MTHFR would result in reduction of MTHFR enzyme activity as well as DNA methylation process, later shown to have significant impacts in various psychiatric diseases. However, it is unclear whether the polymorphism of MTHFR could be an independent or an add-on risk factor for specific psychiatric symptoms, such as anxiety, depression, positive, or negative symptoms of schizophrenia, or acts as risk factor for specific psychiatric disorders, such as schizophrenia, major depression, autisms, and bipolar disorders. It is also understudied on whether folate supplements could be an effective treatment for psychiatric patients with defect MTHFR activity. In this review, we not only gathered the most recent discoveries on MTHFR polymorphism and related DNA methylation in various psychiatric disorders, but also highlighted the potential relationships between MTHFR activity and implication of folate-related function in specific mental diseases.Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for the critical process of one-carbon metabolism involving folate and homocysteine metabolisms. It is known that some polymorphism of  As consequences of polymorphism of MTHFR, reduction of MTHFR enzymatic activity would cause impaired methylation as well as deficiency of folate. There are plenty of relevant studies on linkage between MTHFR and human diseases including cardiovascular diseases, tumors, neurologic diseases, and psychiatric disorders5. Moreover, there are stratified factors that have been identified to be involved in the relationship between MTHFR and diseases, such as gender, age, and ethnicity9. As both DNA methylation and folate are important in mental health, reduction of MTHFR activity or folate deficiency have been associated with an onset of several psychiatric diseases10, schizophrenia, bipolar disorder, depression, autism, and ADHD. In this review, we specifically focus on the MTHFR polymorphism and related methylation and folate effects on psychiatric diseases as well as the possibility of relationship between clinical phenotypes of MTHFR-related diseases and effectiveness of clinical treatment in psychiatric patients11.Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolism in the process of one-carbon metabolism. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and participate in folate and homocysteine conversion correlated to DNA methylationMTHFR resides on chromosome 1 location p36.3 and was originally described as containing 12 exons as shown in Fig. MTHFR transcripts are respectively at 2.2 kb, 7.5 kb, and 9.5 kb12. The cDNA of 2.2 kb-fragment sequence codes for a 656 residue and 70–77 kDa protein13. The cDNA of 7.5 kb and 9.5 kb sequence code a second isoform of 77 kDa protein. Among the exons of MTHFR, the first one is noncoding1. Apart from the coding region, variable 5’ and 3’ noncoding regions (UTR) were identified, resulting in transcript heterogeneity. The 5’ and 3’ termini of the MTHFR cDNA overlap with the 5’ terminus of a chloride ion channel gene and the 3’ terminus of an unidentified gene, respectively. The MTHFR gene has multiple promoters and several polyadenylation sites creating 3’UTR lengths of 0.2 kb ± 5.0 kb or 0.6 kb ± 4.0 kb in human12. The MTHFR gene has been identified to possess 14 common or rare single nucleotide polymorphism that are associated with enzymatic deficiency14. Among them rs1801133(C677T) and rs1801131(A1298C) are most reported that may reduce the MTHFR activity in various degrees. For C677T, the enzyme activity of heterozygous and homozygous mutant individuals are respectively 67 and 25% of the wild-type ones. And for A1298C, the enzyme activity of heterozygous and homozygous mutant individuals are respectively 83 and 61% of the wild-type subjects15, as shown in Fig. In humans, the 17. As shown in Fig. 18. The properties and crystal structure of MTHFR from the bacterium Thermus thermophilus HB8 have been determined19. While the regulation of MTHFR activity is closely controlled by SAM at C-terminal regulatory domain, more studies indicated that the human MTHFR enzyme activity is also regulated by multiple phosphorylated sites on a serine-rich N-terminal extension region20. The phosphorylation leads downregulation of MTHFR activity and upregulation of allosteric inhibition by SAM. It is suggested that phosphorylation impacts on the allosteric regulation of MTHFR via altering the equilibrium of active and inactive states of the enzyme, favoring the inactive state which SAM preferentially binds21. The active form of MTHFR could impact on the generation of 5-methyl THF, which is the active form of folate in vivo. Then methionine level increases and related methyl group donation is driven which successively exert potential mechanism on psychiatric diseases, as shown in Fig. While MTHFR gene codes for different variants, the most common form of MTHFR in human is a 656 amino acids protein. Human MTHFR consists of an N-terminal catalytic domain (amino acids 1–356) which binds 5,10-methylenetetrahydrofolate , and a C-terminal regulatory domain (amino acids 363–656) which binds S-adenosylmethionine 22, which is dependent on SAM as a methyl donor. SAM originated from methionine cycle in which 5-methyl THF transfers methyl groups to homocysteine in a reaction catalyzed by methionine synthase to produce methionine. In this process, 5,10-methylene THF play a critical role in methionine regeneration and methyl donation, meanwhile MTHFR catalyzes the irreversible conversion of 5,10-methylene THF to 5-methyl THF that participate in generation of SAM in methionine cycle and offer methyl group23.Another important role of MTFHR is to participate in donating methyl group to regulate epigenetic modification in the one-carbon metabolism. Methylation is a common regulation process of gene expression that influences cellular development and functionMTHFR polymorphism that have been reported including 2 enzyme activity associated locuses C677T and A1298C and 6 enzyme activity unassociated locuses6. As shown in Table MTHFR gene and its enzyme products, some of the studies revealed severe enzymatic deficiency. The encoding of MTHFR appears to be polymorphic such as the gene site C677T, one of the most studied and clinically important variant in exon 4. The C677T variant results from a single nucleotide substitution at this position, in which cytosine is replaced by thymine resulting a conversion of alanine to valine residue24. The substitution lowers the affinity of MTHFR and its cofactor, which promotes the thermolability and diminishes the enzyme activity. Comparing with wild genotype (CC), the heterozygote (CT) and mutation homozygote (TT) lead to the decline of enzyme activity by about 34 and 75%, and increased thermolability in lymphocyte extracts25. In 2001, the Ala222Val mutation was created in human MTHFR, and the mutant protein was successfully purified and its properties were determined. Different from the former studies, the Ala222Val variant exhibits identical catalytic properties as the wild-type enzyme, but it is thermolabile17.There are several sites of 26. The Ala177Val was established in the MTHFR of E. coli to study the biochemical phenotype of the Ala222Val variant. Then literatures reported the Ala177Val mutation has no influence on the kinetic parameters of bacterial MTHFR, but rather reduces enzyme stability and affinity for cofactor, and thus increases the tendency to form inactive enzyme via flavin dissociation, compared to the wild-type enzyme27.Another common polymorphism is A1298C, in which adenine is replaced by cytosine resulting a conversion of glutamate to alanine at 429 residue, which also diminishes the enzyme activity. Lymphocyte extracts from homozygous 1298CC individuals showed 61% of wild-type enzyme activityMTHFR polymorphism is also associated with global methylation activity. For example, a study of coronary artery patients indicated that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine levels. After genotype analysis, TT genotypes had a diminished level of global DNA methylation compared with those with CC wild type28. Such a change was also found in healthy individuals which showed reduction of DNA methylation in individuals with the TT MTHFR genotype compared to subjects with CC MTHFR29. While DNA methylation may be age, gender, and cell-type specific, MTHFR polymorphism might not be always associated with hypomethylation of DNA. For example, a study of aging-related DNA methylation found hypomethylation in aged individuals compared to young populations without significant association with C677T MTHFR genotypes30. Studies also demonstrated no significant inference of MTHFR C677T polymorphism in global DNA methylation in oral epithelial cell samples31 or lymphocytes of healthy individuals32, as well as cutaneous squamous cell carcinoma in renal transplant patients33. Those reports suggested a MTHFR polymorphism independent mechanism in aging and cell-type specific global DNA methylation. Furthermore, a similar results were reported in a study of individuals with or without oligozoospermic which showed no significant association between DNA methylation in spermatozoa and the MTHFR C677T genotypes although a trend for higher incidence of methylation alterations in severe oligozoospermic infertile men with CT genotypes were observed34, suggesting that a much more complicated or indirect interactions between MTHFR polymorphism and methylation are involved.MTHFR polymorphism could also destruct gene-specific methylation process which refers the methylation status of specific genes. For example, a study of MTHFR polymorphism genotypes in colorectal cancer patients reported that the frequency of methylated Bcl-2 promoter was significantly higher in individuals with CC genotype than that of those with CT and TT genotypes, and a significant difference of C and T alleles distribution were observed between patients with methylated and unmethylated Bcl-2 promoter35. Furthermore, studies of IGF-2 gene in transitional cell carcinoma of the bladder and MGMT gene in gastric cancer showed that patients with CT or TT MTHFR genotypes had reduced methylation of IGF-2 or MGMT compared those with CC genotype37. Together, as MTHFR is an important enzyme for folate metabolism which plays critical role in epigenetic as DNA methylation, accumulated evidence showed that global DNA methylation can be associated with MTHFR polymorphism genotypes in both healthy populations and individuals with various diseases. However, some cell type- and age-related global DNA methylation showed independent of MTHFR genotypes. While the underlying mechanism of MTHFR independent global DNA methylation remains unknown, the MTHFR polymorphisms related gene-specific DNA methylations were commonly reported in various pathological conditions.As global DNA methylation refers to the average methylation status that occurs across the whole genome, Mthfr of mice were knockout to investigate MTHFR deficient by animal models38. The Mthfr+ /− mice showed normal growth and similar survival to that of wild-type mice39. The Mthfr−/− mice were with none MTHFR enzyme activity in all tissues, whereas the Mthfr+/− showed 60% residual activity, similar to the value observed in patients homozygous for the C667T polymorphism40. In the Mthfr+/− and Mthfr−/− mice, the plasma total homocysteine levels were 1.6- and 10-fold higher, respectively, than the wildtype controls. SAM levels were decreased, but S-adenosylhomocysteine  levels were elevated considerably, with global DNA hypomethylation observed in both heterozygotes and homozygotes38. Then researchers proposed that heterozygous knockout mice appeared to be a good animal model for individuals homozygous for the C667T polymorphism, whereas the homozygous null mice were a better one for severely MTHFR-deficient individuals19. Apart from human studies, mice with heterozygous and homozygous mutation in Mthfr C677T still accompany with global DNA hypomethylation, decreased SAM and increased SAH levels41.The MTHFR polymorphism and various diseases, such as cardiovascular diseases, neuronal developmental diseases, cancers as well as psychiatric disorders. Among which, C677T and A1298C polymorphisms of MTHFR have been studied the most in psychiatric diseases and showed significant association with reduction of MTHFR enzymatic activity and methylation. In this session, we will focus on the polymorphisms in the gene encoding for MTHFR in schizophrenia (SZ), bipolar disorder (BPD), depression, autism disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Table Extensive clinical studies demonstrated a significant linkage between 42. Later, a regression model was created in a study of MTHFR C677T genotype and DNA methylation in schizophrenia subjects, which found females with TT genotype were associated with the lowest global methylation43.For decades ago, there was a report of MTHFR enzymatic activity reduction in two schizophrenia patients which were 18 and 21% percent of the normal level, respectively, while homocysteine remethylation was also defectedMTHFR polymorphism in C677T locus is associated with the risk of schizophrenia. As indicated in a meta-analysis of MTHFR consisted of 7 studies, individuals carried with TT homozygotes had the greatest risk of schizophrenia, compared to the subjects with CC wild type and CT heterozygous genotypes44. An allele study with well-defined patients and healthy controls indicated that people with CT heterozygotes had the higher risk of schizophrenia than CC carriers45. Furthermore, a genotype study also reported that homozygous TT genotype of MTHFR was also associated with risk of schizophrenic patients accompanying with bipolar disorder46.Amounts of studies have demonstrated that the level of MTHFR also has an influence on symptoms of schizophrenia. For example, an increased T allele load is linked to the increase severity of negative symptoms in schizophrenia, while reducing severity of positive symptoms were also noticed. However, the effect of T allele on the negative symptoms of schizophrenia could be further enhanced by folate deficiency47. Furthermore, comparing with CC and CT, schizophrenia patients with TT genotype exhibited greater deficits on the verbal fluency test (VFT) and more difficulties on the Wisconsin Card Sorting Test (WCST), but not in California Verbal Learning Test (CVLT) performance48. However, the effect of C677T polymorphisms of MTHFR on cognitive function was not significant in normal subjects as a longitudinal cognitive study showed that the MTHFR C677T polymorphism was not associated with cognitive performance at baseline or over 12 years49. In addition, studies also demonstrated that the C677T polymorphism of MTHFR is associated with onset age of schizophrenia in a dose-dependent manner, such as increasing numbers of the mutant T allele is linked with early onset50.It is interesting to mention that the C677T polymorphisms of MTHFR polymorphism and schizophrenia in different ethnic population were also investigated. Study of schizophrenic patients and healthy controls in the Arab population from Syria found a strong association between C677T and schizophrenia, which showed higher variant T allele frequency in the patients group. Interestingly, a statistically significant association was found for 677TT genotype under the recessive model in the male patients subgroup, and CT genotype under the overdominant model in the total patients group51. Studies of Chinese Han population indicated that the T allele shown associated with schizophrenia as a risk allele52 while a case–control association between the MTHFR C677T polymorphism and schizophrenia in a Japanese subjects research also demonstrated a strong linkage between the MTHFR C677T polymorphism and schizophrenia53. Furthermore, a meta-analysis including 38 studies with schizophrenia cases and controls showed the association between C677T polymorphism and risk of schizophrenia in all three ethnic populations—African, Asian, and Caucasian54.The relationship between MTHFR polymorphism might provide some insights for the divergent results from various studies of psychiatric disorders. A strong association between 677T allele and male patients with schizophrenia compared female patients suggest that 677T allele might represent different liability in genders46. While little is known on the sex differences in MTHFR polymorphisms, sex hormones, such as estrogen is known to play a protective effect in female patients with schizophrenia as for the impact of neurodevelopment and social maturation55. On the other hand, testosterone may increase male vulnerability to an adverse illness course compared to estrogen56, attributed to its narrower and sometimes unfavorable neuroprotection and neurotransmitter modulation profile57. Furthermore, progesterone is reported to benefit neurocognition though enhancement of dopamine release in human males and may also have relevance in male physical and mental health while enhancing the benefits of estrogen through potentiation of estrogen-primed effects on dopamine receptors in male schizophrenic patients58.Studies of sex differences in MTHFR polymorphisms associated with psychiatric disorders. A study with patients of schizophrenia and control subjects showed an association between the A1298C allele and schizophrenia59. Another research including 111 families, demonstrated that deficient MTHFR enzyme activity in pregnant women was related to the A1298C variant, which was associated with a higher risk of schizophrenia in the offsprings60.Except for the C677T, there is another site of MTHFR mutations, while no subjects carry both homozygote for MTHFR mutations regardless which SNPs15 Furthermore, There were studies of multiple polymorphisms of one-carbon metabolism and schizophrenia symptoms showed an increase negative symptoms severity with increase of risk alleles, suggesting a cumulative effects of risk SNPs in one-carbon metabolism61.Studies of individual with both SNPs (C677T and A1298C) showed that subjects with heterozygosity for both mutations resulted in an even lower MTHFR activity than heterozygosity for single MTHFR gene and bipolar disorder with stronger linkage in male patients than female patients46. Another study found a higher prevalence of C677T polymorphism in BD patients than healthy subjects, while patients with BD with early onset carried one copy of the T allele62. A meta-analysis of 56 studies examining MTHFR C677T in patients and control subjects indicated that the T allele and TT genotype carriers showed significant increased risk of major psychiatric disorders including schizophrenia and bipolar disorder63. At the same time, some studies found disparate results. For instance, a study reported no significant association between C677T and bipolar disorder64, while another study found no evidence for C677T genotypic or allelic association with BD regardless of type I or II65. A study with bipolar patients and schizophrenia subjects also observed no robust differences between patients and controls either for allele frequencies or genotype distribution of C677T polymorphism66. These discrepancies may result from population stratifications, explicitly, socio-economic status. On the other hand, the included sample size may play a critical role in divergent results.In addition to schizophrenia, study demonstrated an association between homozygous 677TT genotype of MTHFR polymorphism is also noticed in patients with depression. Studies found that MTHFR polymorphisms might be related to the episode and prognosis of depressive disorder, not the stage of the disease. For example,a cohort study of depressive patients and healthy controls found that MTHFR polymorphism were more common in the individuals with depression history compared to controls67, while a study over a 60-month follow-up with depressed subjects indicated that the CC genotype of MTHFR C677T were more likely to have more severe symptoms compared to TT genotype carriers68. Another study showed that hyperhomocysteinemia and TT MTHFR genotype were significantly related to depression only, not comorbid anxiety disorder69. More studies reported that MTHFR C677T is associated with risk of depression, such as postmenopausal depression70 and childhood trauma related major depression disorder (MDD)71. It is important to point out the interaction between MTHFR polymorphisms and environmental risks for MDD, such as dietary and stress. For example, a study of inter-relationship between MTHFR polymorphism and MDD found that the minor T-allele of MTHFR C677T was associated with increased folate deficiency-related body mass index and homocysteine levels in MDD patients only72. Another stress-related MTHFR polymorphism in MDD study showed that traumatic stress in childhood could increase risk of MDD recurrence as well as the development of more severe depressive symptoms in MTHFR TT genotype carriers. This study suggests that the increase of mutant allele number of T in C677T locus will enhance stress risk for depression71. Both above studies suggest that MTHFR polymorphisms might enhance the environmental risks  for MDD via the interaction between genetic and environmental factors. Such a risk was confirmed by a meta-analysis recruiting 26 published studies which showed an association between MTHFR C677T polymorphism and increased risk of depression73. However, some studies showed no association between MTHFR and MDD or antidepressant treatment response75.Depression is another major psychiatric disease. MTHFR TT genotype and depression in a depression cohort76. Another study including depressed subjects indicated no significant differences in frequency of the T allele or TT genotype between the depressed and healthy controls77. A research of TT genotype and depression scores revealed that the C677T gene variation does not play an important role in the depression scores78. In a meta-analysis, no significant differences in genotype or allele frequencies between depressive patients and controls were observed74.Similarly, diverse situation existed in other researches as a study did not find evidence of an association between the 74. Another possibility is that there is an association of this SNP with another disease that is highly correlated with depression. Indeed it has been hypothesized that depression and vascular disease may be different manifestations of the same genetic substrates79. Both of these conditions are a result of the interaction of multiple genetic factors and environment, involving multiple genes with small interactive and additive effects.A possible reason for divergent consequences is population stratification as the frequency of the T allele is subject to considerable ethnic and geographic variation80, or associated with ASD behavior phenotypes81. A risk study of ASD with typical development indicated significant interaction effects between maternal TT genotype and greater risk for ASD82, suggesting MTHFR polymorphism might involve the early development of ASD. Other studies in the Chinese Han and Korean population also found that MTHFR C677T and A1298C mutation genes were risk factors for autism in Chinese Han children and Korean population, respectively84.Comparing to Schizophrenia and depression, relatively limited studies of MTHFR in autism have been conducted. Some studies showed higher frequency of C677T polymorphism in children with ASD than in healthy controls85, individuals with ADHD seem to be related to A1298C polymorphisms86. However, a research with ADHD and healthy controls reported no association between C677T or A1298C polymorphism and ADHD in Turkish children87. Further studies with large sample size or better controls are needed.In terms of the relationship between MTHFR and ADHA, only very few studies have been reported, even with controversial findings. For example, studies demonstrated that A1298C genotype appeared to be the predominant linkage to the inattentive symptoms, leading to a 7.4-fold increase in ADHD, compared with a 1.3-fold increase for the C677T genotypeMTHFR polymorphism not only increase risks for diabetes, cardiovascular diseases, and various cancers, but also increase the risk for various psychiatric diseases. For example, as we described above that MTHFR polymorphism is associated with early onset of schizophrenia and the severity of depressive symptoms in MDD. This is important since neurotransmitter imbalances hypotheses are still the main streams for schizophrenia and MDD. Understanding alternative mechanisms of psychiatric diseases will not only provide potential biomarkers for specific psychiatric diseases, but also new targets for antipsychotic drug development. Due to significant controversial findings in MTHFR mutation and DNA methylation in both healthy populations and psychiatric patients, investigation of MTHFR activity in peripheral samples might be important. As yet, the relationships between enzymatic activity and mutation of MTHFR have been reported in general healthy and mental retardation populations as well as in animals, no studies have been found in clinical test of MTHFR activity in psychiatric patients90. In addition, there are still some shortages on MTHFR mutation and psychiatric disease studies. Except for C677T and A1298C, there were little studies on other SNPs as well as the effect of multiple SNPs on the diseases which may also affect MTHFR activity.In conclusion, MTHFR and correlative enzyme activity decline will affect various of physiological events as well as some pathology states, including psychiatric disorders. Whether we could cope with gene mutation and enzyme activity damage using folate one-carbon metabolism strategy as clinical treatment for MTHFR-related psychiatric disease? Some studies showed some interesting possibilities. For example, studies of healthy females found that the low level of serum folate in 677TT genotype is associated with an increase in homocysteine concentration and DNA hypomethylation92, which reveals the association between MTHFR C677T polymorphisms and nutrient status. As food is a major resource for folate, studies reported that low folate level due to unbalanced diet is associated with higher prevalence on schizophrenia, particularly in infants with maternal nutritional deficiency93. Another study exploring the association between folate and symptoms of schizophrenia indicated that low folate was associated with negative symptoms severity in schizophrenia subjects94. One possible role of folate in mental health is its action on DNA methylation and gene expression which have been wildly reported in human psychiatric disorders.As MTHFR plays a critical role in one-carbon metabolism, which is composed of folate, homocysteine, vitamin B12, and methylation of DNA, mutation of specific gene locus on MTHFR polymorphisms-induced MTHFR activity decline is irreversible, clinicians tried to use supplement of folate to help methylation process and change the pathogenesis state. For instance, methylfolate supplement was used for the improvement of psychiatric symptoms95, while folate supplementation showed reduction of the incidence of neural tube defects which reduces the incidence of schizophrenia96. Although there is no evidence that supplements are helpful in the treatment of psychosis in general, based on the published studies, we believe that if we can detect MTHFR polymorphism in individuals with various psychiatric diseases, we might be able to differentiate those MTHFR-related psychiatric patients from non MTHFR deficient patients and develop specific clinical treatment strategies, such as folate or methylfolate supplement to reverse the symptoms. In summary, due to the higher frequency of MTHFR polymorphism in various psychiatric disease, supplement of folate and cobalamin might be critical when patients with MTHFR deficiency. MTHFR deficiency-related psychiatric diseases should be identified and might be able to be treated with targeted supplement for the diseases and related symptoms.As MTHFR polymorphism including C677T and A1298C is associated with psychiatric diseases. The MTHFR gene polymorphism is linked to onset, clinical symptoms, prevalence as well as response to treatments. The influence of MTHFR on psychiatric diseases is mainly through reduction of MTHFR activity which results in elevation of homocysteine, reduction of DNA methylation-dependent methyl donor, finally induces hypomethylation, and then active disease-related genes. However, some age- and cell type-specific methylation seems independent from MTHFR polymorphism. MTHFR mutation also can increase environmental risks for psychiatric disorders, such as MDD through interaction between genetic and epigenetic factors. Investigation of MTHFR in psychiatric diseases has important clinical implications, such as identification role of MTHFR and its genotypes in the psychiatric patients who respond or not respond to traditional pharmacological treatment for personalized treatment management of psychiatric diseases.Increasing evidence demonstrated that


CTLA-4) is expressed constitutively on regulatory T cells. So far, several studies have focused on association between CTLA-4 gene polymorphisms and recurrent pregnancy loss (RPL). However, above association between the CTLA-4 gene polymorphism and RPL susceptibility is uncertain. Therefore, we performed a timely meta-analysis of all current publications to clarify this relationship. We located articles from the PubMed and Chinese language (WanFang) databases that were published up until July 25, 2018. Finally, we obtained six case–control studies, containing 2405 total cases and 2607 total controls, based on search criteria for abortion susceptibility related to the CTLA-4 +49 G/A polymorphism. The odds ratios (OR) and 95% confidence intervals (CIs) revealed association strengths. There was significantly decreased association between this polymorphism and whole population risk . Additionally, in ethnicity subgroups, similar association was found both in China  and non-China . Current analysis suggested CTLA-4 +49 G/A polymorphism may weakly decrease RPL risk for women of childbearing age.Cytotoxic T-lymphocyte antigen 4 ( A pregnancy loss (PL) is defined as the spontaneous demise of a pregnancy before the fetus reaches viability. It includes all PLs  from the time of conception until 24 weeks of gestation ,2. ApproA series of pathogenic mechanisms associated with PL has been described, including uterine abnormalities, endocrine and metabolic problems, genetic anomalies, acquired and inherited thrombophilia and immunological factors . More anCTLA-4, Gene ID: 1493, MIM number: 123890 also known as GSE, ALPS5, CD152) gene maps to band q33 of human chromosome 2, spans about 6.2 kilobases, and contains four exons and three introns [CTLA-4 expressed on human placental regulatory T (Treg) cells in decidual and peripheral dendritic cells may induce the expression of an immune-suppressive enzyme indoleamine 2,3-dioxygenase (ID), particularly during early phases of pregnancy [reg cells and CTLA-4 in peripheral and decidual lymphocytes was down-regulated in human miscarriages in several in vivo studies [CTLA-4 and its related Treg cells are protective factors for RPL. SNPs are known as the most common type of DNA variation in individuals [reg cells due to the genetic variations in CTLA-4 gene may increase the risk of RPL.The cytotoxic T-lymphocyte antigen 4  and RPL risk. However, the results were not conclusive or consistent. Thus, we conducted this timely meta-analysis of six case–control studies to derive a more powerful estimation of the association between CTLA-4 rs231775 G/A polymorphism and RPL susceptibility [So far, many studies have investigated the association between tibility .CTLA-4’, ‘spontaneous abortion or miscarriage or pregnancy loss’ and ‘polymorphism’ or ‘variant’. The last search was updated on July 25, 2018. In total, 18 articles were retrieved using the abovementioned terms, and six articles contained the inclusion criteria.Searches were conducted in PubMed and Chinese language (WanFang) databases using the key words ‘cytotoxic T-lymphocyte antigen 4 or CTLA-4 rs231775 G/A SNP; (2) be a case–control study; and (3) have sufficient numbers of genotypes  for both the cases and controls. The following exclusion criteria were used: (1) lack of a control population; (2) lack of available genotype frequency data; and (3) duplicated studies.Including studies had to meet following criteria: (1) address the correlation between RPL risk and the The following items were collected: the last name of first author, the year of publication, the country of origin, the ethnicity of subjects, source of control (SOC), the total and number of each genotype frequency in the case–control groups, the Hardy–Weinberg equilibrium (HWE) of the controls, abortion type, control-type and the genotyping method. Ethnicity was categorized as Asian, China, and non-China.The quality score assessment   was seleCTLA-4 rs231775 G/A SNP and RPL risk. The statistical significance of the summary OR was determined with the Z-test. A heterogeneity assumption was evaluated among studies using a chi-square-based Q-test. A P-value of more than 0.10 for the Q-test indicated a lack of heterogeneity among the studies [Odds ratios (OR) with 95% confidence intervals (CI) were used to measure the strength of the association between the  studies . If sign studies ,21.CTLA-4 rs231775 G/A site and RPL risk by the allelic contrast , homozygote comparison (AA vs. GG), dominant genetic model (AA+AG vs. GG), heterozygote comparison (AG vs. GG), and recessive genetic model (AA vs. AG+GG). A sensitivity analysis was performed by omitting studies, one after another, to assess the stability of results. The departure of the CTLA-4 rs231775 G/A SNP from expected frequencies under HWE was assessed in controls using the Pearson chi-square test (P < 0.05 was considered significant). Funnel plot asymmetry was assessed using Begg’s test, and publication bias was assessed using Egger’s test [P-value less than is considered as significant. All statistical tests were performed using STATA Software .We investigated the relationship between genetic variants of the r’s test , both ofCTLA-4 gene was utilized through String online server (http://string-db.org/) [The network of gene–gene interaction for db.org/) .CTLA-4 rs231775 G/A SNP and RPL risk are summarized in In total, 18 articles were collected from the PubMed and WanFang databases via a literature search using different combinations of key words. As shown in CTLA-4 rs231775 G/A SNP and RPL risk susceptibility  (There was significantly decreased association between the P=0.001) .Pheterogeneity<0.001, P<0.001, AG vs. GG: OR = 0.68, 95% CI = 0.59–0.80, Pheterogeneity=0.126, P<0.001, Pheterogeneity=0.406, P<0.001) and non-China risk  was significantly higher in the RPL group than the normal pregnancy group [CTLA-4 and CD86/CD80 are involved in the maternal–fetal immune regulation, which might be potentially useful to immunotherapy for human RPL [reg, CD4+CD25+, Th17) [CTLA-4 and regulate the RPL development, which may become intervention and treatment target genes in the future.In addition, we used the online analysis system String to predict potential and functional partners . Finallycy group . Severaluman RPL . Most st+, Th17) . Karim e+, Th17) . Above iCTLA-4 may modulate RPL risk, which should be included in future research and analysis. In addition, our meta-analysis was based on unadjusted estimates. A more precise analysis should be conducted if individual data are available to adjust for other covariates including age, sex, family history, environmental factors, endocrine abnormalities, each type of PL, and lifestyle.Limitations in the present meta-analysis include the suboptimal number of published studies for a comprehensive analysis. Second, interactions between different polymorphic loci of the same CTLA-4 gene rs231775 SNP and RPL risk. To further confirm the results, larger scale case–control studies with different ethnic groups and multiple PL types are needed.In summary, in the present meta-analysis, a significant decreased association was found between the


GRIA1 rs548294 G>A and rs2195450 C>T polymorphisms and migraine risk has been reported in several case–control studies. However, the results of studies are inconsistent. Thus, we conducted a meta-analysis to more precisely estimate the association of the two polymorphisms with migraine risk.Purpose: The association between Methods: Eligible studies were retrieved and screened from the online databases . The pooled odds ratio (OR) with corresponding 95.0% confidence intervals (CIs) was assessed using random- or fixed-effects model.GRIA1 rs548294 G>A polymorphism was not significantly associated with migraine risk. GRIA1 rs2195450 C>T polymorphism was significantly associated with migraine risk under heterozygous model . Further subgroup analysis based on ethnicity showed a significant association of GRIA1 rs2195450 C>T polymorphism with migraine risk in Asian population, but not in Caucasian population.Results: A total of 1233 cases and 1374 controls from four eligible studies were included. The pooled analysis showed that GRIA1 rs2195450 C>T polymorphism is significantly associated with migraine risk. However, the number of studies included in the meta-analysis was small. Thus, more high quality case–control studies with a large sample size are still required to confirm these findings.Conclusions: Our results indicates that  Migraine is a common neurovascular disorder affecting over 17% of women and 5–8% of men around the world . ClinicaGRIA1 gene is located on chromosome 5q33.2 and belongs to a family of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. This gene encodes a subunit of ionotropic glutamate receptor regulating neuronal excitability. Synaptic hyperexcitability has been recognized as one major factor causing migraine [GRIA1 gene was inferred as a migraine-related gene. Single-nucleotide polymorphism (SNP) is one of the most common forms of human DNA variations. The potentially functional SNPs in migraine-related genes have been reported to be associated with migraine risk [GRIA1 polymorphisms may also be involved in migraine risk. In order to confirm this hypothesis, some case–control studies were conducted to investigate the association of GRIA1 polymorphisms  with migraine risk. However, the results were inconsistent [migraine . Glutamamigraine . Therefoine risk . Thus GRnsistent ,11–13. TThe online databases including EMBASE, PubMed, Web of Science, Wanfang, as well as Chinese National Knowledge Infrastructure (CNKI) were searched in order to obtain all the relevant articles up to August 3, 2018. Keywords for search were: ‘glutamate ionotropic receptor AMPA type subunit 1 or GRIA1’, ‘polymorphism or SNP or variation’, and ‘migraine or headache’. In addition, reference lists in retrieved articles were also screened. All included studies were conducted on human subjects, and published in either English or Chinese.GRIA1 polymorphisms  and migraine risk; (ii) available data of genotype and allele distributions in cases and controls.All studies selected for further meta-analysis should meet the following criteria: (i) case–control studies investigating the association between P value of HWE in the controls. In addition, quality assessment of each included study was conducted using the Newcastle–Ottawa Scale (NOS), which included three assessment categories  [According to the selection criteria, two authors  carefully reviewed all included articles and independently extracted the relevant information, including the first author’s name, year of publication, country of origin, genotyping method, the total number of case and control, and the genotype and allele frequency distribution in case and control, and xposure) . The catGRIA1 rs548294 G>A and rs2195450 C>T polymorphisms. The pooled ORs were calculated under the following genetic models: heterozygous model, recessive model, homozygous model, dominant model, and allelic contrast model. The significance of the pooled OR was examined by the Z-test, and PZ <  0.05 was considered statistically significant. Heterogeneity between studies was estimated by chi-square-based Q-test, and PH < 0.1 was considered statistically significant. The random-effects model was adopted to analyze the pooled ORs if PH value was less than 0.1. Otherwise, a fixed-effects model was exerted. Sensitivity analysis was used to assess the consistence and stability of the present meta-analysis. Additionally, funnel plots were used to estimate publication bias. All the statistical analyses were implemented with the Review Manager software .For each study, the odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the migraine risk associated with After an initial search, 12 potential articles were identified for further analysis. Eight articles unrelated to the present study were excluded after reviewing titles and abstracts. Finally, four eligible articles were included in the meta-analysis . Tables GRIA1 rs548294 G>A polymorphism and migraine risk under all genetic models. Further stratified analysis based on ethnicity also showed no statistical association between GRIA1 rs548294 G>A polymorphism and migraine risk under all genetic models.As presented in GRIA1 rs2195450 C>T polymorphism and migraine risk under heterozygous model . In addition, subgroup analysis based on ethnicity showed that GRIA1 rs2195450 C>T polymorphism was significantly associated with migraine risk in Asian population ((TT+CT) vs. CC, OR = 1.83, 95%CI = 1.26–2.66, PZ = 0.001; CT vs. CC, OR = 1.75, 95%CI = 1.19–2.57, PZ = 0.005; T vs. C, OR = 1.79, 95%CI = 1.28–2.49, PZ = 0.0006), but not in Caucasian population.As shown in GRIA1 rs548294 G>A polymorphism and migraine risk. However, after removing Cargnin’s study, the significant association between GRIA1 rs2195450 C>T polymorphism and migraine risk was observed under homozygous model , heterozygous model , dominant model ((TT+CT) vs. CC, OR = 1.45, 95%CI = 1.19–1.76, PZ = 0.0002), and allelic contrast model . After removing Fang’s study or Formicola’s study, no significant association was observed between GRIA1 rs2195450 C>T polymorphism and migraine risk under heterozygous model.Each study was sequentially removed to assess the impact of single study on the pooled ORs. The result showed that the omission of any one study did not significantly change the overall estimation result on the association between Funnel plots were used to assess the publication bias. As shown in Supplementary Figure S1, the funnel plot seemed symmetric and did not show obvious publication bias.Several genome-wide association studies have identified more than a dozen loci associated with migraine risk, which suggests novel genes and pathways involved in migraine pathophysiology that point toward neuronal and vascular mechanisms of disease . In addiGRIA1 polymorphisms  were significantly associated with migraine risk in an Italian population. Subsequently, three independent case–control studies from different countries were conducted to confirm this findings [GRIA1 rs548294 G>A polymorphism was not significantly associated with migraine risk. For GRIA1 rs2195450 C>T polymorphism, the result of Cargnin’s study and Maher’s study was contrary to that of Formicola’s study [GRIA1 rs2195450 C>T polymorphism was significantly associated with migraine risk [In 2010, Formicola et al.  first refindings . The res’s study ,12,13. Hine risk . These iGRIA1 rs548294 G>A and rs2195450 C>T polymorphisms and migraine risk, and found that GRIA1 rs548294 G>A polymorphism was not significantly associated with migraine risk, but GRIA1 rs2195450 C>T polymorphism was significantly associated with migraine risk. Due to the fact that rs2195450 polymorphism was located in GRIA1 intron (NM_000827.3) and had no impact on splicing by the prediction of Human Splicing Finder tool (http://www.umd.be/HSF3/), we inferred that rs2195450 polymorphism was probably not a functional variant. Further linkage analyses for rs2195450 would contribute to finding functional variant associated with migraine risk. Subgroup analysis based on ethnicity showed a significant association of GRIA1 rs2195450 C>T polymorphism with migraine risk in Asian population, but not in Caucasian population, suggesting that the effect of this polymorphism might depend on genetic background of different ethnicities.Meta-analysis is a very powerful tool for analyzing cumulative data of studies, in which the sample sizes are small and the statistical power is poor. In the present study, we used this method to systematically assess the association between GRIA1 rs548294 G>A and rs2195450 C>T polymorphisms and migraine risk. Although the present results could provide stronger evidence for the association, some limitations should not be ignored. First, the number of studies and samples included in the meta-analysis was small and the analysis was based on only four case–control studies, of which three included Caucasian population and one Asian population. The omission of one study, such as Cargnin’s study, Fang’s study or Formicola’s study, could change the overall estimation results of rs2195450 polymorphism under different genetic model, suggesting that the results were not robust and needed to be treated cautiously. In addition, our meta-analysis was based on unadjusted estimates, while a more precise analysis should be performed if individual data such as gender, age, lifestyle and environmental factors were available.As far as we know, this is the first meta-analysis reporting the association of GRIA1 rs2195450 C>T polymorphism is significantly associated with migraine risk. However, more high-quality case–control studies with large sample sizes are still required to confirm these findings.Our results indicates that


Results: The overall results indicated that polymorphism T>C of rs1058205 was associated with decreased risk of PCa , particularly in Caucasian population . No association was observed between the polymorphism A>G of rs2735839 and risk of PCa. In addition, no association was observed between polymorphism A>G of rs266882 and risk of PCa. Serum KLK3 levels in PCa patients carrying CC/CT genotypes were statistically lower than those carrying TT genotypes. Conclusion: This meta-analysis suggests that rs1058205 polymorphism of KLK3 is a risk factor for PCa development, polymorphism T>C of rs1058205 is associated with decreased susceptibility to PCa particularly in Caucasian population.Background: Epidemiological studies have assessed the association between kallikrein 3 (KLK3) polymorphisms and prostate cancer (PCa) susceptibility. However, published data on this association are somewhat inconclusive. Methods: Articles investigating the association between three KLK3  variants and PCa susceptibility were searched from online databases, which included 35,838 patients and 36,369 control participants. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to demonstrate the strength of the association. We also utilized ELISA to detect serum expression of KLK3. In addition,  Prostate cancer (PCa) is one of the most common cancers among men in U.S.A. . HoweverSerum levels of prostate-specific antigen (PSA) are measured to screen for PCa. Approximately 40–45% of variations in PSA serum levels are estimated to be influenced by genetic components ,8. A preA number of epidemiological studies have explored the relationship between KLK3 polymorphisms and PCa risk. Previous studies have shown that the TT genotype of rs1058205 was associated with decreased PCa aggressiveness in the Caucasian population based on the Gleason score . HoweverTo identify all potentially eligible studies on KLK3 polymorphisms and PCa risk, a systematic search was carried out on PubMed, Embase and SinoMed (from China) databases, covering all researches published literature worldwide due to July 30, 2017. The search terms “kallikrein 3 or KLK3,” “polymorphism or variant,” and “prostate cancer or tumor or adenocarcinoma” were used to identify suitable literature. Furthermore, review articles and bibliographies of other studies were identified through a manual search. All full-text case–control studies were included if they had PCa risk and KLK3 polymorphism, sufficient available data to estimate an odds ratio (OR) with 95% confidence interval (CI) and the frequencies of the allele or genotype available.Two researchers independently extracted and reviewed the information complying with the selection criteria. In the case of a disagreement, the researchers discussed the studies until a consensus was reached. For each study, the following characteristics were summarized: first author’s last name, year of publication, sample size of cases and controls, country of origin, ethnicity, study-design (sources of samples), age range, the number of cases and controls with variant allele and wild type, and genotyping methods. Finally, nine articles were included  and the We collected the blood of participants in standard cubes without anticoagulant according to the instructions. Patients were enrolled from the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University and third Affiliated Hospital of Nantong University. Then, we centrifuged the blood sample immediately at 1000 rpm for 20 min by ELISA kit (Thermo Scientific Ltd.). A standard ELISA plate reader was used for measuring absorbance at 450 and 550 nm. We correlated the absorbance against a standard curve. Written informed consent by each participant was obtained before samples were collected. The present study was approved by Institution Review Board of these two hospitals.Z-test. The heterogeneity assumption among studies was estimated utilizing a chi-square-based Q-test. The wild-type homozygote (WW), the risk of rare allele homozygote (RR), and heterozygous (WR) genotypes were evaluated. Then we assessed the risk of PCa under a dominant model (RR+WR vs. WW) and recessive model (RR vs. WR+WW). Subgroup analysis was stratified by ethnicity and source of control . A P-value of greater than 0.10 for the Q-test indicated a lack of heterogeneity among the studies. If a significant heterogeneity was detected, the DerSimonian–Laird (random-effects model) was applied; otherwise the Mantel–Haenszel (fixed-effects model) was performed to calculate the pooled OR [P-value of less than 0.05 was considered significant [The strength of the association between the three SNPs and PCa risk was evaluated by OR with its corresponding 95% CI. The statistical significance of the OR was evaluated with a ooled OR ,25. Hardnificant . All stahttp://gemini.cancer-pku.cn/).The NOS was used to evaluate the quality of each study . The NOSA total of nine articles (including 12 case–control studies) met the above selection criteria and are included in our meta-analysis . The chaPheterogeneity < 0.001; heterozygote comparison: OR = 0.787, 95% CI = 0.65–0.93, Pheterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.42–0.81, Pheterogeneity < 0.001, Pheterogeneity < 0.001; and recessive genetic model: OR = 0.63, 95% CI = 0.48–0.82, Pheterogeneity < 0.001) , heterozygote comparison ; homozygote comparison ; and recessive genetic model . In addition, no association was observed between rs266882 A>G variant and PCa risk in allele contrast ; heterozygote comparison ; homozygote comparison ; and recessive genetic model .The overall results indicated a significant association between the rs1058205 T>C polymorphism and PCa  , especiaP = 0.021, In silico analysis showed that KLK3 expression in PCa tissue was relatively higher than that in control tissue , rs2735839 , and rs266882 . The shape of the funnel plots seemed asymmetrical in the homozygote comparison for the three KLK3 polymorphisms, which means no publication bias was found (The Egger’s test and Begg’s funnel plot were used to assess the publication bias within the included studies. No obvious evidence of publication bias was indicated in rs1058205 (C-allele vs. T-allele, as found .To our knowledge, the pathogenesis and etiology of PCa is still inconclusive. However, the continuous development in molecular biology and immunology methods can provide a basis for the diagnosis of PCa and evaluation of its prognosis . The KLKThe results of the overall analysis indicated that KLK3 rs1058205 T>C polymorphism was associated with decreased PCa risk, especially in the Caucasians. No association was detected between the KLK3 rs2735839 A>G polymorphism and PCa risk in all comparisons. In addition, no association was observed between rs266882 A>G variant and PCa risk. In population-based studies stratified by source of control, a significant association between the rs1058205 T>C polymorphism and PCa was observed. Furthermore, we assessed the serum expression of KLK3 by ELISA and indicated that individuals who were CC/CT carriers of KLK3 rs1058205 variant had a lower serum expression level than TT carriers. This result shows evidence that mutation from T to C at KLK3 rs1058205 locus may cause lower expression of KLK3. To further demonstrate the influence of KLK3 variants on PCa susceptibility, we used online gene expression mini database to assess the expression of KLK3 in PCa tissues. It indicated that KLK3 expression in PCa tissue was higher than that in normal tissue, which was in line with the results of our study.Some factors can limit the generalization of the above results. The insufficient number of reported cases on KLK3 variations when specifying different ethnic backgrounds of PCa is one of the main limitations of the present study. Although all eligible studies based on the inclusion criteria were collected, the sample sizes of these studies were not large enough to provide adequate statistical power to assess the association between these polymorphisms and PCa susceptibility in further stratified analysis. The quantitative synthesis of several subgroups may have no sufficient testing power to precisely evaluate the true association. Histological types and Gleason score may also have varied between the evaluated studies. Moreover, the impact of environmental factors such as radiation, toxin, diet, and infectious agent were not evaluated in the analyzed studies. The impact of these factors on susceptibility to PCa should be further evaluated in further experiments. Due to the complex effects of the polygenic nature of complex diseases, including PCa, it is possible that gene-to-gene interactions play a more vital role in an individual’s susceptibility to this disease than single polymorphisms . FurtherIn spite of these limitations, some key advantages in the present analysis should also be acknowledged. Five case–control studies with 28,830 PCa cases and 28,999 control subjects related to the KLK3 rs1058205 variant, four case–control studies with 5394 cases and 5389 controls concerning the rs2735839 polymorphism, and three case–control studies with 1614 cases and 1981 controls related to rs266882 polymorphism were pooled in our present analysis. Statistical powers of these studies were strongly increased. Furthermore, publication bias was not identified in any of the genetic models, indicating that the results are relatively dependable and stable. We performed stratification analysis and sensitivity analysis to explore the sources of heterogeneity in the present study. Our data indicated that neither ethnicity nor source of controls was the sources of heterogeneity. Sensitivity analysis showed evidence that our data regarding these KLK3 polymorphisms were generalizable and credible.In summary, our present study showed that rs1058205 polymorphism of KLK3 was a risk factor for PCa development, polymorphism T>C of rs1058205 was associated with decreased susceptibility to PCa particularly in the Caucasian population. Further researches on additional gene–environment interactions are warranted to provide a better understanding on the association between KLK3 polymorphisms and PCa risk.


In colorectal cancer (CRC), whether the immune score can be used to predict the clinical prognosis of the patient has not been completely established. Besides, the prognostic values of tumor-infiltrating lymphocytes (TILs) in different anatomical locations, counting sites, and subtypes have been controversial. The purpose of this meta-analysis is to analyze and determine the prognostic value of TILs indices including TIL subsets, infiltrating sites, and anatomical sites.Relevant literature was obtained by searching PubMed and Google Scholar. The pooled hazard ratio (HR) of the overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) was computed to investigate the prognostic significance of CD3+, CD8+, CD45RO+, and FOXP3+ T cells.P = 0.0007), whereas in invasive margin (IM), high density of CD3+ infiltrating cells indicated increased DFS . At the tumor center (TC), high CD8+ T cells infiltration was associated with improved DFS . In RC, whether CSS or OS, high-density TIL was associated with improved prognosis.A total of 22 studies involving 5108 patients were included in the meta-analysis. In CC, based on T cell subtypes analysis, the final results indicated that CD8+ and FOXP3+ infiltrating cells, but not CD3+ T cells were prognostic markers for DFS and OS. In addition, with regard to the counting location of TILs, subgroup analysis revealed that only high FOXP3+ infiltrates in the tumor stroma (ST) were significantly associated with OS  = 0.22–0.67, In a single counting site, high-density TILs reflect favorable prognostic value in CC or RC. For CC, more prospective studies are needed to verify whether different anatomical sites affect the distribution of TILs and thus the prognosis of patients. For RC, further studies should analyze the prognostic value of the immune score.The online version of this article (10.1186/s12957-019-1621-9) contains supplementary material, which is available to authorized users. The latest report estimated that in all new cases of malignant tumors, the incidence and mortality of CRC accounted for 10.2% and 9.2%, respectively . It has  NK cell . In cont NK cell . Thus, h NK cell –18. Howe NK cell –21. CD45 NK cell .In CRC, the predictive value of different subtypes of TILs varies with the infiltration site . The latWe searched the PubMed for relevant studies up to November 2018 using the following search scheme:  AND  AND . In addition, Google Scholar and Clinical Trial databases were searched to retrieve additional studies and other reviews without any restrictions. The reference list of other meta-analyses was screened to identify additional studies. All included studies were limited to Homo sapiens as subjects and were published in English.Two independent reviewers (YMZ and GXX) selected the retrieved studies based on the title and abstract. If the topic of a study could not be confirmed from its title or abstract, the full-text was evaluated. Any disagreements were resolved by discussing or negotiating with a third party (HJW). In this meta-analysis, studies that met the following criteria were included: (1) All patients in the original study underwent surgical resection of the primary lesion and were diagnosed by pathological examination; the subjects did not receive neoadjuvant chemoradiotherapy or immunotherapy. (2) Researches reported whether the site of infiltration of T lymphocytes was the in left-side or right-side colon or rectal. (3) Researches identified TILs or subsets of TILs  and reported their association with CSS, DFS, or OS. (4) Studies provided sufficient data to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). (5) TILs or the subtypes of TILs were identified by HE staining, immunohistochemistry, or flow cytometry. Exclusion criteria include insufficient data or case reports, reviews, comment, letters, and conference abstracts. Noteworthy, we incorporated some references from ineligible articles which met the above inclusion criteria. In addition, if a study had multiple publications, the one with the most suitable data was selected.Four investigators  independently selected articles and extracted data according to a prepared form. The following primary information was extracted: the name of first author; year of publication; the number of patients; primary survival endpoint , and OS); T lymphocyte subtype; T lymphocyte counting site; cutoff definition; and use of multivariate or univariate analyses  was used for statistical analysis and meta-analysis. Implement statistical analysis was used to evaluate the association between survival endpoint , and CSS) and subtypes of TILs  in different anatomical regions . Due to insufficient number of studies and data on partial T lymphocyte subtypes, subgroup analysis was only based on TILs located in colon cancer and then described the relationship between high density of CD3+, CD8+ T cells infiltration, and DFS, as well as high density of CD8+, FOXP3+ T cells infiltration, and OS.P value < 0.05 was considered to be significantly different and was calculated by the z score and t test.The HRs and 95% CIs extracted from each study were used to assess the association between high-density TILs and survival rate. A pooled HR > 1 reflected undesirable survival in groups with high number of TIL subtypes. On the contrary, a pooled HR < 1 reflected a favorable survival rate. A Q test [I2 value of 25%, 50%, and 75%, respectively. A random effects model was used to calculate the total HR, when the I2 value > 50% or P < 0.05. Otherwise, a fixed effects model was applied. Sensitivity analysis was performed by changing the analytical model or excluding studies one by one while observing the stability of the results. The sources and reasons of heterogeneity were determined using a quality assessment form     Fig. a, c. TheI2 = 72%, P = 0.006)    Fig. a. The hiP = 0.0006; I2 = 0%, P = 0.80) and OS  . Markedly, positive pooled HRs were obtained for DFS  and OS     Fig. .Fig. 4InP < 0.00001)  . For OS, two studies explored FOXP3+ T cell and the results were pooled  , and the association between two TIL subtypes and the prognosis was described. In CSS, the pooled result for CD3+ T and CD8+ T cells was 0.47  , the effect of each TIL type varies when combining different survival endpoints and anatomical regions. In colon cancer, the results revealed strong evidence that CD8+, FOXP3+, and CDRO45+ T cell are correlated with increased DFS. CD3+, CD8+, and FOXP3+ T cells are correlated with improved OS, but only CD3+ T cell is associated with CSS. Subgroup analysis was performed based on the counting position of TILs, and the results from subgroup analysis were different from those of total analysis regarding DFS, and only CD3+ T cells in IM reversed the original analysis results, while CD8 + T cell in TC maintained the original statistical significance. In ST, subgroup analysis indicated that the positive prognostic value of FOXP3+ T cell on OS was not altered, and heterogeneity disappeared. From the pooled results of colon cancer, the positive prognostic value of FOXP3+ T cell in IM for OS was inconsistent from the results of a previous meta-analysis, which illustrated that high FOXP3+ T cell infiltrates were not correlated with improved OS . Given tThe mechanisms of the prognostic effect of the location of TILs in colon cancer or rectal cancer are not known. But, numerous studies and the immune score indicated that immune cells were associated with prognosis , 56, 57.hi Treg cells and FOXP3lo non-Treg cells. FOXP3hi Treg cells are those that highly express the transcription factor FOXP3 and are regarded as real Treg cells. Conversely, FOXP3lo Treg cells do not express the naive T cell marker CD45RA or stable FOXP3 and are therefore considered to be non-inhibitory T cells. When many FOXP3lo non-Treg cells infiltrated the tumor instead of FOXP3hi Treg cell, they were found to have a strong prognostic value [According to a previous report, the prognostic role of FOXP3+Treg in colorectal cancer is controversial. Nevertheless, in many reports, FOXP3+ TILs were positively related to the survival , 59. In ic value . Thus, tic value . AlthougThis meta-analysis has inevitable limitations. Although the number of studies included was sufficient, some studies did not provide detailed information regarding the subtypes of TILs or each infiltrating site. Therefore, the data used in the subgroup analysis was not sufficient which may introduce some publication bias. In addition, in the analysis of some subsets of TILs, the level of heterogeneity was relatively high, which is thanks to different cutoff values of the high-density and low-density groups of TILs, techniques of detecting TILs, and the source of specimen; one HR of study was extracted from Kaplan-Meier survival curves due to insufficient direct data of the original study, which may result in a certain data deviation. To minimize bias, we contacted the authors of one study whose data was not enough to calculate HR through email, but were not successful. In addition, the studies on rectal cancer did not conduct subgroup analysis stratified by T lymphocyte subtype due to insufficient number of studies.Despite these limitations, the results stratified by the subtype of TILs in different location might shoulder as a positive indicator for predicting the prognosis of patients with colon cancer or rectal cancer. It is imperative to develop standard evaluation tools for TILs in colorectal cancer. In the future, more prospective studies are needed to validate on the prognostic value of TILs by dividing the colon into left and right hemi-colon with splenic flexure as the boundary. In addition, a combination of other markers such as T cell receptor (TCR), programmed death-1(PD-1), and common types of genetic mutations such as RAS mutation and BRAF mutation should be tested to design effective prognostic indicators of the so-called cold tumors which are infiltrated with low levels of TILs.In conclusion, high-density TILs or subtypes of TILs were closely associated with prolonged survival rate, especially in CC. Moreover, only high-density infiltration of some TIL subtypes at a particular infiltrating site was associated with favorable prognosis. Further prospective studies are needed to validate the prognostic value of TILs at a single counting site in colon or rectal cancer, in order to further supplement the immune score and immunotherapy targeting TILs.Additional file 1:Table S1. General characteristics of the studies included in this meta-analysis (XLSX 15 kb)Additional file 2:Table S2. The quality assessment of all included studies in this meta-analysis (XLSX 12 kb)


Current evidence remains equivocal as to whether and how consumption of coffee may be associated with risk of bladder cancer, and potential influence of confounding by smoking on this association is yet to be elucidated. We conducted an updated meta-analysis of prospective studies to address these issues.Relevant studies were identified by searching PubMed and EMBASE databases from inception to April 2019. A random-effects model was used to estimate summary relative risk (RR) with corresponding 95% confidence interval (CI) of bladder cancer associated with coffee consumption.high-vs-low = 1.07, 95% CI: 0.96–1.20). The lack of association persisted in the strata defined by sex or participants’ smoking status. Meta-regression analyses identified the number cases (Pdifference = 0.06) and the degree of adjustment for smoking (Pdifference = 0.04) as potential sources of heterogeneity. There was an increased risk of bladder cancer related to higher coffee consumption among studies with fewer cases  and among those with poorer adjustment for smoking . Results were similar in the dose-response analyses .The final analysis included 16 prospective studies comprising 2,122,816 participants and 11,848 bladder cancer cases. Overall, coffee consumption was not associated with risk of bladder cancer (RR Best evidence available to date does not support an independent association between coffee consumption and bladder cancer risk. Some direct associations observed in individual studies may be a result of residual confounding by smoking.Supplementary information accompanies this paper at 10.1186/s12986-019-0390-3. Coffee is among the most commonly consumed beverages worldwide. As such, a small impact of coffee drinking on health risk could lead to significant public health consequences. Over the past decades, many epidemiologic studies have been carried out to extensively evaluate potential influences coffee drinking on multiple health outcomes, including the developments of various types of cancer . While iSince the release of the 2016 statement, five large prospective studies –9 examinWe performed a literature search in PubMed and EMBASE databases for potentially relevant studies published from inception to April 2019. We used the search term “coffee” in combination with “bladder cancer”, “urinary cancer”, or “urothelial carcinoma”, without imposing language restrictions. The detailed search strategies are reported in Additional file Potentially eligible studies were prospective studies  that evaluated the relationship between coffee consumption and risk of incident or fatal bladder cancer. To be included in the meta-analysis, studies also had to report risk estimates such as hazard ratio, relative risks (RR), or odds ratio with corresponding 95% confidence intervals (CI) of bladder cancer associated with coffee consumption, or report relevant data for deriving these estimates. We did not exclude studies that had small sample sizes or poor adjustments for potential confounders; instead, we evaluated the impacts of these study characteristics in predefined subgroup analyses.Using a standardized data-collection form, we extracted the following characteristics from each included study: the first author’s last name, publication year, country, sources of study population, years of follow-up, number of participants, age and sex of participants, the proportion of current smokers among participants, number of bladder cancer cases, and proportion of male cases. We further extracted information on different categories of coffee consumption and the corresponding fully adjusted risk estimates with 95% CIs , as well as adjustments for potential confounders in the statistical models. Because the association between coffee consumption and risk of bladder cancer could be particularly prone to confounding by cigarette smoking, we extracted detailed information on how smoking habits were adjusted for in the analyses . Data were extracted by one author (Z-WD) and independently verified by other two authors (K-DC and F-RL), with any disagreement resolved by group discussions.Given the substantial differences in the levels of coffee consumption among individual studies, we calculated both summary risk estimates of bladder cancer for the extreme categories (i.e. highest vs. lowest) and for each 1 cup/d increment of coffee consumption. We combined study-specific risk estimates using a random-effects model to account for both within- and between-study variations . For stuP value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to zero.If dose-response relationships between coffee consumption (e.g. 1 cup/d) and risk of bladder cancer was not examined in the original studies, we calculated the estimates using the generalized least squares trend estimation . AccordiTo explore potential sources of heterogeneity, we conducted stratified and meta-regression analyses according to the following study and population characteristics: geographic region, duration of follow-up, number of participants, sex of participants, percentage of current smoker among the study population, number of bladder cancer cases, percentage of male cases, smoking status, and adjustment for potential confounders. To better capture the different degree of being subject to confounding by smoking across individual studies, we categorized the adjustments for cigarettes smoking into three groups including: poorer adjustment for smoking: no adjustment for smoking or adjustment for smoking status only; moderate adjustment for smoking: adjustment for smoking status in addition smoking frequency  either continuously or categorically; better adjustment for smoking: adjustment for smoking status, smoking frequency, in addition to smoking duration or lifetime smoking intensity.2 statistics [P values were two-sided, and the level of significance was at < 0.05, unless explicitly stated.Heterogeneity among studies was assessed using Iatistics , with a atistics , 25. AllA flow chart of study selection is reported in Fig. The characteristics of the included studies are summarized in Table I2 = 30.4%) and dose-response analyses (I2 = 56.3%). There was no evidence of a nonlinear association between coffee consumption and risk of bladder cancer (Pnonlinearity = 0.65).A meta-analysis of the 16 prospective studies yielded a summary RR of 1.07 (95% CI: 0.96–1.20) for the highest compared with the lowest categories of coffee consumption  in addition to the degree of adjustment for smoking  were suggested as potential sources of heterogeneity. A stronger positive association between coffee consumption and risk of bladder cancer was observed for studies with smaller (< 200) number of cases , and for those with poorer adjustment for smoking  . Adjustment for tea consumption also emerged as a potential source heterogeneity in the high-vs-low analysis (Pdifference = 0.042) but not in the dose-response analysis (Pdifference = 0.26).Results of subgroup analyses according various predefined study and population characteristics are shown in Table high-vs-low = 1.15, 95% CI: 0.79–1.67; RR 1 cup/d = 1.02, 95% CI: 0.95–1.09). The lack of association persisted in other smoking categories, although dose-response (but not high-vs-low) analysis suggested modestly increased risk among current smokers. Results of the meta-analysis were similar after excluding one study [Combined results from six prospective studies , 17, 26 P values > 0.40).For both high-vs-low and dose-response analyses, there was no evidence of publication bias according to results of Begg test or Egger test


FGFR2) polymorphism rs2981582 with breast cancer has been extensively studied, whereas the role of this polymorphism in non-functioning pituitary adenoma (NFPA) has not been elucidated. We thus investigated a potential association of rs2981582 with NFPA. A total of 79 patients and 142 healthy control participants were enrolled in our study. DNA of the participants was extracted from peripheral blood samples and genotyped by using the MassARRAY method. We found that the AA genotype was associated with a higher risk of developing NFPA . After adjusting for risk factors, significant difference was still observed between the two groups . Moreover, under the assumptions of the recessive model  and the additive model , rs2981582 was associated with an increased risk of NFPA. Our results proved that FGFR2 rs2981582 AA genotype was associated with a higher risk of NFPA. The recessive model and additive model also showed increased the risk of NFPA.The association of the fibroblast growth factor receptor 2 gene ( Non-functioning pituitary adenomas (NFPAs) are benign pituitary neoplasms that arise from adenohypophyseal cells and are not associated with any clinical syndrome related to hormone overproduction from the tumor ,2. NFPAsFGFR2 gene is located on chromosome 10q26 and contains 22 exons [FGFR2 polymorphism rs2981582, which was first identified by Easton et al. in a large-scale GWAS, were most commonly reported to be associated with breast cancer or prostate cancer [FGFR2 rs2981582 G/G genotype was observed less frequently in the non-invasive PA subgroup than in healthy controls, whereas the G/A genotype was more frequently observed in the non-invasive PA subgroup than either in control group or invasive PA subgroup [FGFR2 rs2981582 on sporadic NFPA and determine a possible association of rs2981582 variants with NFPA risk in Chinese population in a case–control study.Several studies have explored the relationships between single nucleotide polymorphism (SNP) sites and pituitary adenoma (PA) in general by large genome-wide association studies (GWAS) . However22 exons ,12. FGFR22 exons . Variante cancer ,15. Glebsubgroup . NeverthParticipants were consecutively recruited from June to December in 2017 among inpatients in the Beijing Tiantan Hospital. The inclusion criteria were as follows: (1) diagnosis of PA in patients confirmed via magnetic resonance imaging (MRI); (2) normal laboratory tests for the growth hormones prolactin and adrenocorticotropic hormone; (3) absence of other serious diseases. In the control group, age, gender, symptoms, physical examinations, and medical history were recorded. Control group participants were enrolled among healthy individuals after examination that did not reveal any disease or family history of related diseases. Patients with severe hepatic, renal, or cardiac impairment, or any serious illness were excluded. The study was performed according to the guidelines of the Declaration of Helsinki, and was approved by the Ethics Committee of the Beijing Tiantan Hospital. A signed informed consent was obtained from all patients or from their direct relatives.FGFR2 rs2981582 were as follows: ACTGCTGCGGGTTCCTAAAG (forward); CACTCATCGCCACTTAATG (reverse). Genotyping was performed by using time-of-flight mass spectrometry on a MassARRAY iPLEX platform  by Bio Miao Biological Technology . The average genotype call rate for this SNP was >98%.Blood samples of each participant were collected into tubes containing ethylenediaminetetraacetic acid and stored at −80°C until use. Genomic DNA was extracted from the whole blood using a commercial kit  according to the manufacturer’s protocol. DNA quantity was examined by a NanoDrop2000 spectrophotometer . Polymerase chain reaction (PCR) primer pairs used to amplify 2 test and a P-value <0.05 was considered to indicate significant disequilibrium. Differences in genotypic frequencies between groups were calculated by the Pearson’s χ2 test or Mann–Whitney U test. Odds ratio (OR) values with 95%CI were calculated. Logistic regression analysis was used to evaluate the contribution of genetic and non-genetic factors to NFAP risk. Patients’ gender, age, bodyweight, smoking, and drinking habits were treated as risk factors to be adjusted in the analysis.All statistical analyses were performed by SPSS . The Hardy–Weinberg equilibrium (HWE) was assessed by using a χP>0.05). The minor allele frequency was 0.3455. Demographic characteristics of the participants are given in A total of 79 patients  with a mean age of 41.37 ± 11.63 years and bodyweight 72.26 ± 13 kg were enrolled in this hospital-based case–control study. All patients were Chinese and with confirmed diagnosed of NFPA. Of them, 24.5% had a history of smoking and 13.9% were drinking alcohol. The control group enrolled 142 healthy persons  with a mean age of 42.12 ± 11.63 years and bodyweight 69.04 ± 14.35 kg. Nearly 17.6% and 16.8% of control group participants smoked and consumed alcoholic beverage, respectively. No deviation from the HWE was observed . In addition, there was also a significant difference in the recessive model (P=0.007). To analyze the influence of gender on the development of NFPA, we also divided all participants into males and females. There were no significant differences in the frequencies of AA, GA, and GG between patients and healthy controls in males or females considered separately. However, we found that there was a difference in the recessive model (AA vs. GA + GG) in females  even after adjusting for gender, age, bodyweight, smoking, or drinking habits  (P=0.300). However, rs2981582 had a significant impact in the recessive model  and the additive model , even after adjusting for gender, age, bodyweight, smoking, or drinking habits  . In addig habits .In the absence of clinical manifestations of hormonal hypersecretion, NFPAs are usually found when they are large enough to exert pressure on surrounding structures . Until nFGRF2 polymorphism rs2981582 has been extensively evaluated in breast and prostate cancers, the role of this polymorphism in NFPA patients has not been elucidated yet [FGFR2 rs2981582 AA genotype or the recessive model was associated with a higher risk of NFPA. To the best of our knowledge, this is the first study of the relationship between FGFR2 polymorphism rs2981582 and NFPA.NFPA emergence involves a complex combination of genetic, environmental, and lifestyle factors. Inherited susceptibility makes an important contribution to cancer development . Identifated yet ,20–22. OFGFR2 rs2981582 polymorphism with PA was also reported by Glebauskiene et al. [FGFR2 rs2981582 G/G genotype was less prevalent in non-invasive PA cases than in healthy controls [The relationship of e et al. . Howevercontrols . In contAlthough our results are promising and might be useful in helping to stratify patients, they should be considered as preliminary ones and further research is necessary. There were also some limitations that may not be ignored. First, as the mechanism of NFPA is dramatically complex, and we only focused on a polymorphism in one gene, this cannot completely explain the morbidity. Furthermore, the function of FGFR2 in NFPA is still unclear, and more experimental data on this subject are required. Second, as the sample size was limited in our study, several indices bordered the level of statistical significance. In this regard, larger cohorts of patients and healthy controls will be needed in future studies. Third, although we chose the control subjects strictly from the individuals deemed to be healthy by necessary examinations, they did not undergo MRI diagnostics to fully exclude the PA risk. Thus, in future, even stricter inclusion and exclusion criteria should be adopted.FGFR2 polymorphism rs2981582 with NFPA. However, this result needs to be replicated in a larger sample of patients, and functional studies will be necessary to investigate whether and how this polymorphism might affect NFPA pathogenesis.In summary, we for the first time showed an association of


Background: Adiponectin has been suggested as a marker of many cardiovascular diseases. However, the association between serum adiponectin and incidence of atrial fibrillation (AF) in general population remains unclear. A meta-analysis was performed to systematically evaluate the potential influence of serum adiponectin at baseline on the incidence of AF during follow-up in general population.Methods: Prospective cohort studies were identified via electronic search of PubMed and Embase databases. A randomized effect model was applied to combine the results. Predefined subgroup analyses were performed to evaluate the influence of study characteristics on the association between baseline adiponectin and risk of new-onset AF.Results: Six cohort studies with 18558 community-derived participants were included, and 3165 AF cases were developed with a mean follow-up duration of up to 22 years. Meta-analysis showed that higher baseline circulating adiponectin was significantly associated with higher risk of new-onset AF during follow-up . Subgroup analyses showed that the association between adiponectin and new-onset AF was significant in studies with mean follow-up duration over 10 years , but not in that with a follow-up duration < 10 years .Conclusions: Higher circulating adiponectin at baseline may be an independent risk factor for the development of new-onset AF during follow-up, particularly in cohort studies with longer follow-up durations. Atrial fibrillation (AF) is one of the most common chronic arrhythmia which is associated with increased risk of stroke, heart failure (HF) and all-cause mortality . The preCurrently, established risk factors for AF include known cardiovascular diseases (CVDs), such as coronary artery disease (CAD), HF, and valvular heart disease, as well as conventional risk factors of CVDs, including aging, hypertension, diabetes mellitus (DM), and tobacco smoking . MoreoveWe followed the MOOSE   and CochWe searched the databases of PubMed and Embase for relevant records, using the terms ‘adiponectin’ and ‘atrial fibrillation’. We limited the search to studies in humans published in English language. The reference lists of original and review articles were also analyzed using a manual approach. The final literature search was performed on 10 July 2018.Articles were included in the current meta-analysis if they met all the following criteria: (i) published as full-length article in English; (ii) reported as prospective cohort studies (regardless of sample size) with the follow-up duration of at least 1 year; (iii) included community-based adult population (≥18 years of age); (iv) circulating level of adiponectin was measured and identified as exposure of interest at baseline; (v) documented the incidences of AF during follow-up; (vi) reported the hazard ratios  and their corresponding 95% confidence intervals (CIs) of the risk of new-onset AF per 1-standard deviation (SD) increase in logarithmically transformed baseline adiponectin levels, or these data could be calculated. The diagnosis of new-onset AF was based on the definitions and criteria of the original articles. Reviews, letters, editorials, and studies with designs other than prospective cohort study were excluded from the current meta-analysis.The processes of database searching, data extraction, and quality assessment were performed by two independent authors according to the predefined criteria. Discrepancies were resolved by discussion with the third author. Data that were extracted include: (i) study names, locations, and periods; (ii) characteristics of the participants ; (iii) forms and methods of adiponectin measurements; (iv) follow-up durations; and (v) outcomes ; and (vi) primary data regarding the HRs and 95% CIs for the incidence of AF per 1-SD increase in logarithmically transformed adiponectin at baseline. The quality of each study was evaluated using the Newcastle–Ottawa Scale  which raP values, and were logarithmically transformed to stabilize variance and normalized the distribution [2I test to evaluate the heterogeneity among the included cohort studies [2I > 50%. A random-effect model was applied to synthesize the HR data because this model is expected to retrieve a more generalized result via incorporation of the potential heterogeneity [Association between baseline adiponectin and risk of new-onset AF was presented as HRs and 95% CIs for the incidence AF per 1-SD increase in logarithmically transformed adiponectin, and the most adequately adjusted data were extracted. Data of HRs and their corresponding stand errors (SEs) were calculated from 95% CIs or ribution . We used studies . A signiogeneity . Sensitiogeneity . Predefiogeneity . RevMan The processes of literature search and study selection were presented in The characteristics of the included prospective cohort studies are presented in P<0.001; P for Cochrane’s Q test =0.07, 2I = 52%). Sensitivity analyses by excluding one study at a time did not change the results  after excluding the Framingham Offspring Study [Pooled results with a random-effect model showed that higher baseline circulating adiponectin was significantly associated with higher risk of new-onset AF during follow-up , but not in that with a follow-up duration < 10 years .The funnel plots regarding adiponectin at baseline and the risk of AF during follow-up is shown in In the present study, by pooling the results of all available prospective cohort studies, results of our meta-analysis showed that higher circulating adiponectin at baseline is independently associated with increased risk of AF incidence in general population. Subgroup analyses indicated that the association between adiponectin and AF incidence is significant in cohorts with longer follow-up durations (≥10 years), but not in studies with shorter follow-up durations (<10 years). These findings are paradoxical to previous notion that adiponectin may be a protective factor against AF incidence since it is an anti-inflammatory factor.To the best of our knowledge, our study is the first meta-analysis that evaluates the association between circulating adiponectin at baseline and the risk of AF in general population. We found that higher adiponectin at baseline appeared to be an independent risk factor for AF during follow-up. Although findings from experimental studies demonstrated that adiponectin, via exerting its insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties, may be cardioprotecive, findings from epidemiological studies regarding the association between adiponectin and CVDs showed different results. In a meta-analysis of 24 prospective studies, circulating adiponectin at baseline was found to have no significant association with CAD incidence . MoreoveSensitivity analyses and subgroup analyses indicated that the Framingham Offspring Study  is the mOur study has limitations. First, adiponectin was measured via different methods in the included studies, and the strategies for the detection of new-onset AF varied. These may confound the result and contribute to the heterogeneity. In addition, as mentioned above, the results of subgroup analyses should be interpreted cautiously because limited studies were available and the results were based on data of study-level rather than individual patient-level. Moreover, a dose–response association between circulating adiponectin at baseline and the AF risk was unable to determine, because limited cohorts were included. Besides, as a common limitation of meta-analyses of observational studies, the association between adiponectin and AF incidence may be confounded by residual factors that were unadjusted when presenting the results. Finally, the clinical relevance of the findings of the meta-analysis should be investigated in the future. Currently, we were unable to determine whether the relationship between higher adiponectin and increased risk of AF incidence is causative. Future studies are needed to elucidate the potential mechanisms underlying the association between higher adiponectin and increased risk of AF incidence.In conclusion, our meta-analysis indicated that higher circulating adiponectin at baseline may be an independent risk factor for the development of new-onset AF during follow-up, particularly in cohort studies with longer follow-up durations. Whether increased adiponectin is a surrogate marker or a therapeutic target during the pathogenesis of AF in general population deserves further investigation.