COMT) may influence the risk for psychopathy-related behaviors, while acting as a biomarker for predicting treatment response to dopaminergic medications. The literature shows inconsistent findings, making the interpretation of COMT’s role difficult. The aims of this article are (i) to conduct a systematic review to analyze the effects of COMT Val158Met on psychopathic traits in children and adolescents, and (ii) to present new evidence on the developmental trajectory of the association of Val158Met and youth psychopathic traits. For the systematic review, a literature search was conducted using PubMed, EMBASE, OVID Medline and PsychINFO with the search terms for psychopathic traits, Val158Met and age of interest. In our genotype study, the COMT Val158Met genotype of 293 youth with European ancestry was analyzed in association with the psychopathy-related behavior scores from the Child Behavior Checklist and the Psychopathy Screening Device. To examine the potential influence of developmental changes, the sample was split into at or above and below age 13, and analyses were performed in males and females separately. The literature search yielded twenty-eight articles to be included in the systematic review, which demonstrated mixed results on the association depending on environmental factors, sex ratios, age groups and behavioral disorder diagnoses. The results from our genotype study revealed that Met homozygous youth in the below age 13 group and conversely Val carrier youth in the above age 13 group were more likely to display psychopathic traits. To our knowledge, this is the first study to systematically review the effects of COMT Val158Met on psychopathic traits in childhood and adolescence, and to provide new evidence on the changing effects of Val158Met on psychopathy-related behaviors with development. Elucidating the role of the COMT genotype in conjunction with the child versus adolescent stage of development for psychopathic traits may help predict treatment response, and may lead to early intervention and prevention strategies. Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase ( Psychopathy is a neurocognitive personality disorder that involves emotional, interpersonal and behavioral symptoms such as lack of empathy, reduced guilt, increased criminal and violent activity, increased narcissistic tendencies and increased antisociality ,2. AdultWhile the construct of psychopathy is used to define a personality disorder in adults, previous literature has used the term psychopathic traits to describe behavioral tendencies that youth may express at early stages of life ,7,8,9,10Psychopathic traits start early in life and have a high rate of stability across the development from childhood to adolescence . These tThe most studied idea to recognize and conceptualize psychopathic traits in children is by looking at the callous-unemotional (CU) traits in conduct disorder (CD) ,13. CU tIn addition to CD and the CD-CU subcategory, psychopathy-related behaviors can also be found in children with other behavioral disorders. The early signs of CD can be found in children with attention deficit hyperactivity disorder (ADHD) ,16 and oAlthough children with a behavioral disorder, such as ODD or CD, combined with CU traits have a significantly worse prognosis and response to treatment, children with a behavioral disorder without CU traits are not free from the risk of psychopathy in adulthood . The litAs these early expressions of the psychopathic traits and behavioral problems in youth can lead to psychopathy and antisocial personality disorder (ASPD) in adulthood ,20, undeCOMT) gene.Genetic factors have been associated with both the risk for exhibiting putative precursors of adult psychopathy and the stability during development ,22,23, wCOMT gene is a dopaminergic gene that is located on chromosome 22q11.2 and encodes for the COMT enzyme [The T enzyme  COMT breT enzyme  to theirT enzyme ,32. As tT enzyme . The most commonly studied single-nucleotide polymorphism (SNP) that may modify the activity level of the COMT enzyme is Val158Met (rs4680). This non-synonymous SNP changes the G nucleotide to an A, resulting in a change in the 158th amino acid from valine  to methionine (Met). Met/Met carriers have been shown to have 3–4-fold reduction in COMT activity when compared with the Val/Val carriers ,35. TherCOMT-deficient mice and mice with low enzyme activity of COMT are associated with increased aggression in males [It is hypothesized that the catecholamine pathways and catecholamine levels may influence and alter the formation and expression of psychopathic traits ,36,37. Ain males . Agreeinin males . Howeverin males , while oin males , thus maCOMT polymorphism may have different effects in males than in females [There are different factors that may affect the interaction between genes and psychopathic traits, thus leading to the inconsistent findings. Firstly, the environment has been demonstrated to have a significant role in the association, where these experiences may act as an increased risk factor or a buffer against the risk gene variant ,43. Anot females ,45. Beha females .COMT. Previous literature demonstrated that the influence of Val158Met may change through development, where Val158Met may have different effects on adolescents’ versus adults’ delay-discounting behavior [MAOA-uVNTR on psychopathic traits may change through development, further point to a differential effect that the gene variants may have in children versus in adolescents [Developmental age is another factor that may influence the association between Val158Met and psychopathic traits in youth. The activity levels of COMT increase through development , thus pobehavior  and in rbehavior . Moreovelescents . Similarlescents . On the lescents , the frelescents ,52. Therlescents ,47,53, aCOMT Val158Met’s overall role challenging. These demonstrate that while analyzing the literature for Val158Met’s role in the early stages of psychopathic traits, it is crucial to consider and recognize environmental factors, sex, behavioral disorder diagnoses and developmental age as they may influence the gene–behavior association, leading to the inconsistent findings in the literature and making the interpretation of COMT SNPs have also been studied in association with psychopathic traits and related behavioral problems. While children heterozygous for rs6269 (at the promoter region) and rs4818 (Leu136Leu) demonstrated increased aggressive behaviors and callous-unemotional traits when compared to homozygous children [COMT polymorphisms and psychopathic traits, thus requiring more research to make a conclusion regarding their effects.Other children , rs4633 children ,55. Morechildren . HoweverCOMT Val158 versus Met158 may affect treatment response to dopamine system medications. Previous studies have demonstrated that adults showed genotype-specific treatment responses to the COMT-inhibiting drug tolcapone depending on their Val158Met genotype. Tolcapone improved executive functioning in the Val/Val group, and decreased it in the Met/Met group [There are diverse antipsychotic and stimulant drugs that influence the dopaminergic pathways, which have been used in the treatment of aggression and externalizing behaviors in youth, including aripiprazole and risperidone . Howeveret group . The resCOMT [COMT on psychopathic traits focusing on youth. Moreover, the changing effects of certain genes on psychopathic traits from childhood to adolescence [COMT on ADHD from early childhood to middle childhood [COMT gene’s contribution to executive functioning from childhood to adolescence [Previous review articles have focused on the association of different candidate genes , and theCOMT , with nolescence , a changhildhood , and thelescence  point tolescence ,49, no rCOMT’s effects on psychopathic traits in children and adolescents, a literature search was conducted with the key words for psychopathic traits and endophenotypes of psychopathy  AND the gene of interest (“COMT” OR “Catechol-O-methyltransferase”) AND age of interest (youth OR child* OR adoles*). The key words were searched in the title and abstracts of online databases of PubMed, Embase, OVID Medline and PsychInfo, which gave 363 results in total. Results were restricted to articles published from 1947 to February 2021. After the duplicates were removed, 160 articles remained for further screening with the inclusion and exclusion criteria   guidelincriteria .The data selection, collection and extraction processes were independently performed and confirmed by TK and EK. The inclusion criteria were studies that were experimentally designed, published in peer-reviewed journals, published in English, based on human participants and consisting of participants aged from 0 to 18 years old. Studies in languages other than English, case studies, studies with animals, studies that included participants older than 18 years old, studies with overlapping samples, studies that looked at the effects of multiple genes combined or a polymorphism different than Val158Met, or tested for outcomes other than endophenotypes of psychopathy were excluded. The review articles were excluded after a search in their reference lists, which did not provide additional eligible articles. The authors of conference abstracts were contacted for full texts which provided 2 additional articles for full-text review. Moreover, the authors of the articles in a language other than English were contacted for a possible English manuscript; however, this did not yield any additional articles.The study participants were recruited for an ongoing study of childhood aggression at the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada . A totalWritten, informed consent was collected from each participant and/or their guardians. This study was approved by the Research Ethics Board at the Centre for Addiction and Mental Health, Canada.Participants and their guardians were asked to fill out the Child Behavior Checklist (CBCL) and the Psychopathy Screening Device (PSD) , where tCOMT (rs4680) was genotyped with the Illumina PsychArray Beadchip v.1.2 and v.1.3 , in CAMH Toronto, Canada. Quality control analyses were completed for the full genotype, where standard individual and SNP variant quality control procedures were performed using PLINK [p = 0.09).Genomic DNA was extracted from saliva, blood, and buccal cells. The Val158Met polymorphism of ng PLINK  and R [6ng PLINK  BiostatiCOMT as the independent variable. Val carrier youth were coded as “0”, whereas youth with the minor allele Met/Met were coded as “1”. As different associations with the Val158Met genotypes were observed in females and males in previous studies, females and males were analyzed separately. Similar analyses were also conducted with a series of Kruskal–Wallis tests to analyze the association between the three genotypes  and the CBCL or PSD subscale scores. The results were further analyzed with Dunn’s Multiple Comparison Test.Data analysis was performed using PLINK  and R 6 Biostatieff [eff: 0.05/3.7. A multiple testing correction for non-independent tests, Meff , was useAfter the application of inclusion and exclusion criteria and full-text review, 28 studies that analyzed the effects of Val158Met on psychopathic traits in youth remained  and are Studies examining the role of Val158Met in psychopathic traits in youth have demonstrated mixed and conflicting results. As different studies used and analyzed different environmental factors, sex ratios, populations, and age groups, the reporting and comparing of the results will be divided with their subsequent categories. Our review/study will provide an opportunity for more in-depth analyses.COMT and psychopathy-related behaviors are socioeconomic status (SES) and serious life events. Hygen et al. [COMT did not have a significant main effect on aggression. On the other hand, the interaction between the COMT genotype and serious life events on aggression was significant, where children aged 4–5 years old with the Val/Val genotype were more susceptible to exhibiting aggressive behaviors after experiencing serious life events. Interestingly, Val/Val carriers displayed lower aggression scores than Met carriers without serious life events, demonstrating the importance of the gene–environment interaction on psychopathy-related behaviors [Different environmental factors have been found to have significant effects on the association between Val158Met and psychopathy-related behaviors. Two of the most common environmental factors that have been studied in relation to n et al.  demonstrehaviors . The genehaviors , where tehaviors  demonstrehaviors . In bothCOMT genotype and parental separation on externalizing problems, where adolescents with the Met allele had the most externalizing problems among the children if they had separated parents. However, they did not exhibit significantly increased externalizing problems if their parents were together [COMT interaction in predicting externalizing symptoms in youth aged 13 [The gene–behavior association may also be significantly affected by the early-caregiving environment and parental factors. A group of youth exhibited a significant interaction of the together . Similartogether  demonstrtogether . On the  aged 13 .COMT psychopathy-related behaviors is prenatal maternal smoking. A study examining the interaction between maternal smoking during pregnancy and Val158Met on aggressive behaviors in adolescents found that while Val158Met alone did not significantly predict aggressive behaviors, youth with the Val/Val genotype and with mothers who smoked during pregnancy exhibited the highest rate of aggressive behaviors [Another environmental factor that may affect the association between ehaviors . On the ehaviors  demonstrehaviors , similarehaviors .Low birth weight has also been associated with the exhibition of psychopathy-related behaviors in youth, making it an important environmental factor to study in relation to Val158Met. In a sample of youth with ADHD, Thapar et al.  found a COMT gene. However, the significant interactions between the environmental factors and Val158Met on psychopathy-related behaviors signifies the importance of analyzing and considering the gene–environment interactions when studying the endophenotypes of psychopathy.Overall, when the environmental factors are being considered, there are mixed results regarding the risk genotype of the COMT–psychopathic traits association studies, which therefore needs to be considered carefully. Almost half of the studies (k = 13) that are included in this systematic review only examined male participants [Sex can significantly affect the results for the icipants ,78,79,80icipants ,82,83,84A group of Russian male adolescent inmates who have been incarcerated for at least 6 months showed a significant positive association between the number of Val alleles and CD diagnosis and symptoms . This hiOn the other hand, by studying a sample of both males and females, Amstadter and colleagues  demonstrCOMT–psychopathic traits association is being diagnosed with ADHD or other externalizing disorders. As the literature indicates a possibility of the COMT genotype being a risk factor for psychopathic traits, there has been a high interest in understanding if it contributes to the externalizing disorders. Almost half of the studies (k = 12) included in this systematic review studied the COMT–psychopathic traits association in a specific population of youth with externalizing disorders such as ADHD, where the majority demonstrated a significant association between Val158Met and disruptive behaviors in children diagnosed with ADHD. One of the initial studies regarding Val158Met and psychopathic traits in youth with ADHD studied a sample of mostly male youth with clinical ADHD and found a significant association between the Val/Val genotype and increased CD symptom scores, when compared with the Met allele carriers [A factor that may significantly affect the carriers . These rcarriers , where tcarriers . They cocarriers , Salatincarriers  showed tcarriers . Moreovecarriers . Adding carriers . Similarcarriers . Moreovecarriers .On the other hand, different studies demonstrated similar associations with the Met allele. A study with males diagnosed with ADHD demonstrated a significant association between Val158Met and impulsivity, where adolescents with the Met/Met genotype showed higher levels of impulsivity than Val allele carriers . AnotherContrary to the previously reported results, there are also studies that demonstrated no significant association. One of the initial research studying youth with Hyperkinetic Disorder or ADHD demonstrated that there was not a significant association between Val158Met and neurocognitive performance including impulsiveness and response inhibition . SimilarCOMT and psychopathic traits. As the systematic review solely focused on youth, there were not many results that indicated change over time. However, a study showed that, even though the main effect of Val158Met on ADHD symptoms was not significant in early childhood, it became significant in middle childhood, where children with one copy of the Met allele had a higher risk of exhibiting ADHD symptoms than Val/Val carriers [Age and development are additional factors that need to be recognized while analyzing and comparing the results of studies examining carriers , indicatAs a summary, the results from the studies that included samples with behavioral disorder diagnoses have been mixed; however, the majority support the importance of Val158Met on the risk for psychopathic traits, with only three non-significant results. Ethnicity may also influence the association between Val158Met and psychopathic traits in youth, where African American participants show an increased chance of having the Val/Val genotype when compared with White participants . AnotherCOMT and psychopathy-related behaviors were replicated in a sample with autism spectrum disorder and a sample with 22q11.2 deletion syndrome. Both studies showed significant associations between the COMT Val/Val genotype and increased scores on impulsivity and aggression [Studies on the association between gression ,83.p = 0.03), impulsivity (p = 0.04), and callous-unemotional traits (p = 0.007). On the other hand, for male children below age 13, the Met/Met genotype was associated with increased conduct problems (p = 0.03) and impulsivity (p = 0.01). While female adolescents did not show any association between Val158Met and psychopathy-related behaviors, female children below age 13 with the Met/Met genotype had an increased risk for ADHD . The results were not significant when the sample was analyzed as one group regardless of their age, and when females and males were further subgrouped based on their diagnosis of ADHD.Meff , a multiThe current systematic review summarized and reviewed the existing literature on the association between Val158Met and psychopathic traits in children and adolescents. Overall, there are mixed results in the literature; however, a few trends are observed within each group of analyses. First, environmental factors had a significant effect on the gene–behavior association. The majority of the studies showed that while Val158Met alone did not have a significant effect on the risk for children exhibiting putative precursors of adult psychopathy, youth with low SES , who expDevelopment may also be a significant factor in the association between Val158Met and psychopathy-related behaviors, as demonstrated both in the literature and in the new evidence from our original data. Youth with the Met allele showed increased risk of disruptive behaviors in the 7–10 age range but not in earlier childhood years before age seven . ResultsCOMT enzyme levels, is shown to be crucial for decision making, controlling behavioral problems, antisocial behavior and substance abuse, where an increase in dopamine may lead to higher scores on psychopathy [COMT levels, thus enzyme activity, increase in the PFC with development since birth, leading to different enzyme levels in different age groups, independent of the genotype [Increasing levels of COMT through development might provide an explanation for the differing contribution of Val158Met to children’s scores on putative precursors of adult psychopathy. Optimal dopamine levels in the PFC, mostly regulated by chopathy . Studiesgenotype . Therefogenotype ,90. As tgenotype , emphasiStudies have pointed out that psychopathic traits have high stability across the lifetime, and although they start in childhood, they can get worse over time ,92 whileCOMT polymorphism and endophenotypes of psychopathy, but did not mention the keywords in their titles or abstracts. Second, only articles in English were included due to language limitations of the author. Even though the authors of the articles in different languages were contacted for English manuscripts, there were no new articles provided with this method. This may have led to a possibility of underrepresentation of certain sample populations in the review, introducing a possible bias. Third, as the inclusion criteria included studies with participants until age 18 to exclude studies that were not focusing on youth, a few studies that examined adolescent groups with a range older than 18 were excluded. Even though this may have led to the exclusion of studies examining late adolescent groups, it was aimed to ensure that data from the early adult groups were not being compared with youth. Lastly, due to the main aim of the systematic review and inclusion-exclusion criteria, studies that examined COMT with different genes simultaneously with polygenic scores were excluded from this review. Limitations of the experimental study should also be considered. The relatively small sample size may have reduced the statistical power of our analyses, while the ethnically homogenous sample may have limited the generalizability of our results to European populations. Moreover, the current data did not account for the environmental factors that are likely to influence behavioral problems. Furthermore, recent research shows that gene-gene interactions in behavioral disorders are crucial, and a gene’s activation and function may be influenced by the polymorphisms of different genes and gene pathways [COMT and their effects on endophenotypes of psychopathy.The current research has several strengths and limitations. One of the strengths of the systematic review is the systematic way of finding, including and excluding the articles, which makes the replication possible, while reducing the possibility of bias. Moreover, the inclusion of clinically aggressive sample and controls in the analysis of the original data may improve the analysis of the effects of gene on behavior by providing a clear distinction between high and low levels of psychopathic traits. Furthermore, a sample of both males and females in the original data allows for the analysis of sex-specific effects the polymorphism may have. However, there are still limitations that should be considered. First, in the systematic review, to limit the possibility of resulting in majorly unrelated articles, the search terms were only searched in the title and abstracts of the articles. However, this may have limited the access to the articles that tested the association between pathways ,97. As tCOMT gene is necessary to address the limitations of the current literature. First, from the studies that were included in the systematic review, the participants of the 8 of the studies were 100% Caucasian, while 12 of the studies were composed of more than 50% European or Caucasians. While only 2 studies were based on 100% of Chinese Han, only one study had the majority of the participants as African Americans with 56%. With limited generalizability of the results from the literature, and the ethnically homogenous sample of the original data suggests that future studies with larger sample sizes, diverse ethnicities are needed.With mixed results in the field, further research in the k = 13) in this systematic review focused solely or majorly on males. Even though it may be an expected ratio for recruiting participants with behavioral problems [COMT genotype and risk-taking behaviors. Moreover, new evidence from the original data has further demonstrated a sex-specific effect of Val158Met on psychopathic traits. To make further conclusions about females, future research on females is required, as the results from males should not be generalized to the female adolescents. Another limitation that future research should focus on is the sex ratio and more studies with females. As mentioned before, almost half of the studies  on psychopathic traits with polygenic scores. As endophenotypes of psychopathy are likely polygenic, more research on the simultaneous effects of dopaminergic genes on psychopathic traits, with an emphasis on epistasis interactions, is necessary for discovering better prevention and treatment techniques. Moreover, studies have shown that environment has a significant effect on the COMT–psychopathic traits association [COMT gene and psychopathic traits, and no account for environmental and psychosocial factors in the presented new evidence, future research should examine the possible differing effects of environment and maltreatment with development on the gene–behavior association. Specifically, future research should examine the changes from the environmental factors in the molecular level, where they should study the effects of the epigenetic modifications in this gene–behavior association. Future research should also focus on the various components of the gene pathway as well as the possible epigenetic modifications. The difficulty of replicating the results of the role of orphisms ,97,99. Dociation . These eociation ,101. WitCOMT as a biomarker for medication treatment response, particularly for drugs that influence the dopamine system [COMT may have implications for the development of personalized medications for psychopathic traits, and may serve as a biomarker in adjusting the type and dosage of medications from childhood to adolescence. As drugs are commonly used for youth with disruptive behavior disorder, with over 70% being prescribed antipsychotics [Finally, future research should investigate the possible role of e system ,57. Chilychotics , future COMT in childhood and adolescent psychopathic traits and the first empirical evidence that the effects of Val158Met on psychopathy-related behaviors may change through development. With inconsistent results in the literature, this review provides clearer information on the effects of Val158Met on endophenotypes of psychopathy, while emphasizing the importance of recognizing environmental and biological factors that may influence this association. Moreover, the results from the empirical study demonstrate the importance of age and development in the association between Val158Met and psychopathic traits, thus supporting that development is an additional factor that needs to be considered while analyzing these effects, and children and adolescents should be analyzed separately for accurate results. Overall, both studies emphasize the non-linear and non-static association between the COMT genotype and psychopathic traits. Learning about genetic risk factors while considering potential covariates, such as the developmental stage, for youth psychopathy can lead to specific early intervention and prevention strategies for different risk groups, thus reducing the risk for adult psychopathy from an early stage. While the majority of the results from the literature conclude that Val158Met has a significant association with the risk of psychopathy-related behaviors in youth, the conflicting results, along with the new evidence demonstrating the importance of development, emphasizes the need for further research. Future studies using similar methodologies and focusing on females and different ethnicities, on the developmental stability and the epigenetic modifications of this association, as well as analyzing multiple genes at the same time are necessary. Moreover, more studies are necessary to elucidate the possible role of COMT as a biomarker for predicting treatment response, while considering the influence of development on COMT–psychopathic traits association.To our knowledge, this article provides the first systematic review analyzing the role of


In the current study, we aimed to investigate the association between rs1800587 and CP in case-control samples of Han Chinese origin. A total of 1,777 study subjects, including 884 CP patients and 893 healthy controls, were collected. Genotyping of rs1800587 was performed using the SNAPSHOT method, and statistical analyses were conducted to evaluate the association between rs1800587 and CP. In our sample, rs1800587 was significantly associated with the onset of CP  = 1.127–1.855; dominant model, (TT + TC) vs. CC, p = 0.00250, odds ratio = 1.502, 95% CIs = 1.152–1.957; overdominant model, TC vs. (TT + CC), p = 0.00264, odds ratio = 1.508, 95% CIs = 1.152–1.976). The T-allele and [TC] genotypes of rs1800587 were significantly overrepresented in CP patients compared with controls. Our data suggest that rs1800587 of IL-1α is significantly associated with the risk of CP in Han Chinese subjects, further confirming its possible involvement in the disease.Chronic periodontitis (CP) is a common inflammatory illness affecting a large proportion of humans. Genetic factors are thought to play important roles in its onset and development. A functional polymorphism (rs1800587) in the promoter of the interleukin-1 Periodontitis is a common inflammatory illness and a major cause of tooth loss in adults and seniors . Periodoα, IL-1β, the IL-1 receptor antagonist IL-1ra, and their two membrane receptors IL-1RI and IL-1RII. They are well-known key regulators in both innate and adaptive immunity and have been highlighted in a variety of infectious and autoimmune diseases, as well as in systemic inflammatory responses  genotype in control Chinese populations (0.123), the present sample size revealed a 85.4% power of detecting a significant association.The demographic information including age, gender, smoking status, and others of our sample is presented in p = 0.00359, odds ratio = 1.446, and 95% confidence intervals (CIs) = 1.127–1.855; p = 0.00382, odds ratio = 1.446, and 95% CIs = 1.126–1.856; p = 0.00250, odds ratio = 1.502, and 95% CIs = 1.152–1.957; p = 0.75, odds ratio = 1.214, and 95% CIs = 0.369–3.991; p = 0.00264, odds ratio = 1.508, and 95% CIs = 1.152–1.976; A significant increase of the T-allele frequency of rs1800587 in our Han Chinese CP patients compared with healthy controls was observed  were significantly higher in CP cases than in controls of the Chinese population [α levels. Additionally, polymorphisms in the IL-1 gene cluster on chromosome 2 are also correlated with the risk of severe periodontitis in adults [α is a question of specific interest for future studies.Alongside the genetic evidence, the potential functional impact of rs1800587  on inflammatory responses involved in CP has also be confirmed. Rs1800587 locates at the position −889 upstream of the IL-1 to RFX1 . Recent  to RFX1 . Intrigumulation , and Weimulation . Similarn levels . Therefopulation , adding n adults . TherefoDespite the identification of genetic predisposing factors of CP, the current study has several limitations. As the sample recruitment was initiated before the publication of the new guidelines for periodontitis in 2017, the current study mainly focuses on the traditionally defined “CP”. Further analyses in larger Han Chinese samples of different types, stages, and grades of the disease are therefore necessary. In addition, radiograph should also be conducted for all participants if possible, which is unfortunately missing for a great portion of cases in the current study, as radiographic bone loss and tooth loss could provide valuable evidence for the disease progression and severity. Similarly, socioeconomic indices should be collected for the participants, as oral hygiene can be jeopardized by insufficient income, limited access to healthcare, and so on. Additionally, although the sample size is relatively larger compared with some earlier studies , further validation of the associations between rs1800587 and CP in an independent cohort is needed.α gene is a risk variant for CP in the Chinese population. This result has promoted our understanding of the genetic mechanisms of this illness in Han Chinese, and further studies focusing on detailed mechanisms underlying this polymorphism and the gene in CP and other periodontal conditions are needed. For example, do the differences in production and function of IL-1α lead to altered inflammatory responses following microbial infection? Hopefully addressing these problems will provide valuable insights for the understanding, treatment, and prevention of CP.Our study suggests that rs1800587 in the IL-1


Twenty-two longitudinal studies met the eligibility criteria, comprising a total of 55,603 patients. Left ventricular hypertrophy (LVH) was associated with non-fatal cardiovascular events , death from cardiovascular disease , and all-cause mortality . Left ventricular diastolic dysfunction (LVDD) and left atrial dilation (LA) were associated with fatal and non-fatal cardiovascular events  and , respectively. Aortic root dilation was associated with non-fatal cardiovascular events . In conclusion, LVH, LVDD, dilations of the LA, and of the aortic root were associated with an increased risk of adverse events in individuals without previous cardiovascular diseases. This study suggests that simple data obtained on conventional echocardiography can be an important predictor of cardiovascular outcomes in a low-risk population.Echocardiographic abnormalities are associated with a higher incidence of adverse cardiovascular outcomes. This systematic review and meta-analysis aimed to evaluate whether echocardiographic abnormalities are predictors of cardiovascular events in individuals without previous cardiovascular diseases. The PubMed, Scopus, and SciELO databases were searched for longitudinal studies investigating the association between echocardiographic abnormalities and cardiovascular events among individuals without known cardiovascular diseases. Two independent reviewers analyzed data on the number of participants, age and sex, echocardiographic alterations, follow-up time, and cardiovascular outcomes. The meta-analysis estimated the risk ratio (RR) and 95% confidence interval (CI). Heterogeneity was assessed using I Cardiovascular diseases are the subject of extensive research because of their significant impact on morbidity and mortality worldwide . Echocare.g., myocardial infarction [MI], heart failure [HF], stroke, and atrial fibrillation [AF]).In this context, studies have reported different results regarding the prognostic impact of echocardiographic abnormalities in asymptomatic individuals ,5. To thi.e., review and meta-analysis) and the use of anonymized data, the requirement for informed consent was waived.This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The revLongitudinal studies that addressed the association between echocardiographic abnormalities and adverse cardiovascular outcomes, including fatal and non-fatal MI, fatal and non-fatal stroke, HF, AF, and all-cause mortality in adults >18 years of age were included. Studies using other diagnostic imaging methods that analyzed other outcomes or whose participants had already experienced one of the outcomes were excluded.Google Scholar. A standard protocol was used for the literature search and, whenever possible, using controlled vocabulary . In the search strategy, three groups of keywords and their synonyms were used: study design, participants, and exposure. The optimally sensitive search strategy was used to identify studies in MEDLINE and PubMed. The full search strategy is presented in Table S1.Eligible studies were identified by searching the PubMed, Scopus, and Scientific Electronic Library Online (SciELO) databases up to December 2019 without language or publication status restrictions. Manual searches of relevant studies were also performed using Two members of the study team (LPF and ATFB) independently evaluated a list of tittles and abstracts from each data source to identify potentially eligible studies for the systematic review. If at least one of the members considered a reference eligible, a full-text article was obtained for complete assessment.i.e., double verification) by two members of the study team (LPF and ATFB). Disagreements were resolved by consensus or discussion with a third investigator (MGN).Data regarding the following variables were extracted from each study: first author, year and country of publication, number of participants, age and sex, echocardiographic parameters analyzed, follow-up, and outcomes evaluated . The extThe Newcastle-Ottawa Quality Assessment Scale  for cohoversus [vs.] control, left ventricular hypertrophy [LVH] vs. control, left atrial [LA] enlargement vs. control, and aortic root dilation vs. control) and used to compare dichotomous variables. Cardiovascular events , cardiovascular mortality, and all-cause mortality were analyzed. Pooled RR was calculated.Risk ratio (RR) was calculated from the number of events and participants in each group  were calculated at the 95% level. The RR and 95% CIs were calculated. The heterogeneity of the treatment effect in the meta-analysis was examined using the I2 statistic. The I2 values >40% were considered to be indicative of high heterogeneity and, in this case, a random-effects model was chosen. Meta-analysis was conducted using Review Manager  (All oration) . We onlyThe initial search retrieved 16,544 abstracts, of which 89 studies were considered potentially relevant and were included in the detailed analysis. Ultimately, 22 studies  met the The studies were conducted in seven countries between 1990 and 2019, including a total of 55,603 patients in the systematic review and 24,639 patients in the meta-analysis. There was a predominance of females (55.6%), with an average age of 55.4 years. Most studies included adults >40 years of age, six elderly individuals, three healthy young individuals, and two evaluated Native Americans. North American population studies (14 studies) predominated, followed by six European and two Chinese studies. The mean follow-up period was 10.4 years. All studies, except for two ,24, wereFour studies -11,14 thRegarding the association between LV mass and cardiovascular outcomes, Armstrong et al.  found thversus the non-LVH group (p<0.01).A meta-analysis of the association between LVH and non-fatal cardiovascular events, fatal cardiovascular events, and all-cause mortality is shown in Meta-analysis of the association between LVDD and cardiovascular events , LA enlargement and cardiovascular events , aortic root dilation and all-cause mortality, aortic root dilation, and non-fatal cardiovascular events are shown in Among the studies that evaluated LVDD -19, NayoIn this study, we found a significant increase in the risk of fatal and non-fatal cardiovascular events in the LVDD group compared to the control group, with an RR of 2.01 (95% CI 1.32-3.07), as shown in Five studies assessed the association between LA dilation and the risk of cardiovascular events -24. BombAs seen in Three studies estimated the association between aortic root dilation and cardiovascular risk -27. CuspIn this study, we found no association between dilation of the aortic root and mortality from all causes, with RR=1.64; 95% CI 0.92-2.94 , but we Three studies analyzed the association between aortic valve (AV) sclerosis and mitral annular calcification (MAC) and the risk of cardiovascular events in healthy individuals -30. VölzEchocardiography is a non-invasive and easy-to-perform test that can detect many changes in cardiac structure and function frequently associated with cardiovascular prognosis in different situations, and it should also be used for this purpose.To the best of our knowledge, this is the first meta-analysis to specifically investigate the role of some typical parameters of a conventional echocardiogram in a long-term prognosis in individuals without known previous cardiovascular events, including a total of 55,603 patients in the systematic review and 24,639 in the meta-analysis.LVH, LVDD, LA enlargement, and aortic root dilation were associated with an incremental risk of adverse cardiovascular outcomes in this population, including fatal and non-fatal events, as well as all-cause mortality for LVH.LVH and geometric patterns have long been recognized as predictors of increased cardiovascular risk. A meta-analysis published in 2001 reported that patients with LVH had twice the risk of cardiovascular events and death, regardless of other risk factors . Our finAn important finding of this meta-analysis is the significant association of any grade of diastolic dysfunction with fatal and non-fatal cardiovascular events in individuals without known previous cardiovascular diseases. This reinforces the view that the finding of LVDD should not be directed towards the diagnosis of HF, but should also be valued as an early marker of cardiovascular prognosis.LVDD is typically seen in patients with hypertension but can also occur in a variety of other clinical disorders and has a particularly high prevalence in the elderly population . The assLA enlargement is a highly valued finding in echocardiography, which provides supportive evidence of structural alteration(s) of the heart. It is a parameter of LVDD and has been considered a predictor of cardiovascular events, HF, arrhythmias , and mortality -24. FroeConcerning aortic root dilation, our results are consistent with those of the Framingham Heart Study cohort  which foAn important contribution of our review stems from the fact that echocardiographic abnormalities were diagnosed using simple and widely available methods (Table S3). Thus, these parameters can be used to assess the risk of cardiovascular outcomes in most echocardiography services without requiring more sophisticated techniques, benefiting a larger number of patients.The findings of this study may have important implications for clinical practice because it increases awareness that individuals with echocardiographic abnormalities, even those who are asymptomatic and without previous diseases, should be monitored more carefully.Two questions are presented here for discussion. LVH, LVDD, LA enlargement and also aortic dilation often occur together, and it is not possible to separate in a meta-analysis study like ours, the weight and independence of each of these parameters, as well as the association of some of them, on future cardiovascular disease events. Studies are needed to create a risk score associated with these factors. Another problem is that many of the studies that make up this meta-analysis used the m-mode to estimate the mass, measure the LA and the diameter of the aortic root. Likewise, for the diastolic function, some studies did not use tissue Doppler and other criteria according to the new guidelines. Therefore, it is possible that using more recent validated methods, different predictive values, and perhaps more significant RRs, can be found.Currently, the concept of multimodal imaging has become increasingly reinforced . Two impOur study had some limitations. First, the reviewed articles used different echocardiographic approaches, thus increasing heterogeneity in the meta-analysis. Second, only 9 of 22 studies could be selected for meta-analysis, as there were few studies addressing the same exposure or with the same outcomes that could be grouped in the same meta-analysis. In this sense, further research is warranted to assess the contribution of echocardiography in monitoring asymptomatic patients without known previous cardiovascular events.This systematic review and meta-analysis revealed that LVH, LVDD, LA enlargement, and aortic root dilation were associated with an increased risk of adverse cardiovascular outcomes in individuals without known cardiovascular diseases. These findings are important because they confirm the clinical value of monitoring patients with echocardiographic abnormalities to prevent major cardiovascular events, using simple data obtained on conventional echocardiography, even if further studies using more homogeneous methods, populations, and outcomes are still needed.Bin KJ, Higa N, Silva J, Quagliano DA, and Ono SK were responsible for the study conception/design, data acquisition, analysis and interpretation, manuscript drafting, review, and final approval. Hangai RK, Cobello-Junior V, Pereira AJR, Carneiro D’Albuquerque LA, Carrilho FJ, and Wen CL were responsible for the data analysis and interpretation, manuscript drafting, review, and final approval.


Background: Insulin resistance (IR) represents a critical regulator in the development and progress of coronary artery disease (CAD). Triglyceride-glucose (TyG) index, a novel surrogate biomarker of IR, has been implicated in several cardiovascular diseases. Accordingly, we conduct a meta-analysis to elucidate the relationship between TyG index and adverse cardiovascular events in patients with CAD.Methods: To identify the studies examining the predictive capacity of the TyG index for adverse cardiovascular events in the setting of CAD, we performed a comprehensive literature retrieval of Scopus, PubMed, EMBASE, and Web of Science, from the inception of databases to October 5, 2021. We pooled the adjusted hazard ratio (HR) along with 95% CI using a random-effects model. The primary outcome was a composite of major adverse cardiovascular events (MACEs), including all-cause death, cardiovascular death (CV death), myocardial infarction (MI), stroke, hospitalization for unstable angina or heart failure, and revascularization. The secondary outcomes were all-cause death, CV death, MI, stroke, and revascularization. Additionally, we conducted subgroup analyses stratified by diabetes status, age, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), category of TyG index, sample size, follow-up duration, and study design.Results: About 12 studies involving 28,795 patients with CAD were finally taken into the quantitative analysis. Our findings showed that there was a 2.14-fold higher risk of MACEs among CAD populations in the highest TyG group compared with those in the lowest TyG group . A greater risk of MACEs was observed in participants with higher BMI than those with lower BMI (P = 0.03 for interaction). In the analysis of secondary outcomes, we also observed a markedly increased risk of MI, stroke, and revascularization in the highest TyG group compared with the lowest TyG group. No evidence of a significant association between TyG index and CV mortality or all-cause mortality in patients with CAD was identified.Conclusions: The elevated TyG index is a promising predictive factor of adverse cardiovascular events in patients with CAD.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42021228521. Despite the guideline-directed therapy, coronary artery disease (CAD) is still the primary cause of death globally , 2. AlthInsulin resistance (IR) is characterized by metabolism disorders, especially abnormal glucose, and lipid metabolism, leading to aggravation of atherosclerosis in the coronary artery , 5. Recehttps://www.crd.york.ac.uk/PROSPERO). The registration number is CRD42021228521. We performed this meta-analysis in accordance with the recommendations of the Meta-analysis of Observational Studies in Epidemiology group  observational studies (cohort study or nest case-control study); (2) participants were diagnosed with CAD (≥18 years old); (3) participants were exposed to different levels of TyG index at baseline; (4) the outcomes of interest were composite cardiovascular events, all-cause death, CV death, MI, stroke, and revascularization; (5) Adjusted hazard ratio (HR) with 95% CI from multivariate Cox regression models was available. The exclusion criteria were: (1) follow-up duration <3 months; (2) non-English works of literature; (3) duplicate reports, if studies including the same participants or overlapping participants were published, the study with the largest sample size was chosen.Two investigators independently abstracted the following data from each enrolled study: (1) basic characteristics of eligible study: name of the first author, publication year, country origin, sample size, and follow-up duration; (2) baseline demographic and clinical characteristics of subjects: age, sex, diabetes status, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C) as well as the highest TyG index group, and lowest TyG index group; (3) outcomes: adjusted HRs for all-cause death, cardiovascular death (CV death), myocardial infarction (MI), stroke, revascularization, and a composite of cardiovascular events. In instances where there was insufficient information, we contacted the corresponding author. If disagreements occurred, an expert (WH Duan) in the field was consulted and made a judgment.To assess the methodological quality of each selected study, we adopted the Newcastle-Ottawa-Scale (NOS)  designedI2 statistic and Cochran's Q-test were used as a measure of heterogeneity across the included studies (I2 > 50% or P < 0.05), sensitivity analysis, meta-regression analyses as well as subgroup analyses were conducted to explore the potential sources of heterogeneity. The random-effects model was used as the primary statistical analysis model in the estimation of pooled HR, even without significant heterogeneity, owing to the unavoidable clinical and methodological heterogeneity .Our primary outcome was major adverse cardiovascular events (MACEs), including all-cause death, CV death, MI, stroke, hospitalization for unstable angina or heart failure, and revascularization. The secondary outcomes were all-cause death, CV death, MI, stroke, and revascularization. To assess the relationship of the TyG index with the risk of future poor prognosis in individuals with CAD, we pooled the adjusted HRs and 95% CIs. If more than one model was used for the multivariate analysis, the most fully adjusted one was chosen. If outcomes were analyzed as relative risk (RR), we considered RR as an approximate HR in the meta-analysis . If the  studies . If therP < 0.05 was considered as statistically significant. Statistical analyses were performed using STATA software version 12 .Sensitivity analysis by omitting one study at a time was conducted to assess the impact of every study on global HR. Meta-regression identifying the potential factors that might influence the pooled HR analyses were performed only if covariates were available in at least 10 studies. Moreover, we conducted subgroup analyses stratified by diabetes mellitus (DM) (with DM or without DM), age (<60 or ≥60), BMI <26 or ≥26), LDL-C (<1.8 or ≥1.8), category of TyG index (median or tertiles), sample size , follow-up duration (<36 or ≥36), study design (retrospective or prospective) and treatment . To assess the publication bias, we performed Begg's test or Egger's test , 26. P < or ≥26, P < 0.001). Nevertheless, we detected obvious heterogeneity across the 10 studies . The approximately symmetric funnel plot indicated a low risk of publication bias which was consistent with the Egger's test (P = 0.273)  . SimilarMI , revascularization , and stroke  in patients with CAD. However, no statistic difference was observed in the analysis of risk of all-cause death  or CV death . Evidence of publication bias was detected in the analysis of the risk of all-cause death (Egger's test: P = 0.04), but not in the analysis of the risk of MI, revascularization, or stroke by Begg's test or Egger's test . Compared with the lowest TyG index group, the highest TyG index group was associated with an increased risk of I2 = 66.1%, P = 0.003). It should be noted that the study of Zhang et al. , age (P = 0.245), proportion of male (P = 0.654), follow-up duration (P = 0.611), and BMI (P = 0.074).Meta-regression analyses of primary outcome did not detect any correlations between HR of MACEs with sample size (P = 0.03 for interaction). No significant difference was identified across other subgroups (both P > 0.05 for interaction). Notably, the heterogeneity within the subgroup remarkably reduced in patients younger than 60 years old  and moderately reduced in patients after PCI  as well as studies in which TyG index was reported as tertiles , meaning that age, treatment of PCI and category of TyG index might be the factors contributing to heterogeneity. In the subgroup analyses of secondary outcomes, we stratified studies according to diabetes status. As demonstrated in P > 0.05 for interaction).In subgroup analyses of the primary outcome, we separated studies according to diabetes status (with DM or without DM), age (<60 or ≥60), BMI (<26 or ≥26), LDL-C (<1.8 or ≥1.8), category of TyG index (median or tertiles), sample size , follow-up duration (<36 or ≥36) and study design (retrospective or prospective) and focused on the patients after PCI. As demonstrated in This meta-analysis shows that the elevated TyG index is associated with increased risk of MACEs, MI, revascularization, and stroke in patients with CAD. A greater risk of MACEs is observed among participants with higher BMI. Nevertheless, the current evidence suggests that the TyG index may not be an indicator of CV mortality or all-cause mortality in patients with CAD.P > 0.05 for interaction). Age, the concentration of LDL-C, and treatment of PCI are the suspect factors of heterogeneity. However, we did not detect a significant difference in the subgroup analyses stratified by age. We failed to compare the risk of MACEs between patients with LDL-C below 1.8 mmol/L and patients with above 1.8 mmol/L, and between patients treated with PCI and patients not treated with PCI, due to the limited number of studies. Thus, further studies are needed to elucidate the effect of those suspect factors on the risk of MACEs associated with elevated TyG index in patients with CAD.Consistent with a previous study , our finIn this meta-analysis, five articles , 32–35 rIn this meta-analysis, only three studies , 34, 35 In the present study, compared with the lowest TyG index group, patients in the highest TyG index group have a 1.89-fold risk and 2.6-fold risk for MI and revascularization, respectively. Similarly, in a prospective cohort study with 98,849 subjects, there was a 2-fold higher risk for MI in participants with a higher TyG index . AccumulP = 0.75 for interaction). To confirm the predictive role of the TyG index in non-diabetic patients with CAD, further studies are needed.As for the risk of stroke associated with elevated TyG index, an earlier meta-analysis showed that a higher TyG index was associated with a 26% increased risk of stroke among participants without atherosclerotic cardiovascular diseases at baseline . SimilarP = 0.08). The predictive role of the TyG index for heart failure in patients with CAD needs further assessment.It has been reported that IR, prediabetes, and diabetes may mediate the development and progression of heart failure , 55. A mThere are several limitations in the present study. First, all the participates included in our study were from China. The prognostic role of the TyG index for CAD in other countries remains unclear. Second, there were a small number of studies assessing the relationship of the TyG index with the risk of CV death, revascularization, and stroke in individuals with CAD. Additionally, the predictive capacity of the TyG index for adverse events is not separately analyzed in different types of CAD due to a limited number of studies. A study on the prognostic significance of the TyG index in chronic coronary syndrome is lacking. Finally, our analysis only focused on the prognostic value of the baseline TyG index in CAD. The effect of longitudinal changes in the TyG index on the risk of MACEs in patients with CAD remains uncertain. Thus, one should be cautious to interpret the results of our study. More large-scale prospective studies should be conducted to validate the prognostic significance of the TyG index for adverse cardiovascular outcomes in patients with CAD.In this meta-analysis, the elevated TyG index was found to be closely associated with increased occurrence of MACEs, MI, revascularization, and stroke in patients with CAD, and a stronger risk of MACEs was observed in patients with higher BMI. These data provided a rationale to consider the elevated TyG index as a valuable predictor of cardiovascular events in CAD. Measuring the TyG index could contribute to risk identification and proper management in patients with CAD.The original contributions presented in the study are included in the article/J-WL, W-HD, and D-ZS conceived the idea of this meta-analysis. J-WL developed a protocol with the assistance of W-HD. J-WL and Y-QY performed the data analyses independently. J-WL and LS participated in the data interpretation and drafting of the manuscript. D-ZS and W-HD critically reviewed the manuscript. All the authors had browsed and approved the final version of the manuscript.This study is supported by Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No: ZYYCXTD-C-202007).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Sc) derived from endogenous forms of prion protein (PrPC). Several case–control and genome-wide association studies have reported that the M129V polymorphism of the human prion protein gene (PRNP) is significantly associated with susceptibility to sporadic Creutzfeldt–Jakob disease (CJD). However, since some case–control studies have not shown these associations, the results remain controversial. We collected data that contain the genotype and allele frequencies of the M129V single-nucleotide polymorphism (SNP) of the PRNP gene and information on ethnic backgrounds from sporadic CJD patients. We performed a meta-analysis by collecting data from eligible studies to evaluate the association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD. We found a very strong association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD using a meta-analysis for the first time. We validated the eligibility of existing reports and found severe heterogeneity in some previous studies. We also found that the MM homozygote is a potent risk factor for sporadic CJD compared to the MV heterozygote in the heterozygote comparison model . To the best of our knowledge, this was the first meta-analysis assessment of the relationship between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD.Prion diseases are fatal, chronic, and incurable neurodegenerative diseases caused by pathogenic forms of prion protein (PrP Sc) derived from benign prion protein (PrPC), which is encoded by the prion protein gene (PRNP) [PRNP gene. These forms include fatal familial insomnia (FFI) with the D178N-129M genotype; Gerstmann–Sträussler–Scheinker syndrome (GSS) with P102L, A117V, and F198S mutations; and genetic CJD, including the G114V, D178N-129V, V180I, E200K, and V210I mutations. Acquired forms of human prion disease account for less than 1% of all CJD cases, including iatrogenic CJD, kuru, and variant CJD, which are caused by consuming meat from bovine spongiform encephalopathy (BSE)-affected cattle [Prion diseases are chronic, lethal, and malignant neurodegenerative diseases caused by toxic forms of prion protein (PrPe (PRNP) ,2,3,4,5.d cattle ,7,8,9,10PRNP gene was found to be extremely related to susceptibility to sporadic CJD [PRNP gene is significantly associated with susceptibility to sporadic CJD [PRNP gene at codon 129 and susceptibility to sporadic CJD is needed in quality-checked and quantitatively synthesized studies.In previous genome-wide association studies (GWAS), the locus of the adic CJD ,12. Seveadic CJD ,23,24,25adic CJD ,20,22,24adic CJD ,18,19,23PRNP gene and susceptibility to sporadic CJD, we collected data on the genotype and allele frequencies of the M129V SNP of the PRNP gene and information on ethnic backgrounds from sporadic CJD patients. The information on matched-control populations was supplemented from the 1000 Genomes Project and used for an association analysis. Then, we performed a meta-analysis by collecting data from eligible studies to evaluate the association of the M129V SNP of the PRNP gene with susceptibility to sporadic CJD.To evaluate the association between the M129V SNP of the PRNP gene from sporadic CJD patients. The following search terms were used: “PRNP”, “prion”, “CJD”, or “Creutzfeldt–Jakob disease” combined with “SNP” or “polymorphism” or “susceptibility” (the last search update was performed on 8 March 2021). We also supplemented our search by screening reference lists of all the relevant studies, including original articles and reviews. Irrelevant studies were excluded after the initial screening of titles and abstracts. Eligible studies met the following inclusion criteria: (1) relating to the association between the M129V SNP and sporadic CJD; (2) being a cohort or case–control study; (3) containing genetic information on the M129V SNP of sporadic CJD patients; (4) having full text available; and (5) being published in English. The exclusion criteria were as follows: (1) animal studies; (2) case reports; and (3) insufficient genotype data.A literature search was performed in the PubMed database to identify studies relating to the M129V SNP of the PRNP gene in sporadic CJD patients and information on their ethnic background. Information on matched control populations, including Caucasian and East Asian populations, was obtained from the 1000 Genome Project. Comparison of the genotype and allele frequencies between sporadic CJD patients and control populations was analyzed using SAS version 9.4 . Statistical significance was measured by p-values obtained using the χ2 test and Fisher’s exact test. The HWE test was performed using Haploview version 4.2 .We collected 13 studies that contained the genotype and allele frequencies of the M129V SNP of the PRNP gene and susceptibility to sporadic CJD was estimated in a meta-analysis. The pooled odds ratios with 95% confidence intervals were calculated based on additive (M vs. V), recessive (MM vs. MV + VV), dominant (MM + MV vs. VV), and over-dominant (MV vs. MM + VV) genetic models and homozygote (MM vs. VV) and heterozygote (MM vs. MV and MV vs. VV) comparisons. Heterogeneity was evaluated by the p-value and I2 value. Fixed and random effect models were selected to calculate the pooled odds ratios according to the value of the I2 test. Publication bias was evaluated using Egger’s weighted regression methods. A meta-analysis was conducted using the meta package of the R program (https://www.r-project.org/ (accessed on 14 August 2021)).The strength of the association between the M129V SNP of the PRNP”, “prion”, “CJD”, or “Creutzfeldt–Jakob disease” combined with “SNP” or “polymorphism” or “susceptibility” (the last search update was performed on 8 March 2021) in PubMed. After excluding duplicate and irrelevant articles, a total of 13 relevant studies were extracted from the databases based on our inclusion and exclusion criteria.We searched 278 research articles using the search terms “PRNP gene and susceptibility to sporadic CJD, we performed an association analysis between sporadic CJD patients and matched control populations, including Caucasian and East Asian populations obtained from the 1000 Genomes Project. Except for two groups, Salvatore et al. 1994 and Croes et al. 2004, the genotype frequencies of the control population of all groups tested were in HWE. Except for one group, Martins 2007, the genotype frequencies of M129V of the PRNP gene exhibited a strong association (p < 0.05) with susceptibility to sporadic CJD in all groups tested  with the vulnerability of sporadic CJD in all groups tested.To identify an association between the M129V SNP of the s tested . Except p-value and I2 value  and random (>50%) models for the meta-analysis.First, we performed a meta-analysis with all 13 groups tested and found severe heterogeneity and publication bias induced by Doh-ura et al. 1991, Salvatore et al. 1994, Croes et al. 2004, Jeong et al. 2005 and Bishop et al. 2009 (data not shown). Except for the five studies listed, a total of eight studies showing the association between the M129V SNP and susceptibility to sporadic CJD were included in this meta-analysis , recessive model , over-dominant model , and heterozygote comparisons . However, no significant association was found in the homozygote comparison . To examine potential publication bias, Egger’s tests were performed, and publication bias was not observed in this meta-analysis (p > 0.1). The details of the outcomes are shown in Our data revealed an association between the risk of sporadic CJD and the M129V SNP of the PRNP gene and susceptibility to sporadic CJD using a meta-analysis. To do so, we validated the eligibility of each study and identified that several studies were not suitable due to HWE violation and significant heterogeneity  showed the highest risk of susceptibility to sporadic CJD in the meta-analysis. MM homozygote is an especially potent risk factor of sporadic CJD compared to MV heterozygote. To the best of our knowledge, this was the first meta-analysis assessment of the association between the M129V SNP of the PRNP gene and susceptibility to sporadic CJD.In conclusion, we identified a strong association between the M129V SNP of the


OR) with the 95% confidence intervals (CI) for each outcome was calculated by using the RevMan 5.3. The methodological bias of included studies was evaluated and the potential heterogeneity sources were analyzed. Thirteen comparative studies including a total of 24853 hips (9575 hips in the DAA group and 15278 hips in the LA group) were eligible for this meta‐analysis. There was no significant difference in the rate of surgical site infection [2.59% vs 2.14% ], heterotopic ossification [12.16% vs 26.47% ] and reoperation [2.70% and 2.11% respectively ] between the DAA and LA groups. Although a lower rate in prosthesis malposition [36.19% vs 54.86% ], leg length discrepancy [1.87% vs 2.37% ] and Trendelenburg gait [1.68% vs 4.78% ] was observed in the DAA group, a higher rate in dislocation [0.77% vs 0.18% ], periprosthetic fracture [1.05% vs 0.41% ], prosthesis loosening [0.61% vs 0.37% ] and nerve injury [0.95% vs 0% ] was found in the DAA group. This meta‐analysis demonstrated several evidences indicating that the DAA exhibited the advantages in the accurate prosthesis placement and less damage of surrounding hip musculature. However, a higher rate in dislocation, periprosthetic fracture, prosthesis loosening and nerve injury in the DAA group should be paid more attention, due to the limited exposure and a longer learning curve, compared to the LA.The direct anterior approach (DAA) are attracting increasing attention from orthopedic arthroplasty surgeons, due to the less blood loss, mild soft tissue invasion, rapid rehabilitation and shorter length of stay. However, the longer learning curve in DAA can give rise to several complications, such as intraoperative femoral fracture, lateral femoral cutaneous nerve injury, wound‐healing problem, premature revision and so on. This meta‐analysis was performed to compare the rate of postoperative orthopedic complications between the DAA and the lateral approach (LA). All studies involving the comparison of postoperative orthopedic complications after THA between the DAA and LA group were searched in 7 databases prior to October 2020. The odds ratio ( DAA exhibited the advantages in the accurate prosthesis placement and less damage of surrounding hip musculature. However, a higher rate in dislocation, periprosthetic fracture, prosthesis loosening and nerve injury in the DAA group should be paid more attention, due to the limited exposure and a longer learning curve, compared to the LA. Total hip arthroplasty (THA), an extensive clinical application for patients with painful hip disorders such as osteoarthritis (OA), osteonecrosis of the femoral head (ONFH) and femoral neck fracture, contributes to the excellent results in pain relief and function improvement of the hip joint. The clinical outcomes after THA are associated with various factors: prosthetic design, surgical procedure and perioperative management. Among them, the selection of surgical approaches is a focus of interest in the recent studiesThe lateral approach (LA), one of the most common surgical approaches used in THA around the worldThe direct anterior approach (DAA) is a popular surgical approach for THA in recent years and is considered a variant of the Smith‐Peterson anterior approach. The DAA is performed in the interval between the tensor fasciae latae and the sartorius muscles, avoiding splitting the muscle attachments from bone and leading to the less soft tissue disruption around the hip. Therefore, the DAA is advocated by many arthroplasty surgeons based on the following benefits: minimal soft tissue invasion, mild postoperative pain, short hospitalization and rehabilitationAs a result of this, it is still controversial as to the ideal surgical approach of THA. Although the comparison of DAA and LA has been performed by several studiesHere, we performed a meta‐analysis with the aim to: (i) systematically review applications of the two surgical approaches (DAA and LA) in THA; (ii) conduct a more comprehensive assessment in the following postoperative orthopedic complications of THA: surgical site infection; prosthesis‐related complications ; surgical trauma‐related complications (nerve injury and heterotopic ossification); dysfunction (leg length discrepancy and Trendelenburg gait); reoperation, and (iii) provide evidence to support the objective chosen for the two surgical approaches (DAA and LA) for THA.This study was conducted based on the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement (PRISMA)A comprehensive search was conducted for the published literatures by four English databases  and three Chinese databases (China Knowledge Resource Integrated Database (CNKI), VIP Database, and Wan fang Database) from their inception to October 2020, with the following search terms: (“direct anterior approach” OR “Hueter approach” OR “SmithPetersen approach”) AND  AND . Moreover, the other relevant studies were collected from the reference lists of retrieved literatures and previous systematic reviews or meta‐analyses.Three investigators  independently reviewed the titles and abstracts of articles, and then selected full texts by the following inclusion criteria: (i) study design included randomized controlled trials (RCTs), case–control studies or comparative studies in English or Chinese; (ii) patients suffered from primary THA; (iii) comparisons between DAA and LA were conducted for THA; and (iv) at least one of the following complications were reported: surgical site infection, prosthesis‐related complications, surgical trauma‐related complications (nerve injury and heterotopic ossification), dysfunction (leg length discrepancy and positive Trendelenburg sign), reoperation.Studies were excluded based on the following exclusion criteria: (i) study design included non‐comparative studies, cohort studies, reviews or meta‐analysis, case reports, surgical techniques reports, editorials, letters to editors and animal experiments; (ii) studies involved hemiarthroplasty, computer navigation or robot‐assisted THA; and (iii) studies with incomplete data or incorrect data.Two investigators (Xiaotao Huang and Dongguang Liu) independently extracted data from the included studies according to the following items: (i) first author's surname; (ii) publication year; (iii) studies' methodological features; (iv) characteristics of the cases: sample size, age range, gender ratio; (v) follow‐up time; and (vi) postoperative complications rate . If the important data was not available, the listed authors would be contacted to request the original data by email. Disagreements between the two investigators were resolved by discussion and consultation with a senior researcher (Yingxing Xu).Two investigators (Xiaotao Huang and Bin Jia) evaluated the ROB of included studies independently by the Newcastle‐Ottawa Scale (NOS) for non‐randomized studiesOR) and 95% confidence interval (CI) were calculated for the meta‐analysis due to that the postoperative complications rate was binary classification data. The P value < 0.05 was considered as statistically significant. Meanwhile, the I2 value based on standard chi2 test was used to assess statistical heterogeneity. When the P value > 0.1 and I2 value <50%, the study was considered as statistically homogeneous, and was assessed by the fixed effects model for meta‐analysis. When the P value > 0.1 and I2 value > 50%, the study was considered as statistically heterogeneous, and then was assessed by the random effects model for meta‐analysis, while analyzing the sources of heterogeneity. The publication bias was evaluated by funnel plot. If an asymmetry was shown in the funnel plot, publication bias existed in the included studies.The Review Manager (RevMan) version 5.3  was used to analyze the extracted data. The odds ratio . The results showed that the surgical site infection rate in the DAA group (1966 hips) and the LA group (1356 hips) was 2.59% and 2.14% respectively , indicating that there was no difference in surgical site infection rate between the two groups  showed that the postoperative dislocation rate in DAA group and LA group was 0.77% and 0.18% respectively , suggesting that the postoperative dislocation rate in DAA group was significantly higher than that in LA group.As shown in Fig. et al.,I2 = 82%, P = 0.0008). Sensitivity analysis showed that the heterogeneity was reduced significantly  after excluding the result of Chen et al.,OR = 0.50; 95% CI 0.35–0.73, P = 0.0003)  Fig. .et al.et al.I2 = 0%, P = 0.46) showed that the periprosthetic fracture rate in the DAA group (6953 hips) and the LA group (9173 hips) was 1.05% and 0.41% respectively , indicating that the periprosthetic fracture rate in the DAA group was higher than that in the LA group  showed that the prosthesis loosening rate in the DAA group (7019 hips) and the LA group (9237 hips) was 0.61% and 0.37% respectively , indicating that the prosthesis loosening rate in the DAA group was higher than that in the LA group  showed that the nerve injury rate in the DAA group (1478 hips) and the LA group (468 hips) was 0.95% and 0% respectively , indicating that the nerve injury rate in the DAA group was higher than that in the LA group  showed that the heterotopic ossification rate in the DAA group (74 hips) and the LA group (102 hips) was 12.16% and 26.47% respectively . However, there was no statistical difference in heterotopic ossification rate between the two groups (P = 0.07) owing to the limited sample size . Sensitivity analysis showed that the heterogeneity was reduced significantly  after excluding the results of Brun et al.OR = 2.35; 95% CI 1.30–4.25, P = 0.005)  Fig. .et al.et al.I2 = 36%, P = 0.21) showed that the Trendelenburg gait rate in the DAA group (416 hips) and the LA group (712 hips) was 1.68% and 4.78% respectively , indicating that the Trendelenburg gait rate in the DAA group was lower than that in the LA group . Sensitivity analysis showed that the heterogeneity was reduced significantly  after excluding the result of Fleischman et al.OR = 0.93; 95% CI 0.68–1.26, P = 0.64), indicating that there was no difference in reoperation rate between the two groups , due to the minimal disruption of the posterior capsule and short external rotatorsFurthermore, a longer learning curve was often considered as the most significant shortcoming of DAA for THA. During the learning curve, a higher rate of femoral failure, including periprosthetic femoral fracture and aseptic loosening, was reported in the DAA in previous studiesIn the aspect of nerve injury, the traditional view is that more attention should be paid to the lateral femoral cutaneous nerve (LFCN) in DAAet al.With regards to the complications for dysfunction, leg length discrepancy and Trendelenburg gait, were included in this meta‐analysis. Leg length discrepancy has been confirmed to correlate with the pain, excessive prosthesis wear, loosening and instabilityFurthermore, reoperation was considered as an undesirable and serious postoperative issue in THA, involving debridement and prosthesis revision for various infectious or non‐infectious factors. In spite of previous studies, there was no difference in the risk of reoperation for periprosthetic fractures and aseptic loosening under different surgical approachesIn addition, several limitations in this meta‐analysis still need to be considered. First, we were unable to control heterogeneous factors such as surgical knowledge of approaches, patient characteristics and perioperative management. Also, among the 13 included articles, only five were RCTs, indicating that the level of evidence provided was limited. Moreover, the funnel plot used to evaluate the publication bias was not performed in this meta‐analysis, due to a small number of included studies for each complication. Therefore, larger multi‐centre RCTs need to be performed to update the results of our meta‐analysis.Collectively, based on the results of our meta‐analysis, although there was no difference in the rate of surgical site infection, heterotopic ossification and reoperation between the DAA and LA groups, a lower rate in prosthesis malposition, leg length discrepancy and Trendelenburg gait were observed in the DAA group, exhibiting the advantages of DAA in the accurate prosthesis placement and less damage of surrounding hip musculature. However, a higher rate in dislocation, periprosthetic fracture, prosthesis loosening and nerve injury was also found in the DAA group, suggesting that the exposure provided by DAA was relatively limited and a longer learning curve for DAA needs to be overcome. Keeping this in mind, the key to reducing the complications of THA depends on familiarity of the surgical approach.


The severity of influenza disease can range from mild symptoms to severe respiratory failure and can partly be explained by host genetic factors that predisposes the host to severe influenza. Here, we aimed to summarize the current state of evidence that host genetic variants play a role in the susceptibility to severe influenza infection by conducting a systematic review and performing a meta-analysis for all markers with at least three or more data entries.A total of 34 primary human genetic association studies were identified that investigated a total of 20 different genes. The only significant pooled ORs were retrieved for the rs12252 polymorphism: an overall OR of 1.52 (95% CI [1.06–2.17]) for the rs12252-C allele compared to the rs12252-T allele. A stratified analysis by ethnicity revealed opposite effects in different populations.With exception for the rs12252 polymorphism, we could not identify specific genetic polymorphisms to be associated with severe influenza infection in a pooled meta-analysis. This advocates for the use of large, hypothesis-free, genome-wide association studies that account for the polygenic nature and the interactions with other host, pathogen and environmental factors.The online version contains supplementary material available at 10.1186/s12864-021-08240-7. The severity of disease resulting from infection with influenza viruses can range from mild symptoms to severe respiratory failure. This variability is due to multiple host- and pathogen-related factors and the interplay between them. Clinical risk factors for severe influenza have been well documented –5. PatieCandidate genetic markers typically only demonstrate small effects in genetic association tests , 26. ConThe study selection process is summarized as a PRISMA flow diagram in Fig. n = 74), including the study characteristics, CSI score, genotype frequencies, HWE in controls, and re-calculated ORs. There were a total of 20 different genes assessed by the included studies (n = 34), with most frequent results for interferon-induced transmembrane protein 3 (IFITM3) . Other genes investigated were C-C motif chemokine receptor 5 , Fc fragment of IgG receptor IIa , tumor necrosis factor , toll-like receptor , complement decay-accelerating factor , surfactant protein , ST3 beta-galactoside alpha-2,3-sialyltransferase 1 , angiotensin I converting enzyme , complement C1q binding protein , C-X-C motif chemokine ligand 14 , glycine decarboxylase , mannose binding lectin 2 , natural killer gene , transmembrane serine protease 2 , and phosphoinositide-3 kinase . A total of 34 distinct markers were recorded in the database, but only four met the inclusion criteria of at least three data points available per marker and were used in the subsequent meta-analysis. The majority of included studies (76%) was performed in influenza A(H1N1)pdm09 positive patients. Among investigated data points, a total of 19 (26%) investigated severity indicators  among hospitalized patients, 11 (15%) focused specifically on mortality among hospitalized patients, 10 (14%) on mortality among hospitalized and ambulant patients combined, 17 (23%) on severity indicators among hospitalized and ambulant patients combined, and 17 (23%) assessed the risk for hospitalization. From the total of 74 data points, 40 (54%) were characterized by a post-hoc stratification of cases and controls. Out of the 34 data points with all three CSI score domains scored, only 5 (15%) had a credible CSI score .Additional file IFITM3 gene, rs333 in the CCR5 gene, and rs1801274 in the FCGR2A gene, in all four genetic models. Table IFITM3 gene. In the homozygous model, the odds for severe influenza disease was multiplied by 2.68 (95% CI [1.22–5.88]) when having the C/C genotype as compared to the T/T genotype. Similar results were obtained in the allelic model, with an overall OR of 1.52 (95% CI [1.06–2.17]) for the rs12252-C allele compared to the rs12252-T allele, albeit with more heterogeneity across studies (I2 = 54%). Indeed, a stratified analysis by ethnicity revealed opposite effects in different populations: there was a 2.42-fold (95% CI [1.58–3.72]) increase in odds for severe influenza disease when having the rs12252-C allele within an Asian population, whereas the odds for severe influenza diseases when having the rs12252-C allele was decreased by 13% within a Caucasian population  , or  : the name of the first author, the country where the study was conducted, the year of publication, the study design (cohort or case-control), the sampling period, the setting, the patient selection criteria, the characteristics of the study population in terms of ethnicity and age groups, the influenza subtype(s), a description of cases and controls based on the severity, the genotyping method, and the SNPs/deletions/insertions and corresponding human genes that were investigated, number of eligible cases and controls, and the frequency of the alleles and genotype distributions for both the cases and controls. Genotype counts were extracted as raw numbers or were calculated from the reported percentages and total sample sizes. If the distribution of alleles was not given, it was calculated by genotype distribution. Some studies provided genotype distributions for more than one marker and were consequently represented with more than one data point in our database. Similarly, when multiple cases or control groups could be defined based on the severity within one study, they were either pooled or retained as multiple data points from the same study with a clear description of cases and controls in the data extraction. All data points were classified according to the study population and/or underlying definition of severity.p < 0.05 were downgraded to C in the CSI score.The Confounding-Selection-Information (CSI) bias score developed by Patarčić et al  was used2 statistic . The third score was fixed as C (weak credibility), given the high risk of bias in primary studies  and 95% confidence intervals (CI) were calculated anew from raw genotype and allele counts. Results from four different genetic models assuming different inheritance effects  were compared in order to provide broader insight into the underlying genetic architecture. In addition, a common OR and corresponding p-value based on the Armitage’s trend test was calculated [http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). A series of meta-analyses using four different genetic models  were performed for all markers where three or more data entries were available. For the purpose of the meta-analysis, the risk allele was uniformly defined for all data points based on literature, independently of the minor allele within individual studies. It was ensured that each data point in the meta-analysis represents an independent sample of data. When multiple cases or control groups were available in one study, the data point with the largest total sample size and/or focusing on severity  was considered for the main analysis. The presence of heterogeneity was assessed using the Cochran’s Q-test and quantified with the I2 metric. A random effects model for meta-analysis was used to calculate the overall OR with their 95% CI assuming differences in designs, severity definitions and ethnicity of individual studies. Peto’s method was used to pool odds ratios [The HWE was (re-)calculated for every control group of each included study using an exact test. A lculated , 76. Thes ratios . Stratifs ratios  were uses ratios .Additional file 1. Data extraction of the included studies in the systematic review of host genetic factors and influenza disease severity.Additional file 2. Results of the meta-analyses, leave-one-out analyses, and funnel plots for the association between the rs12252, rs333, rs1801274, and rs34481144 polymorphisms and influenza disease severity.Additional file 3. Search strategy using the MEDLINE and EMBASE databases, eligibility criteria, and risk of bias score to assess the quality of included studies for the systematic review and meta-analysis of host genetic factors and influenza disease severity.