensive treatment or as a lifestyle intervention to reduce blood pressure.n = 2340) relative to data from the meta-analysis by Soedamah-Muthu et al. [n = 7641) and is likely to modify pooled risk estimates. In this context, Drouin-Chartier et al. [In their systematic review, Drouin-Chartier et al.  concluder et al.  suggester et al.  that yogTaken together, none of the dairy products, including fermented dairy products, are associated with an increased risk of hypertension. Half of the studies reported weakly beneficial effects but the results are inconsistent.No meta-analysis is available that summarizes studies characterizing the association of fermented dairy products and myocardial infarction risk.Five meta-analyses have investigated the associations between fermented dairy products and T2DM risk in the last five years ,27,28,41The meta-analysis by Gijsbers et al.  providedIn their systematic review, Drouin-Chartier et al.  concludeTaken together, these meta-analyses provide evidence for a positive impact of fermented dairy, in particular yoghurt, on T2DM risk.One meta-analysis has investigated the association between dairy products and metabolic syndrome risk in the last five years .This meta-analysis indicated that dairy intake may be inversely associated with the incidence and prevalence of metabolic syndrome. Also, weak evidence from cross-sectional studies suggests that dairy, milk and cheese, but not yoghurt, may moderately decrease the incidence of diabetes.In their systematic review, Drouin-Chartier et al.  judged tTaken together, none of the dairy products, including fermented dairy products, are associated with an increased or a decreased risk of MetS.One meta-analysis has investigated the association between dairy products and metabolic obesity risk in the last five years .This meta-analysis indicated, with weak to moderate evidence, that yoghurt consumption weakly decreases weight gain, waist circumference, risk of being overweight, and risk of abdominal obesity. The study also provided moderate evidence that cheese consumption weakly increases weight gain. In addition, dairy was negatively associated with weight gain, waist circumference, risk of being overweight and risk of abdominal obesity. Finally, milk consumption was negatively associated with waist circumference.Taken together, yoghurt might be beneficial preventing obesity. However, no significant association for yoghurt consumption was observed for most of the endpoints related to obesity when comparing the highest versus the lowest categories of consumption. Further, the overall interpretation of the results is limited by heterogeneous risk estimates. The level of evidence for impacts of fermented dairy products on obesity risk is limited, and further studies are needed.Drouin-Chartier et al.  conducteDrouin-Chartier et al.  focused In summary, an overview of the RCTs available on the impact of fermented dairy products on cardio-metabolic factors indicate that these products do not differentiate themselves from milk or total dairy in that their impact can be characterized as neutral.Nine meta-analyses, summarizing several cohort and case-control studies that were published in the last five years were used to characterize fermented dairy products in the evaluation of the influence of dairy products on cancer risk and cancer mortality ,57,58,59Two meta-analyses from the last five years investigated the association between dairy products and colorectal cancer risk ,52. The There is no evidence for a beneficial or detrimental effect of fermented dairy products on colorectal cancer. The potential beneficial effects of dairy products regarding colorectal cancer are thus unlikely to be attributed to the fermentation process.One meta-analysis investigated the association between dairy products and prostate cancer risk . High inThere is no evidence for a beneficial effect of fermented dairy products on prostate cancer. As different outcomes were reported for yoghurt and cheese intake, the weak evidence for a negative association of cheese consumption with prostate cancer is unlikely to be attributed to the fermentation process.One meta-analysis investigated the association between dairy products and pancreatic cancer risk that was published in the last five years . IntakesThere is no evidence for a beneficial or detrimental effect of fermented dairy products on pancreatic cancer.Two meta-analyses investigated the association between dairy products and gastric cancer risk ,56. NoneThere is no evidence for a beneficial or detrimental effect of fermented dairy products on gastric cancer. The potential effects of dairy products on gastric cancer are thus unlikely to be attributed to the fermentation process.One meta-analysis from the last five years, summarizing 19 cohort and case-control studies, investigated the associations between fermented dairy products and ovarian cancer risk . This stThere is no evidence for a beneficial or detrimental effect of fermented dairy products on ovarian cancer.One meta-analysis from the last five years has summarized cohort and case-control studies in order to investigate the associations between fermented dairy products and lung cancer risk . Weak evTaken together, there is no evidence for a beneficial or detrimental effect of fermented dairy products on lung cancer.No meta-analysis is available that summarizes the impact of dairy products or fermented dairy products on other types of cancer. Also, to our knowledge, no individual study has been published focusing on the effects of fermented dairy product intake on additional types of cancer whose results would justify a critical appraisal in this report.In their review, Thorning et al.  concludeEight RTCs have evaluated the impact of probiotics on cardio-metabolic risk factors in the last five years ,67,68,69However, as already mentioned above, after reviewing the results, we decided to exclude probiotics because not enough information was available to differentiate between the different strains or to find any clear association between specific strains and non-communicable diseases.lactobacillus and bifidobacterium genera [saccharomyces cerevisiae and other yeast species or to a combination of these [Fermented plant products comprise a large variety of foods, including, for example, coffee, chocolate, sourdough, soybeans, cabbage, olives and alcoholic beverages, such as wine or beer. Similar to dairy products, plant foods are subjected to diverse strains of the m genera  or, in tof these . In geneof these .In fact, hardly any studies or meta-analyses have been published regarding the effects of plant-derived fermented foods on human health and disease. Most of the existing studies were performed in in vitro or sometimes, animal models, and very often, researchers tested single food compounds rather than the whole product. This needs to be considered when interpreting data as the concentrations of the phytochemicals, for example, vary with varying fermentation times leading to different metabolic responses.Hardly any information is available in terms of the risks of developing diet-related chronic diseases and the consumption of Swiss-typical fermented foods of plant origin.However, in Switzerland, there is not one specific fermented food of plant origin, except for wine, beer and coffee, being traditionally and regularly consumed, such as kimchi in Korea or fermented soy sauce in Asia. However, the sum of all fermented products, including dairy products, is estimated to comprise approximately one third of the daily diet  .Hereafter, we focus on certain fermented foods of plant origin with relevant intake frequencies amongst the Swiss population and their effects on health and disease.Coffee, and its effects on health and disease, have been extensively studied in the past in comparison to other fermented foods of plant origin. The meta-analyses performed in the past have produced controversial results in regard to positive, neutral or inverse associations with CVD incidence, CVD risk factors and CVD mortality. Four cups of coffee per day were found to be the optimal amount of coffee for inverse associations with death, CVD and CVD-related risk factors ,78,79,80The association between wine consumption and the risk of CVD and cancer is controversial, ranging from protective, to neutral, to deleterious effects; this association is strongly dependent on the quantities consumed. High levels of consumption (270 mL/day) were associated with a reduced risk of CVD (by a maximum of 45%) and cancers , as reported by Fardet and Boirie . HoweverBeer consumption was inversely associated with CVD risk and CVD related risk markers, although the associations were less strong in comparison to wine ,83.Clinical data about the effects of sauerkraut on the human organism, health and disease are scarce. There is knowledge concerning particular compounds in sauerkraut and their impacts on diseases; however, a literature search revealed mostly cell line or rat experiments with very limited conclusions for humans. Nonetheless, those study outcomes are promising in terms of positive effects of sauerkraut in humans, e.g., as a vehicle of probiotics, in cancer prevention, its free radical scavenging and anti-inflammatory potential. However, evidence for these implications is low .Fermented olives are a rather unexplored fermented food and a source of potentially beneficial compounds, including microbial strains and bioactive components. It is assumed that fermented olives display anti-cancer, antioxidant, anti-inflammatory and anti-bacterial properties, with oleic acid, antioxidants, phenolic compounds and lactic acid bacteria being proposed as the strongest contributors to these effects . HoweverThe first clear outcomes of this report are that (i) the consumption of fermented foods is not associated with negative risks to humans with regard to the discussed clinical indications, i.e., cardio-metabolic health and cancer; and (ii) the majority of the results are associated with neutral effects.Most, if not all, of the clinical data summarized in meta-analyses have been obtained with fermented products as part of total dairy intake (mostly prospective cohort studies), with other sources of fermented foods being much less investigated so that studies of sufficient quality are not available to perform meta-analyses.Generally, the associations of fermented dairy with cardio-metabolic diseases and cancer comply with those of dairy products—this association being neutral for cancer and weakly beneficial, though inconsistent, for specific aspects of cardio-metabolic health. The strongest evidence for a beneficial effect of fermented dairy products was found for the effects of yoghurt on risk factors associated with type 2 diabetes. However, for all combinations of indications and dairy products reviewed in this report, the heterogeneity in the design of the studies as well as in the products being investigated, impedes a definitive assessment of the association between product consumption and health. In that context, it is unclear, and rather unlikely that additional studies will provide more robust answers to these questions. The above statement is not only restricted to the evaluation of fermented dairy products but is also relevant to other fermented foods.The literature provides some information on the bioactivity and mechanisms mediating the impact of fermented foods in health and disease prevention, in particular, in regard to dairy products . The heaMore specifically, several mechanisms associated with the fermentation process may contribute to the inverse association between yoghurt intake and risk of T2D. On one hand, probiotic bacteria have been shown to improve lipid profiles and antioxidant status in T2D patients  and haveThus, the literature is characterized by a wealth of data on the bioactivity of fermented foods, including metabolites and bacteria, which might beneficially contribute to a large range of physiological properties. However, the mechanistic data is not strongly linked to the results of the studies reviewed by meta-analyses. This gap can be explained by a range of factors, including the complexity of the investigated food–health interactions, the quality of the studies, and the real magnitude of the health benefits offered by these products. Further research should specifically integrate the impact of fermentation on risk factors in the study design, including the statistical approach. Such an approach may indeed provide a better indication of the impact of fermented foods on health.Our report indicates that the consumption of fermented foods in the context of particular indications, such as yoghurt intake and diabetes or cheese intake and stroke, can only be recommended on the basis of weak and inconsistent evidence. Intervention studies on fermented foods with appropriate controls, study design and statistical methods, would ameliorate the evidence rating. Ideally, future meta-analyses should be able to summarize data from a range of RCTs evaluated in a cross-over study design, e.g., the effects of yoghurt, compared to unfermented milk in interventions of several weeks in prediabetic or diabetic subjects.


Yet, there have been variances on what homocysteine-related and dietary factors play on the risk of CRC or AP, in association with folate-related one carbon metabolism pathways. We pooled analyses to examine comprehensively all homocysteine related factors including blood tests measurements, dietary, and lifestyle factors for their associations with the risk of CRC and AP. We located 86 articles published from 1995 to 2017. The results revealed that elevated homocysteine levels and decreased vitamin B12 levels in the blood were associated with increased risks of CRC and AP, with case-control studies having greater significant effect sizes compared to that of cohort-control studies. Decreased methionine and vitamin B6 levels in the blood increased the risk of CRC. MTHFR 677 TT and CT polymorphisms were interacting with elevated homocysteine levels to increase the risk of CRC. Decreased dietary fiber, methionine, vitamin B9 or folate, and vitamin B6 intakes were associated with increased risks of CRC; whereas, increased dietary B12 intake, alcohol intake, and smoking were associated with increased risk of CRC. Further studies can be conducted to examine the mechanistic differences of blood levels of homocysteine-related and dietary factors, including different types of dietary fiber, for their effects on decreasing the homocysteine toxicity to prevent CRC.The major objective of this meta-analysis was to examine the association between homocysteine and related measurements with the risk of colorectal cancer (CRC) and adenomatous polyps (AP). Many studies presented an association between  Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States, and the third leading cause of cancer-related deaths in both men and women , 2. Chromethylenetetra-hydrofolate reductase (MTHFR) C677T (rs 1801133) polymorphism, there is a deficiency in the methyl-folate enzyme and the activity in the OCM pathway is impaired [MTHFR gene is known to be associated with many chronic diseases, including CRC [MTHFR and other genes in the OCM pathway play important roles in DNA methylation, a key mechanism in epigenetics, and more specifically nutrigenomics within the OCM pathway [When gene mutations in the OCM pathway occur, such as with the 677T rs 101133 polimpaired , 16–18.  pathway , 20.Six previous meta-analyses were published on the effects of diet and OCM factors with the risks of cancer. Two of the six meta-analyses included the effects of folate deficiency  and hypeIn 2007, the American Institute for Cancer Research (AICR) published a comprehensive report providing a major review of the evidence on food, nutrition, physical activity and cancer. They provided convincing evidence that beneficial factors such as physical activity decreased the risk of CRC; whereas, risk factors such as red or processed meat, alcohol, elevated body fat and abdominal fatness, and adult attained height all contributed to increased risk of CRC . AdditioThe progression on the selection of studies is summarized in Figure When extracting data from each paper, we separated studies for additional subgroups of case types, cancer sites, gender, and racial status when available, which yielded an additional 19 studies for a total of 105 study groups. Specifically, 1 paper included data with one additional study group (population and clinic based) ; 5 paperMTFHR 677 gene polymorphism and blood homocysteine levels for CRC; however, only 2 studies [A total of 8,401 cases and 11,009 controls were included in 32 papers (37 study groups) that included homocysteine-related blood measurements, and had data needed for effect size (ES) analysis. These factors included homocysteine, vitamin B12, methionine, vitamin B9 (folate), vitamin B6, and vitamin B2 (ordered by the most number of studies with relevance). A total of 14,900 cases and 149,950 controls were included in 47 papers (60 study groups) that included dietary factors; 31 papers (40 study groups) had data for ES analysis with means and standard deviations (SD), and 34 papers (42 study groups) for relative risk (RR) analysis with the counts per groups. Dietary factors included vitamin B12, methionine, vitamin B2, fiber, vegetables, red meat, multivitamins, and folate (vitamin B9) and vitamin B6, from food sources and/or dietary supplements. Lifestyle factors included alcohol consumption and smoking. A total of 26,107 cases and 163,231 controls were included in 63 papers (73 study groups) that included lifestyle factors; 20 papers (25 study groups) had data for ES analysis and 54 papers (61 study groups) had data for RR analysis. Additionally, 4 studies included data on  studies  were anaThese studies included populations drawn from countries and continents across the globe . We checked the racial and ethnic compositions included in each study to be sure that we have properly accounted data from distinct groups versus mixed racial/ethnic groups. The most investigated racial/ethnic populations in these studies were Caucasians (41 studies) and Europeans (35 studies), followed by Asians (23 studies which included 20 East Asians and 3 South Asians), then Middle-Easterners (4 studies), African Americans (1 study), and Hispanics (1 study).We pooled analyses per categories of blood, dietary, and lifestyle factors in relation to the risk of CRC. Each factor was analyzed by case-control and cohort studies combined and individually, CRC and AP combined and individually, colon and rectum individually, colorectal combined, and for various ethnic groups. Significant ES calculated from mean and SD parameters per groups, and RR generated from frequency counts per groups are presented in the Schema Tables p < 0.0001) (p < 0.0001) for case-control, and 0.27 mmol/L  for the cohort studies. The case-control studies had a greater ES compared to the cohort studies. For the cancer sites in cohort studies and homocysteine levels, there were not enough studies per colon and rectal sites individually to see a difference between cases and controls. However, the ES was significant for homocysteine levels in CRC studies  (Table We present an overview of significant homocysteine-related measurements (from blood tests of plasma or serum) associated with the risk of CRC by ES  in Table p < 0.0001) for CRC group, and 1.13 mmol/L  for the AP group comparisons. The AP group had a greater ES than the CRC group in case-control studies. Amongst Europeans, homocysteine level was higher in the CRC and AP groups than the healthy control groups, with mean differences of 1.09 mmol/L  for CRC group, and 0.87 mmol/L  for the AP group when compared to the control groups. There were no significant differences in homocysteine levels for other subgroups including East Asian CRC and AP cases and Caucasian AP cases in comparison to the controls (p = 0.0169). For Caucasians in the cohort studies, the CRC group had higher homocysteine levels compared to the control group, with a mean difference of 0.40 mmol/L . There was no significant difference in homocysteine levels for Europeans’ CRC group in comparison to the control group.For the case-control studies, CRC and AP individually had elevated homocysteine levels compared to the healthy control group, with mean differences of 1.43 mmol/L  (p = 0.0009) for the case-control group, and –12.29 mmol/L  for the cohort-control group comparisons. For the case-control studies, the CRC group had lower B12 blood levels that the control group, with a mean difference of –5.83 pmol/L . European CRC cases had lower B12 blood levels when compared to the healthy controls, with a mean difference of –3.6 pmol/L . There was no significance in the AP cases or for the European subgroup on B12 levels when compared to the controls. Within the cohort studies, there were no significant differences in the European or Caucasian ethnic subgroups compared to the controls. For cancer sites and B12, there were not enough number of studies per colon and rectal sites individually to see a significant difference between the case and control groups.Case-control and cohort studies combined had lower B12 blood levels than the healthy control groups, with a mean difference of −11.46 pmol/L (ES = −0.55 p = 0.0038) for Caucasians. For the cohort studies, there was no difference in folate levels with CRC and AP individually, or per ethnic subgroup except in the European CRC group which had lower folate levels than the control, with a mean difference of –0.13 mmol/L .There was no significance for folate levels in case-control or cohort studies combined. For the case-control studies, there were no significant differences in CRC or AP groups individually or per ethnic subgroup, except in the Caucasian and East Asian AP subgroups, both had lower folate blood levels than the control groups, with a mean difference of –1.25 nmol/L  for 2 studies only conducted with Europeans using case-control designed studies. The CRC group had lower B6 levels than the healthy control group, with a mean difference of –3.38 nanomoles per liter (nmol/L) . In the Caucasian subgroup, CRC cases had lower B6 levels than the control group, with mean difference of –7.35 nmol/L . B2 Level was not significantly different between cases and controls across CRC and AP subgroups, which was conducted in the European population only  for TT genotype, 2.85 mmol/L  for CT genotype, and 2.47 mmol/L  for CC genotype.From the two pooled studies , 50 withes Table . MTHFR pAn overview of significant dietary factors by ES based on means and SDs , and RR based on frequency counts per groups , are presented in Table p = 0.0033). Caucasian CRC cases had higher dietary B12 levels than control group, with a mean difference of 0.25 mcg/d . There was no significant difference on dietary B12 intake levels among European and Caucasian AP cases in case-control studies, and among European CRC cases in cohort studies, compared to the control groups. Higher dietary B12 intakes (>3.5–7.8 mcg/d) increased CRC risk  and lower dietary B12 intake levels (< 3.5–4.8 mcg/d) was protective against CRC  in Caucasian   (p < 0.0001)   . Higher  0.0001) . There wp = 0.0036) (p = 0.0068). There was no significant difference on dietary folate levels in European and Caucasian CRC and Caucasian AP compared to the controls in cohort studies. High levels of dietary folate (>282.72–508 mcg/d) was protective against CRC  and low folate levels increased CRC risk  for case-control and cohort studies combined. Individually, high levels of folate in case-control studies (>282.72–508 mcg/d) was protective against CRC , as was high levels of folate in cohort studies . For East Asian in case-control studies, higher levels (>282.72–484 mcg/d) of dietary folate were protective against CRC  and lower levels (<169.8–484 mcg/d) increased risk . For Caucasian in the cohort studies, higher levels of dietary folate (≥542 mcg/d) were protective against CRC risk  and lower levels (<242–542 mcg/d) increased risk . There was no significant difference on dietary folate intake levels between CRC and control groups for European or Caucasian in the case-control studies, or between AP and control groups for Caucasian in the cohort studies. There were also no significant differences between the cancer or polyp cases and control groups on folate supplement use across ethnic subgroups  . There wubgroups .p = 0.0405). In cohort studies, there was no significant difference between the cases (CRC and AP) and controls, and across ethnic subgroups except for European CRC, which had lower mean dietary B6 than the healthy control group, with a mean difference of –0.11 mg/d   . There wp = 0.0094) (p = 0.003) and dietary vitamin B2  levels were significantly different per rectum cases compared to the controls  . There w p = 0.00 and dietp = 0.0106). The case group in case-control studies had lower fiber intake levels compared to the control, with a mean difference of –0.52 g/d . There were no significant differences across ethnic subgroups between cancer and polyp cases and control, except for Caucasian in the CRC group which had taken lower levels of fiber than those in the control group, with a mean difference of –0.43 g/d  (p = 0.0333), as were Caucasian who did not take multivitamins . There were no significant differences in cancer or polyp cases and controls per ethnic subgroups for case-control studies.The case group had lower levels of dietary fiber than the control when case-control and cohort studies were combined, compared to the control group, with a mean difference of –0.47 g/d  . Within  0.0003)  per case 0.0003) . In cohoAn overview of significant lifestyle factors by ES and RR is presented in Table p = 0.0013) (p = 0.0004). The AP group had higher alcohol intake than the control group, with a mean difference of 7.05 g/d . Caucasian AP cases also had higher alcohol intake levels than the control group, with a mean difference of 2.45 g/d  (p = 0.0033). When analyzed per case type for RR in the case-control studies, lower alcohol levels were protective against AP , while higher levels (1–80 g/d) increased risk of AP . Lower alcohol intake levels were also protective for European  and Caucasian . There was no significant difference in cancer or polyp cases (CRC or AP) compared to controls and across ethnic subgroups in cohort studies.  . When an 0.0001) . There wstudies. .p < 0.0001) (p = 0.0006) (p = 0.0364). The CRC group in cohort studies had higher packs smoked per year compared to the control group . Significance was found in the cases of case-control and cohort studies combined, where never or former smokers  were protected against CRC/AP and current smokers  had increased risk for CRC/AP. There was no significance in CRC and controls per ethnic subgroups for smoking within the case-control studies. When the AP group was analyzed individually, never or former smokers were protected against AP  as compared to current smokers which had increased risk for AP . Across ethnic subgroups, never or former smokers were protected against AP and currents smokers had increased risk. In European, never or former smokers had a protective effect for AP risk  compared to current smokers . In Caucasian, never and former smokers had a decreased risk of AP  compared to current smokers . In East Asian, never and former smokers were also protected against AP , compared to current smokers . Within the cohort studies, with CRC and AP combined, current smokers had increased risk for CRC/AP . When analyzed individually, current smokers had increased risk for CRC . There is no significance in cases (CRC or AP) compared to control for smoking status across ethnic subgroups in the cohort studies  . The AP  studies .MTHFR 677 gene polymorphisms were associated with increased homocysteine levels and CRC risks. Associated blood test measurements support the enzyme functions in homocysteine recycling to prevent the toxicity. Dietary and lifestyle factors contribute further to the compensatory mechanisms or mitigate the effects of toxicity from elevated homocysteine levels. Hence, our meta-analyses provided more definitive scientific evidence to suggest monitoring closely on homocysteine-related measurements for best practice on CRC prevention, potentially through the compensatory mechanisms in the OCM pathways for CRC prevention.In this meta-analysis, we investigated homocysteine-related blood test measurements, and dietary and lifestyle factors involved in the OCM pathway for the risk of CRC. Higher homocysteine levels were associated with the increased risk of CRC, and MTHFR 677 TT genotype [MTHFR 677 TT genotype and increased homocysteine levels can lead to methyl donor deficiency that can increase MSI particularly for aging populations [Our study highlights the role of homocysteine metabolism and related measurements in carcinogenesis for CRC, to provide a synthesis of current scientific evidence. Previous studies presented the associations of increased homocysteine levels with microsatellite instability (MSI) in CRC case-only design (no control group) , and MSIgenotype . Both MTulations . Lower culations , 46.Folate may be supplemented to compensate for increased levels of homocysteine, for DNA synthesis and methylation to prevent carcinogenesis in early prevention , 49. HowFor vitamin B12 and methionine, our analyses presented opposite levels in the blood and dietary measurements. For B12 blood levels, CRC and AP groups had lower levels than the healthy counterparts; whereas, CRC and AP groups had higher dietary B12 intake levels than the control groups. For methionine, the CRC group had lower blood levels than the healthy control group; whereas, the CRC group had higher dietary B12 intake levels than the control group. The differences could be due to multiple reasons. Most plausible reason being that while CRC patients consume higher B12 and methionine levels then the control groups, their B12 and methionine blood levels remain lower than the control groups possibly due to wasting to the cancer cells. Future studies are needed to follow these blood tests and dietary measurements longitudinally to observe chronological changes on the higher consumption of these nutrients and the need for more supplementation of these two nutrients to the CRC cases. Deficiency of these nutrients in blood levels may be more important to follow as the basis for supplementation in meeting the needs for the OCM pathways –10.Identifying specific dietary factors linked with CRC risk is challenging because of the complex composition of food and the fact that dietary changes will affect multiple nutrients . Given tMTHFR gene, MTHFR in CRC, epigenetics, nutrigenetics, environment, diet, diet prevention, folate, folate pathways, blood and/or plasma folate, homocysteine, micronutrients, dietary fiber, red meat, iron, lifestyle, behavior, case–control design and meta-analysis, then entered the resulting articles into a database organized by key words. We used previous meta-analysis and review papers to cross check and trace back to all original studies. Two raters, one who was familiar with the literature search process and organization and one who was familiar with meta-analytic methods, conducted the literature search at four different times at least 3 months apart until all possible studies were identified.Following the guidelines for reporting meta-analyses of observational studies , we searMTHFR genotype frequency counts in association with homocysteine and related factors and CRC risk were also identified and analyzed separately. Articles were excluded if they 1) were not written in English and without tables listing any counts or statistical measurements, 2) did not provide data per case or cohort versus control groups or 3) had duplicate use of data by another study with more comprehensive data.The inclusion criteria were: the studies: 1) included data for the association of homocysteine-related blood tests, and dietary and lifestyle factors with CRC risk using a case-control, cohort or RCT design, 2) were written in English, or 3) were written in non-English but provided tables that clearly listed blood, dietary or lifestyle measurement levels or counts. Articles with Of the 301 articles we identified involving CRC and homocysteine related factors, we excluded 147 from the analysis because they did not provide data per case and control groups, including 6 meta-analyses. From the remaining 154 articles, we excluded 55 for not having any homocysteine-related blood tests, or dietary or lifestyle factors associated with colorectal health. Of the remaining 99 studies, 13 involved subsidiary or redundant use of data contained in other included studies that had more current and/or complete data, thus we excluded them as well. Finally, we included 86 articles with usable data for pooled analysis, 63 papers reported CRC only, 5 papers had both CRC and AP, and 18 reported AP disease only   guideline , guideli and CRC , 9, 21. methods) , in assoThe ranges of quality scores for all included studies were from 15 to 23. The reviewed studies thus all scored at 50% or higher of the total possible score of 0 to 30, suggesting that their findings are trustworthy. All studies included the use of biological samples of blood levels, and some form of a food questionnaire (ie. Food Frequency Questionnaire) for dietary and lifestyle levels. We checked data extractions and entry for accuracy and ran the preliminary analyses to make sure the ranges of entries and pooled results were accurate for all studies. The extracted data  were all converted to the International System (SI) of Units and referenced using the recommended dietary allowance (RDA) by the National Institute of Health , 66. We ® pro 13 programs  for exploration on meta-predictive analyses, plots and curve-fitting of MTHFR genotypes and homocysteine levels.We entered data into Excel , and analyzed data using StatsDirect Version 3 updated software . We calculated pooled RR and 95% confidence intervals (CI) for the measurements between cases and controls for the associations with CRC or AP risks. We compared the pooled RRs to be more conservative and yielding standardized risk ratios per AICR guidelines . We used


P > 0.01) showed no evidence of publication bias. In conclusion, our meta-analysis showed an inverse association between tea consumption and ovarian cancer risk. High quality cohort-clinical trials should be conducted on different tea types and their relationship with ovarian cancer.A large number of epidemiological studies have provided conflicting results about the relationship between tea consumption and ovarian cancer. This study aimed to clarify the association between tea consumption and ovarian cancer. A literature search of the MEDICINE, Scopus, PubMed, and Web of Science databases was performed in April 2016. A total of 18 (11 case-control and 7 cohort) studies, representing data for 701,857 female subjects including 8,683 ovarian cancer cases, were included in the meta-analysis. A random-effects meta-analysis was used to compute the pooled relative risks (RR), meta regression, and publication bias, and heterogeneity analyses were performed for the included trials. We found that tea consumption had a significant protective effect against ovarian cancer . The relationship was confirmed particularly after adjusting for family history of cancer , menopause status , education , BMI , smoking  and Jadad score of 3  and 5 . The Begg's and Egger's tests (all  Becaer cells , 9.Several epidemiological studies including case-control and cohort studies have investigated the association between tea consumption and ovarian cancer risk; however, their results were inconsistent. In 2015, Zhang et al.  performeIn order to clarify whether tea consumption is associated with ovarian cancer risk, this study aimed to perform a comprehensive meta-analysis of 18 epidemiological studies.Figure In a stratified analysis, we found a statistically significant inverse association between tea consumption and ovarian cancer risk in studies that did not adjust for family history of cancer , education , oral contraceptive (OCP) use , BMI , smoking , and menopause status , in studies with Jadad scores of 3  and 5 , in cohort study , in Oceania , and in America . Furthermore, statistically significantly inverse associations were identified in studies from the United States  and Sweden  (Table P > 0.01) indicated no evidence of publication bias among studies  and geographical region 44.60%) was statistically significant in the multivariate model Figure . Interpr0% was st Figures  and 6.This meta-analysis showed that tea consumption significantly reduces the risk of ovarian cancer. Our meta-regression analysis revealed that the study design may be the source of heterogeneity between studies (47.90%), and geographical region was associated with a 44.60% heterogeneity reduction across the studies. In addition, our results were not altered by the control source and most confounder adjustments such as education, OCP use, BMI, and smoking in the subgroup analyses. However, the association was substantially altered by a few confounder adjustments, i.e., family history of cancer, menopause status, and Jadad score.Stratification by country showed that tea consumption decreased the risk of ovarian cancer only in studies conducted in the United States and Sweden. Geographical differences may be a result of various factors such as the differences in genetic susceptibility, culture, and lifestyles. Moreover, the types of tea and frequency of tea consumption differ among different areas. Our sensitivity analysis indicated that omission of any study did not significantly alter the magnitude of the observed effect, indicating the stability of our findings. Moreover, the Begg's and Egger's tests showed that no publication bias existed.in vitro experiments and animal experiments have shown that tea has significant anti-cancer effects [Many cell  effects –32. To a effects –13; thesTea is a relatively inexpensive and safe drink and prevents ovarian cancer by a variety of mechanisms. Tea polyphenols are useful components of the tea extract that can down-regulate the expression of a variety of tumor genes, induce tumor cell apoptosis, block tumor cell cycle, up-regulate the body metabolism, and remove excess free radicals, ultimately playing a role in the prevention and inhibition of tumors –36. SomeThe strength of the present meta-analysis is its large sample size  and no significant evidence of publication bias. Furthermore, our findings were stable and robust. However, there were several limitations that should be noted. First, as a meta-analysis of observational data, the possibility of recall and selection biases cannot be ruled out. Only 5 cohort studies investigated the association between tea intake and ovarian cancer risk, which was a rather small number to draw concrete conclusions from. Compared with case-control studies, cohort studies are less susceptible to bias  due to their nature. Therefore, more prospective cohort studies are required on this issue in the future. Second, we did not search for unpublished studies, and only published studies were included in our meta-analysis. Third, publication bias may have occurred, although no publication bias was indicated from both visualization of the funnel plot, the Begg's test and the Egger's test. Fourth, no subanalyses on the histological types of ovarian cancer were performed. Given the heterogeneity of ovarian cancer, this is an important limitation of the study. Fifth, most of the included studies originated from the United States and Europe. Finally, although different types of tea  may have different effects on the risk of ovarian cancer, we did not perform a detailed meta-analysis to determine these differences due to the lack of available studies.In conclusion, the present meta-analysis of 7 cohort and 11 case-control studies showed that tea consumption was significantly associated with a reduced risk of ovarian cancer. More population-based studies, especially high-quality cohort trials, may be more effective in confirming whether tea consumption prevents ovarian cancer. Further studies in different populations with different tea types in varied dosages are required to correctly ascertain the relationship between tea consumption and the risk of ovarian cancer. Future studies on tea consumption and ovarian cancer risk should focus on the most-common ovarian cancer histotypes separately.A literature search was conducted using MEDICINE, Scopus, PubMed, and Web of Science databases for all relevant studies published in English-language journals up to April 2016. Methodology adhered to the PRISMA guidelines. The search terms included “tea” or “black tea” or “green tea” and “ovary” or “ovarian” and “malignancy” or “neoplasm” or “tumor” or “cancer.” We also reviewed the list of references of each comparative study.Observational studies that investigated the relationship between tea consumption and ovarian cancer risk were collected independently by two authors. The inclusion criteria were as follows: (i) a case-control or prospective cohort design; (ii) investigation of the association between tea consumption and ovarian cancer incidence; (iii) availability of RR (relative risk) estimates or odds ratios or risk ratios or hazard ratio and 95% CIs. The exclusion criteria were (i) lack of available data and (ii) the following types of articles: news, previews, reports, reviews, comments, and discussions. When there were multiple publications from the same period or in the same population, studies with publication bias were excluded from our meta-analysis. Rate ratio, risk ratio, odds ratio (OR), and hazard ratio (HR) were used as the different measures of RR in all included studies. Because the absolute risk of ovarian cancer is very low, these values were equal to the RR.Two authors independently collected the following data from each study: first author of the study, publication date, location of the population studied, study period, number of cases or subjects and study population, exposure range, study-specific adjusted ORs, RRs, or HRs with their 95% CIs for the highest category of tea consumption versus the lowest, confounding factors for matching or adjustments, and Jadad scale from the literature. The methodological quality of the enrolled studies was assessed independently by two authors using the Jadad scale .I2 statistics. For the I2 statistic, heterogeneity was interpreted as absent (I2: 0%–25%), low (I2: 25.1%–50%), moderate (I2: 50.1%–75%), or high (I2: 75.1%–100%). Subgroup analyses were performed according to (i) adjustment for family history of cancer (yes/no), adjustment for menopause status (yes/no), adjustment for education (yes/no), adjustment for OCP use (yes/no), adjustment for BMI (yes/no), adjustment for smoking (yes/no); (ii) Jadad scale, impact factor, and study design; and (iii) country where the study was conducted. Pooled RR values and corresponding 95% CIs were estimated using the random-effect model [The RR's adjusted for most confounding factors were used for the association across studies. The heterogeneity was assessed using ct model , which act model . Publicact model , 43. How


Single nucleotide polymorphisms (SNPs) of Excision repair cross-complementing group 2 (ERCC2) gene are suspected to affect the risk of pancreatic cancer. Many studies have reported the association between ERCC2 Lys751Gln polymorphism (rs13181) and the susceptibility to pancreatic cancer, but the outcomes remained controversial. To comprehensively determine this association, we conducted a meta-analysis based on a total of eight studies. Evidence for this association was obtained from the PubMed, EMBASE, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases. In general, a significant association was found between ERCC2 rs13181 polymorphism and the susceptibility to pancreatic cancer in four genetic models . Furthermore, stratified analyses by ethnicity indicated a significant association only in the Asian population. Our results indicate that the ERCC2 Lys751Gln polymorphism might be important in stimulating the development of pancreatic cancer, especially for Asians. As a highly lethal disease, Pancreatic cancer is correlated with a very poor prognosis, characterized by the close parallel between incidence and mortality . In the According to the genetic profiles of pancreatic cancer, genomic instability mediated by DNA repair deficiency is a vital event in development of pancreatic carcinoma. DNA repair machinery plays a crucial role in defending cells against environmental hazards like ionizing radiation, ultraviolet (UV) rays, diet and smoking. As a key DNA repair mechanism, Nucleotide excision repair (NER) can influence gene-gene rearrangement, deletion, translocation and amplification , 7. ExciThere are many studies which focus on the relationship between this SNP and pancreatic cancer –18. JiaoThe flow diagram of study exclusion and inclusion with specific reasons is shown in Figure Forest plots of overall analyses with different models on the association between the rs13181 polymorphism and risk of pancreatic cancer are shown in Figure Of the eight studies included, four reported an association between the rs13181 polymorphism and risk of pancreatic cancer while the others did not. A significant association was observed between ERCC2 Lys751Gln polymorphism and susceptibility to pancreatic cancer in four genetic models  Figure , Table 2Subgroup analysis by ethnicity showed that a significant association was identified in the Asian population , but not in the Caucasian population Figure , Table 2The genetic heterogeneity between studies was evaluated based on all the five models and the data from the selected studies. By the Chi-squared-based Q-test, heterogeneity between studies was not identified in overall genetic models (P > 0.1). Table To further validate the robustness of the outcomes, we conducted sensitivity analyses by repeating the meta-analysis while sequentially omitting the studies included (one omitted each time) for every genotype model. The pooled ORs were not influenced significantly by removal of each single study under four genetic models Figure , suggestTo determine the possible publication bias of the literature, Begg's test and Egger's test were performed. The results of both Begg's and Egger's test showed no evidence of publication bias for ERCC2 Lys751Gln polymorphisms Table . In addiPancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence . As a muMany previous genetic association studies on pancreatic cancer risk have focused on the effects of single nucleotide polymorphisms in ERCC2 gene. ERCC2, also known as Xeroderma pigmentosum D (XPD), is a key DNA repair gene in nucleotide excision repair (NER) pathway which could repair a wide variety of structurally DNA lesions, including cross-links, bulky adducts , thymidiThe current study is the first meta-analysis of the association between ERCC2 rs13181 and the risk of pancreatic cancer. Analysis among all subjects suggested a significant increase in the risk of pancreatic cancer associated with Gln/Gln or Lys/Gln genotype. All studies included were found homogeneous without any study disproportionately driving the combined estimates. In our meta-analysis, the genetic heterogeneity between the selected studies was evaluated, and no significant heterogeneity was observed in the homozygous, dominant, recessive and allele models.Interestingly, the association remained statistically significant in subgroups  analyses. In subgroup analysis of ethnicity, our results showed that the C allele of rs13181 had a 1.22-fold risk of pancreatic cancer in overall populations, a 1.37-fold risk (95% CI 1.21-1.56) in Asian populations. Compared to the dominant and recessive models, the homozygous model showed the highest odds ratio in all populations  and in the Asian population . The differences between Asians and other races may be partly due to the different genetic backgrounds and environments or lifestyles.Meta-analysis is a very powerful tool for analyzing cumulative data of studies where the individual sample sizes are small and the statistical power is low. However, there are still some limitations in the current meta-analysis. To begin with, our analysis was based on ORs estimated without adjustment for several potential confounding variables, because of a lack of information about cigarette smoking , chronicIn conclusion, our meta-analysis suggests that ERCC2 Lys751Gln polymorphism is a risk factor of pancreatic cancer for all of the ethnicities, and presence of this polymorphism in Asian population will increase their susceptibility to pancreatic cancer. However, additional larger and ethnically diverse studies are needed to further clarify the role of this polymorphism in the development of pancreatic cancer.We searched for relevant studies up to July 18, 2016 in both English and Chinese through PubMed, Web of Science, EMBSE and the China National Knowledge Infrastructure (CNKI) platforms database with the following terms and their combinations: “ERCC2 or XPD”, “polymorphism or variant”, “Lys751Gln”, “rs13181”. “K751Q” and “pancreatic cancer”, “pancreatic ductal adenocarcinoma”. To prevent the loss of any important data, we also identified additional investigations by screening the reference lists of key studies and reviews.Studies involved had to satisfy the inclusion criteria: (a) case-control design was utilized; (b) researches focused on the association of ERCC2 Lys751Gln (rs13181) polymorphisms with the risk of pancreatic cancer; (c) sufficient data for estimating an odds ratio (OR) with 95% CI were available. The major exclusion criteria were as follows: (a) no obtainable genotype frequency data; (b) unpublished papers, dissertations, conference articles, reviews and duplication of publications (select the study in the latest and largest sample size); (c) studies designed as a case-case or case-only study.All the following information was extracted separately by two investigators  and recorded in a standardized form, including: first author's name, year of publication, ethnicity of each study population, source of controls, sample size, genotyping method, number of pancreatic cancer cases and controls, allele frequencies and genotype distributions of ERCC2 rs13181 in pancreatic cancer cases and controls respectively, and results of the Hardy-Weinberg equilibrium (HWE) test, as shown in Table The rs13181 polymorphism includes the two alleles A and C, of which C is the minor allele. C is assumed to be the high-risk allele and A is the low-risk allele. We selected the homozygous model (C/C vs. A/A), heterozygous model (A/C vs. A/A), dominant model (C/C + A/C vs. A/A), recessive model (C/C vs. A/C + A/A) and allele model (C vs A) for further meta-analysis.Stata software  was applied in the whole statistical analyses. P values were all two-sided and regarded as statistically significant if less than 0.05.To evaluate the strength of association between rs13181 and the risk of pancreatic cancer, the pooled odds ratios (ORs) with 95% CIs were calculated in the five genetic models. Meanwhile, between-study heterogeneity was evaluated using two methods including Cochran's Q-statistic and I2 = (Q-(k-1))/Q*100% statistic. Cochran's Q statistic approximately follows a χ2 distribution with k-1 degrees of freedom . A significant Q-statistic (P < 0.1) indicates heterogeneity among selected studies. I2 is a measure of heterogeneity and a statistic that indicates the percentage of variance in a meta-analysis that is attributable to study heterogeneity. The intervals including 0-25%, 25-50%, 50-75% and 75-100%, represent the low, moderate, large and extreme heterogeneity. The interval I2 > 50% indicates statistically significant heterogeneity. If heterogeneity P value was lower than 0.10, we considered the heterogeneity to be significant and random-effects model (The DerSimonian-Laird method) was used . OtherwiSensitivity analysis was performed to assess the influence of individual studies on the pooled ORs, with the method of calculating the outcomes again by omitting one single study each time. Publication bias was evaluated with Begg's funnel plots and Egger's linear regression method and a P < 0.05 was set as the significance threshold . HWE was


Rs1344706 in the the zinc finger protein 804A (ZNF804A) gene has been identified to be associated with schizophrenia and bipolar disorder (BD) in Europeans. However, whether rs1344706 is associated with schizophrenia in Chinese populations remains inconclusive; furthermore, the association between rs1344706 and BD in Chinese populations has been rarely explored. To explore the association between rs1344706 and schizophrenia/BD in Chinese populations, we genotyped rs1344706 among 1128 Chinese subjects (537 patients with BD and 591 controls) and found that rs1344706 showed marginal allelic association with BD (P = 0.028) with T-allele being more prevalent in cases than that in controls . Meta-analysis of rs1344706 by pooling all available data showed that rs1344706 was significantly associated with BD (P = 0.001). Besides, positive association of rs1344706 with schizophrenia was observed in Northern Chinese (P = 0.005). Furthermore, ZNF804A is highly expressed in human and mouse brains, especially in prenatal stage. Schizophrenia and bipolar disorder (BD) are two severe neuropsychiatric disorders, with each affecting approximately 1% populations worldwidei.e., psychosis in BD and affective disruption in schizophrenia as observed in clinical practiceThough schizophrenia and BD have been defined as separate mental disorders over the past 100 years, both disorders share some clinical symptoms with each other, rs1006737 in CACNA1C and rs10994336 in ANK3)6rs1109803 in NDST3)Till now, several dozens of risk single nucleotide polymorphisms (SNP) and genomic regions which showed significant association with both schizophrenia and BD have been identified through candidate gene association study (rs1344706 in the zinc finger protein 804A (ZNF804A) gene, which was first identified by a GWAS in samples of Caucasian ancestryrs1344706 is probably an authentic risk SNP for schizophrenia and BD in Europeans10rs1344706 and schizophrenia, subjects from which were all from northern China 1213i.e., Jiangsu, Yunnan, Sichuan and Guangxi province) failed to replicate this association151617rs1344706 in the ZNF804A gene is associated with schizophrenia therefore remains inconclusive. To address this issue, meta-analyses were performed in Chinese populations and Asian populations by multiple groups; however, the results from different groups remain still elusive, due to limited sample size and different inclusion criteria of eligible studies19rs1344706 and schizophrenia in Chinese populations, whether rs1344706 confers risk to BD in Chinese remains largely unknown, although nominal association between rs1344706 and BD has been observed recently by Zhang et al. in Shanghai , with a relatively small sample (746 patients of BD and 762 controls)Another promising common risk variant for schizophrenia and BD is rs1344706 and BD in our Chinese sample consisting of 537 cases and 591 controls, and then conducted a meta-analysis to test the association of rs1344706 with either schizophrenia  or BD (1274 cases and 1343 controls) in Chinese populations with the largest sample size available to date. Moreover, temporal and spatial expression patterns of ZNF804A in different human brain regions were investigated using available online database.In this study, we first explored the association between rs1344706 confirmed to HWE in both control  and case  groups. As shown in rs1344706 showed marginal allelic association with BD in our samples , with T-allele more prevalent in patients of BD than that in healthy subjects , which survived after adjusting for age and gender (P = 0.047). Moreover, there was no significant difference in genotype frequencies of rs1344706 between the case and control group . We further analyzed the association of rs1344706 with BD by gender, which revealed significant allelic association between rs1344706 T-allele and BD in males  but not in females (P > 0.05). The association of rs1344706 with disease characteristics, i.e., age of onset, depressive or manic episodes, were summarized in The genotypic distribution of rs1344706 with the following assumptions: P = 0.05, OR = 1.20 corresponding to a “weak to moderate” effect, and a given MAF of 0.453 according to the 1000 Genomes project (www.1000genomes.org/) (the same bellow).The present sample size (537 BD cases and 591 controls) revealed approximately 32.6% power of detecting a significant association for rs1344706 with psychiatric disorders, mainly BD and schizophrenia, we performed a meta-analysis by pooling our data and those from published studies conducted in Chinese populations. Following our literature search strategy, a total of 11 studies involving 15 independent samples which encompass 11573 cases and 15321 controls, as well as 101 schizophrenia trios, were identified for schizophrenia9121314151617182223P = 0.596) and the Begg–Mazumdar test (P = 0.235).To obtain a more comprehensive interpretation of the association of P of 0.05, OR of 1.20 and MAF of 0.453. For schizophrenia, the pooled sample size revealed 100% power to detect a significant association of rs1344706; for BD, the pooled sample size could provide 64.2% power to detect a significant association. Meta-analysis showed that there was significant association between rs1344706 T-allele and BD  by the fixed-effect model, since no significant evidence of between-study heterogeneity was observed . However, we observed no significant difference in T-allele distribution of rs1344706 between schizophrenia and controls  using the random-effect model due to significant evidence of between-study heterogeneity   .rs1344706 in controls was slightly different among Northern (0.489)rs1344706 T-allele and schizophrenia  was observed in Northern Chinese populations by the random-effect model, but not in Central (P = 0.357) or Southern (P = 0.132) Chinese populations by the fixed-effect model.After careful examination of the regional distributions of recruited populations, we found that most of them resided in Northern China, followed by Southern and Central China. Moreover, the MAF of hern 0.489 and Sours2709373 in CREB1rs6001946 in MKL1rs1344706 in 53 world populations using the HGDP databasers1344706 showed dramatic frequency differences among world populations, with the highest frequencies in most Asian populations, followed then by Middle East and Europe. At the extremes, we found that rs1344706 is nearly fixed for ancestral allele  in most African populations   . After brs1344706 in the ZNF804A gene was implicated as one of the most compelling genetic loci that contribute to the susceptibility of both schizophrenia and BD in European populations, supported by the GWAS and follow-up replications. In the present study, we detected significant association between rs1344706 T-allele and BD in Chinese samples both in our case-control cohorts and subsequent meta-analysis. It should be noted that, as the sample size increased, this association between rs1344706 and BD was strengthened as indicated by sharply reduced P-value , suggesting that rs1344706 may serve as an authentic risk SNP for BD in Chinese populations. Moreover, stratified analysis by gender showed that rs1344706 was associated with male BD (P = 0.034) but not with female BD (P = 0.218) in our samples, which was consistent with previous studiesrs1344706 with BD should be treated scrupulously, since the sample size used in the present study was underpowered which might inflate potential false positive associations and even drew an opposite conclusion. We noticed that our in-house samples (537 BD cases and 591 controls) revealed approximately 32.6% power of detecting a significant association for rs1344706, and even by combining all available data, the sample size (1274 patients with BD and 1343 controls) could only provide 64.2% power to detect a significant association.Recently, rs1344706 showed dramatic difference among worldwide populations, suggestive its implication in psychiatric disorders. From the aspect of evolution, the prevalence of specific disorders should decrease with time, however, this is not the case for psychiatric disorders which maintain a stable or more prevalence across all human cultures. One potential explanation for this paradox suggests positive selection as the driving force in maintaining risk loci of psychiatric disorders in the gene pool. In line with the hypothesis, genetic variants conferring risk of psychiatric disorders might show significant frequency differences among worldwide populations, and several risk loci of psychiatric disorders were thus identified, including rs2709373 in CREB1rs6001946 in MKL1Intriguingly, the allelic frequency of rs1344706 with schizophrenia in Northern Chinese populations , i.e., Shanxi, Xinxiang and Shandong1213151617rs1344706 in controls was slightly different among Northern (0.489)rs1344706 was a risk variant for schizophrenia in Northern Chinese populations, but not in Central or Southern Chinese populations.In addition, our meta-analyses indicated significant association of ZNF804A, consisting of four exons and three introns (rs1344706 in intron 2), is located on chromosome 2q32.1 and potentially encodes a transcription factor. It has been shown that T-allele of rs1344706 can weaken the binding affinity of unidentified nuclear protein with ZNF804A in neural cells, indicating that rs1344706 may have a direct effect on ZNF804A expression and transcriptional regulation of its target geneset al. demonstrated that rs1344706 T-allele was significantly associated with elevated expression level in both the occipital cortex and hippocampus via the BRAINEAC databasers1344706 may confer susceptibility for BD by influencing early brain development. Finally, we found that ZNF804A was mainly expressed in cortical regions, followed by hypothalamus. In previous studies, abnormal cortical structures and functions have been extensively reported in BD patients. For example, BD patients exhibited significantly decreased thickness and increased activation in occipital cortex compared with healthy subjects, as demonstrated by MRIrs1344706, was analyzed in our samples, and SNPs located in other LD blocks and rare variants were not studied, which might miss some important genetic information.However, there are several limitations to our interpretation of this study. First, the sample size in our initial case-control cohort was relatively small (528 patients of BD and 581 controls). Even when pooled with previously published data, the sample size (1274 cases and 1343 controls) was still modest. In order to exclude the possibility of false-positive, replication studies in more Chinese samples from different regions are required. Second, only one SNP, rs1344706 in the ZNF804A gene with BD and schizophrenia, especially in Northern Chinese populations. However, the association between rs1344706 and BD susceptibility should be interpreted with caution as a result of the limited sample size used in the present study and hereby produced false positive associations. Further investigations in larger samples are warranted to draw a solid conclusion.In summary, we observed significant association of In the present study, we recruited a total of 537 unrelated patients with BD type I or type II and 591 healthy subjects. All participants were of the Han Chinese origin and geographically came from the South of China. The patients who met DSM-IV criteria for BD type I or type II were recruited from outpatients that were admitted to the department of Psychiatry, the Affiliated Hospital of Southwest Medial University between June 2011 and January 2014.All patients underwent the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) -Patient Edition independently by two experienced psychiatrists. Meanwhile, the Hamilton Rating Scale for Depression-17 (HRSD-17) and Young Mania Rating Scale (YMRS) were used to assess depressive and manic features, respectively. Subjects with co-morbid diagnosis of other psychiatric disorders or severe organic disease were excluded from this study. The Extensive Clinical Interview contains items to assess demographics, ages at onset, episodes (depressive and manic) and mental status for the patients. Meanwhile, healthy controls were recruited from local communities. The detailed description of patients and controls were seen in Rs1344706 was genotyped by a TaqMan method as described in our previous studyrs1344706 was 98.3%.Genomic DNA was extracted from peripheral blood leukocytes according to the standard phenol/chloroform procedure. Each subject provided written informed consent to attend this studyZNF804A; rs1344706, SNP or common variants; schizophrenia; bipolar disorder, BD or BPD in varying combinations. Eligible studies included in our meta-analysis must meet the following criteria: 1) manuscripts written in English; 2) study design being case-control or family-based association studies; 3) subjects being of Chinese ancestry; 4) commonly acceptable diagnosis criteria for patients, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM); 5) available odds ratio (OR) with 95% confidence interval (95% CI), or sufficient data to calculate these statistics; 6) the genotypic frequencies of rs1344706 in Hardy–Weinberg equilibrium (HWE) in healthy controls. Authors were contacted in case that the genotypic data was unavailable or there were other queries regarding their studies. Two independent authors extracted the following data from the main text: 1) author and publication year; 2) sample size, sample origin and genotyping method; 3) samples’ clinical status; 4) genotypic data of rs1344706 in both cases and controls; 5) P-value, OR and 95% CI.Meta-analysis was performed in agreement with previously described methods3637rs1344706 from Huang et al. studyFor those samples used twice or more in different studies by the same group, only the studies with the largest sample size were included for analysis. Three samples394013162223rs1344706 in global populations were derived from the Human Genome Diversity Project (HGDP) selection browser (http://hgdp.uchicago.edu/cgi-bin/gbrowse/HGDP/)www.1000genomes.org/)The allelic frequency distributions of ZNF804A in diverse tissues and developmental stages of human brains using the following three data sets. 1) BRAINEAC (www.braineac.org/)ZNF804A expression in all covered brain regions. 2) BrainCloudhttp://biogps.org/)ZNF804A in mouse. More detailed description of these data sets can be found in the original manuscripts.We detected the expression pattern of 2 goodness-of-fit test to estimate the Hardy-Weinberg equilibrium (HWE) for the genotypic distributions of rs1344706 in our samples. Analysis of allelic and genotypic associations was performed by either the UNPHASED program (version 3.1.4) as used in our previous studiesrs1344706 T-allele in all analyses. We applied the Power and Sample Size Program software to perform power analysis, and the Stata12.0 statistical software package (http://www.stata.com/) to conduct publication bias analysis and meta-analysis. Degree of potential publication bias was checked using the Egger regression test for a funnel plot and the Begg–Mazumdar test. Cochran’s χ2-based Q-statistic was performed to assess the heterogeneity between individual OR estimates, which is considered significant at P < 0.10. When heterogeneity was present, the random-effects model was used to combine the OR; otherwise, the fixed-effect model was used. The significance of the pooled OR was determined by the Z test and P < 0.05 was considered statistically significant.We applied the χThe study was approved by the Institutional Reviewing Board of Southwest Jiaotong University. All the procedures were in compliance with the Declaration of Helsinki and other relevant national and international rules.How to cite this article: Rao, S. et al. Genetic association of rs1344706 in ZNF804A with bipolar disorder and schizophrenia susceptibility in Chinese populations. Sci. Rep.7, 41140; doi: 10.1038/srep41140 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


The finding did not support an association between rs4957014 T>G polymorphism of PDCD6, and different cancers risk.This study was designed to evaluate the relationship between Programmed cell death protein 6 (PDCD6) polymorphisms and cancer susceptibility. The online databases were searched for relevant case-control studies published up to November 2017. Review Manage (RevMan) 5.3 was used to conduct the statistical analysis. The pooled odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the strength of association. Overall, our results indicate that PDCD6 rs3756712 T>G polymorphism was significantly associated with decreased risk of cancer under codominant (OR = 0.82, 95%CI = 0.70–0.96,  Cancer is a major public health burden, with an estimate of 14.1 million new cancer cases and 8.2 million cancer-related deaths occurred globally in 2012 . In 2018Apoptosis, also known as programmed cell death, is involved in physiological cell death . Many faPDCD6), located on chromosome 5p15.33 contains 43351 bp, is also known as apoptosis-linked gene-2 (ALG-2). PDCD6 gene encodes a 22 kDa calcium-binding protein comprising five serially repetitive EF-hand structures. This protein is one of the prototypic members of the penta-EF-hand protein family. Initially, PDCD6 was considered as a pro-apoptotic protein contributing to T-cell receptor-, Fas-, and glucocorticoid- induced programmed cell death [Programmed cell death protein 6  studies provided sufficient information of the genotype frequencies of PDCD6 polymorphism in both cases and controls; 3) the studies have not repeated reports in the same population. The criteria for exclusion were: 1) the articles that describe case reports, reviews, overlapped data, animal or mechanism studies for PDCD6 polymorphism and cancer; 2) no genotype frequency or genotype information were provided for PDCD6 polymorphism and cancer; 3) insufficient information for data extraction.A comprehensive search in PubMed, Web of Science, Scopus, and Google Scholar databases was performed for all articles describing an association between Extraction of the data has been conducted by two independent scientists. The data were collected from each study including the first author’s name, publication year, ethnicity of participants, the sample size, and the genotype and allele frequencies of cases and controls.2 statistic, interpreted as the proportion of the total variation contributed by inter-study variation, and the Cochran chi-square Q-test, with a significance level of P < 0.10 and I2 > 50%. When significant heterogeneity values were returned, the random-effects model (the DerSimonian and Laird method) was used to estimate pooled ORs. Otherwise, the fixed-effects model (the Mantel-Haenszel method) was employed. The significance of the pooled OR was assessed by the Z-test, and P < 0.05 was considered to be statistically significant.Meta-analysis was carried out using Revman 5.3 software, which was provided by the Cochrane Collaboration  and STATA 14.1 software . All of the data in the studies are dichotomous data, which has been expressed as odds ratios (ORs) with 95% confidence intervals (CIs) to assess the association between the polymorphisms and cancer. Hardy-Weinberg equilibrium (HWE) for each study was determined by the chi-square tests of control group data. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled to evaluate the association between the polymorphisms and risk of cancer. For each polymorphism the ORs were calculated for dominant, codominant, recessive, over-dominant, and allele genetic models. Heterogeneity also assessed using the Ip < 0.05 was considered significant publication bias [PDCD6 polymorphisms in controls were all in accordance with HWE (P > 0.05) except for Zhou et al. [Publication bias was evaluated by funnel plot. The degree of asymmetry was measured using Egger’s linear regression test; ion bias . The chau et al.  , dominant , recessive , and allele  genetic model. Regarding rs4957014 T>G polymorphism of PDCD6, the finding did not support an association between rs4957014 T>G polymorphism and cancer risk . For rs4957014 polymorphism, the findings indicated that the publication bias exist only for recessive model  and overdominant (TG vs TT+GG) model Figure . Therefo2+ binding protein of the EF-hand type belonging to the subfamily of penta-EF-hand (PEF) protein that is required for the induction of apoptosis by a variety of stimuli [2+ to PDCD6 induces a conformational change [PDCD6, a proapoptotic protein, is a Ca stimuli , 20. Binl change , which el change , Sec31A l change , 16, andl change , 29. Sevl change , 13.PDCD6 gene. Several investigations have been done to find the possible association between two tag SNPs of PDCD6, rs3756712 and rs4957014 polymorphisms, and various cancer risk [et al. [PDCD6 significantly decreased the risk of bladder cancer. He et al. [PDCD6 rs3756712 variant and risk of Non-small cell lung cancer (NSCLC). Their findings proposed that rs4957014 variant of PDCD6 significantly decreased the risk of NSCLC. On the other hand, it has been revealed that rs3756712 and rs4957014 polymorphisms of PDCD6 significantly increased the risk of cervical squamous cell carcinoma (CSCC) [et al. [PDCD6 and risk of CSCC. Their findings suggested that both of the variants significantly increased the risk of CSCC.The pathogenesis of carcinogenesis involves environmental factors, molecular signaling pathways, and host genetic factors , 6. Sinccer risk , 42. Zho [et al.  reporteda (CSCC) . RecentlPDCD6 polymorphism in certain types of cancers, the present meta-analysis was performed to evaluate the impact of two SNPs of PDCD6 on cancer risk. To our knowledge, this is the first meta-analysis evaluating the impact of PDCD6 polymorphisms on cancer. The attained results suggest that the PDCD6 rs3756712 T>G polymorphism significantly decreased the risk of cancer under codominant, dominant, recessive, and allele genetic model. The findings did not support an association between rs4957014 T>G polymorphism of PDCD6 and cancer risk.Due to contrasting findings about PDCD6 rs3756712 T>G polymorphism and cancer. The rs3756712 T>G variant may be a potential marker for cancer. Further well-designed case-control studies with a larger sample size and different ethnicities should be done to confirm the findings.In conclusion, to our knowledge, this fist the present study suggested that there is an association between the