Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS.Online electronic databases , and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software.P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores , and methylenetetrahydrofolate reductase (MTHFR) C677T genotype.Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups , registration number:  Ankylosing spondylitis (AS) is an immune-associated systemic inflammatory rheumatic disease characterized primarily by progressive inflammation of the spine, sacroiliitis, and various extra-articular manifestations such as anterior uveitis, inflammatory bowel disease, subclinical inflammation of the gut, psoriasis, airway disease, and interstitial lung abnormalities –6. IncreHomocysteine (HCY) is a sulfur-containing amino acid formed during the metabolism of methionine to cysteine . HCY levHCY could modify Human Leukocyte Antigens-B27 (HLA-B27) through forming a disulfide bond with an unpaired cysteine residue at position 67 (Cys67) of the HLA-B27 heavy chain , and subPrevious studies have shown both pro-inflammatory and anti-inflammatory properties of HCY –25. An aBased on the facts that AS is associated with increased cardiovascular morbidity and mortality, the high level of HCY is considered a well-known risk factor for cardiovascular disease , 8, it iWe performed electronic literature searches in PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data up to May 7, 2020 with keywords including Homocysteine, Hyperhomocysteinemia, Ankylosing, and Spondylitis.The article inclusion criteria were as follows: 1) a case-control or cross-sectional study; (2) based on adults; (3) AS patients must conform to the American College of Rheumatology (ACR) criteria  or Europ a case-cEach of the enrolled articles was extracted by two researchers independently for the following information: first author’s name, year of publication, study design, the language of the article, region, participants’ characteristics (age and gender), disease activity score  , diseaseQ statistics  were employed to evaluate statistical heterogeneity. The I-square (I2) statistics was used to further assess the extent of heterogeneity (I2 = ([Q − df]) × 100%) [I2 statistic between 0 and 40% as representing an insignificant amount of heterogeneity; 30 to 60% as moderate heterogeneity; 50 to 90% as substantial heterogeneity; and 75 to 100% as considerable heterogeneity [P < 0.05 for the Q test or I2 > 50, it indicated that heterogeneity was significant in the study. Assuming that the heterogeneity is significant, the random-effects model was adopted to pool the SMD value; or else, the fixed-effect model was adopted. Subgroup analysis was performed to discover the sources of heterogeneity. Sensitivity analysis was also executed to detect studies that extremely contributed to the observed heterogeneity. This was done by omitting each study one after the other to measure its impact on the summary estimate. To evaluate the publication bias, Egger’s and Begg’s tests were used. Stata 16 software was used in this meta-analysis to perform statistical analysis.The extracted results that were presented in median, standard error, range, and interquartile range were converted to mean and standard deviation (SD) , 48. The × 100%) . Based oOut of a total of 15 relevant studies found, 9 original studies met our inclusion criteria and were selected for this meta-analysis. These 9 studies were published between 2005 and 2020 and included 778 AS patients and 522 controls , 34–41. t = − 0.74, P = 0.48) and Begg’s test , suggesting no publication bias present. Among the enrolled studies, significant heterogeneity was observed . Sensitivity analysis by sequentially omitting individual studies did not significantly change the pooled results, suggesting that these results were stable . There were no significant differences in circulating HCY levels between AS patients and controls  . In anti-TNF-α treatment subgroup, HCY levels in AS patients were significantly lower than in controls . Meanwhile, no significant differences of HCY levels between AS patients and controls were detected in NSAIDs or SSZ treatment subgroup. In particular, no significant correlation between HCY levels and disease activity, and MTHFR C677T genotype, as well as in region, sample size, and smoking subgroups was detected.The random-effect model was used for the analysis of results in this study based on the result that significant heterogeneity was observed among the enrolled studies , such as higher disease activity  and highn = 198) [SSZ has also been reported to have anti-folate properties , implyinn = 198) , 40. TheHCY levels are known to be controlled by methylenetetrahydrofolate reductase (MTHFR), which is a key enzyme in HCY metabolism . MTHFR CAs a well-known risk factor for cardiovascular disease, HCY can mediate the development of the cardiovascular disease by acting adversely on vascular endothelium and smooth muscle cells . ElevateTo our knowledge, this is the first meta-analysis that provides evidence of HCY levels in AS patients compared with controls. We are able to extract valid and accurate results from the individual articles and use a sample size of 778 patients of AS and 522 of controls for HCY levels to increase the statistical power and resolution of our analysis compared with the individual studies. However, several limitations are recognized. First, the significant heterogeneity in our meta-analysis may restrict the generalization of the pooled result. Second, due to the lack of sufficient data to perform more exhaustive subgroup analysis and meta-regression, the origin of heterogeneity could not be fully revealed.This meta-analysis suggests that HCY may partially participate in the pathogenesis of AS, although it is not a major contributing factor. Further and larger studies are needed to confirm these findings.


P=0.00), recessive model , homozygote comparison  or heterozygote comparison (AG versus GG)  of CR1 rs6656401A/G. For CR1 rs3818361T/C, a statistical difference was observed in the dominant model , recessive model , homozygote comparison  or heterozygote comparison (TC versus CC) . In summary, despite some limitations, the present meta-analysis indicated that rs6656401A/G or rs3818361T/C polymorphism was related to SAD risk. Moreover, a carrier of rs6656401A/G or T carrier of rs3818361T/C in CR1 genetic polymorphism might be an increased factor for SAD in Caucasians.Complement receptor 1 (CR1) plays an important role in the development of sporadic Alzheimer’s disease (SAD) in Caucasians. However, the influence of CR1 (rs6656401A/G and rs3818361T/C) genetic polymorphisms on the risk of SAD remains controversial. A meta-analysis of 18 case–control studies was performed to derive a more precise association of CR1 (rs6656401A/G or rs3818361T/C) genetic polymorphism with the risk of SAD in Caucasians. A statistical difference was found in the dominant model (odds ratio (OR): 1.23, 95% confidence interval (CI): 1.16–1.30,  Alzheimer’s disease (AD) is the most common neurodegenerative disease causing progressive memory impairment and cognitive dysfunction among elderly people ,2. The pComplement receptor 1 (CR1), located on chromosome 1q32, is a receptor for the complement component (3b/4b) ,8, and iHowever, some studies reported the vast majority of CR1 is detected in the peripheral erythrocytes and not in human brain . And CR1The Medline, Embase and HuGHESNet electronic databases were searched to identify all eligible articles before March 2019 that were conducted on human subjects, without language restriction. The combinations of the following Medical Subject Heading (MESH) terms and text words were adopted: (‘Alzheimer’s disease’ or ‘AD’) and (‘Complement receptor 1’ or ‘CR1’) and (‘polymorphism’ or ‘mutation’ or ‘genes’). The references of all relevant studies were also reviewed for additional relevant publications.The inclusion criteria were: (i) SAD was clinically diagnosed ,34, (ii)All studies were independently reviewed by two investigators (Lingling Du and Pingping Ge), and discrepancies were resolved by discussions. The following characteristics of eligible studies were extracted: first author, year of publication, country, genotyping method, ethnicity and clinical characteristics . The quality evaluation score was calculated based on the Newcastle–Ottawa Scale (NOS) .P≤0.1 considered as significant). Any study in which the genotype distribution was not in accordance with HWE was excluded.The genotype distribution of the control population in eligible studies was tested for deviation from the Hardy–Weinberg equilibrium (HWE) using the chi-square test (with 2I statistic (P>0.10 was considered representative of homogeneity). The significance of odds ratio (OR) and 95% confidence interval (CI) were determined based on the fixed-effect model (Mantel–Haenszel method) (heterogeneityP>0.10) [P≤0.05 was considered statistically significant.The heterogeneity among the studies was evaluated with Cochran’s Q and the ty>0.10) . Otherwity>0.10) . Five diP≤0.10 was considered statistically significant). Individual studies were sequentially removed to explore the influence of each individual study on the pooled OR and the stability of the combined results.The visual Begg’s funnel plot and the Egger’s linear regression test  were utiA total of 196 studies were identified based on a comprehensive search of databases and other sources. A total of 104 duplicated or non-relevant studies were removed after the primary screening. Based on further screening of the title or abstract, 50 studies were excluded . After a detailed full-text review for eligibility, seven studies with other CR1 variants, seven articles with insufficient data, three studies of Asian descendants, and eleven studies with no controls were excluded. Finally, 12 studies pertaining to CR1 (rs6656401A/G and rs3818361T/C) polymorphisms and SAD risk were included ,39–42. IThere were 10704/12360 (rs6656401A/G) cases/controls or 4740/8495 (rs3818361T/C) cases/controls included in this meta-analysis. Non-dementia, age- and sex-matched controls were included in most studies ,39–41. DP=0.00 (P=0.02 (P=0.002) (P=0.00) , (AA ve (P=0.02 ), (AA veP=0.002)  or (AG v(P=0.00) . These iP=0.00, TT versus (TC+CC): OR = 1.28, 95% CI: 1.07–1.53, P=0.006, TT versus CC: OR = 1.35, 95% CI: 1.13–1.62, P=0.001 or TC versus CC: OR = 1.20, 95% CI: 1.11–1.29, P=0.00). So, T carrier of rs3818361T/C might be an increased factor for SAD risk  versus GG, AA versus (AG+GG), AA versus GG, AA versus AG and AG versus GG) A–E and rP=0.875; AA versus (AG+GG), t = 0.84, P=0.417; AA versus GG, t = 0.80, P=0.442; AA versus AG, t = 0.92, P=0.379; and AG versus GG, t = −0.61, P=0.557) and rs3818361T/C genetic models ((TT+TC) versus CC, t = 0.59, P=0.597 and TC versus CC, t = −0.08, P=0.943). However, a statistic difference was found in rs3818361T/C genetic model (TT versus (TC+CC), t = 2.94, P=0.061; TT versus CC, t = 2.77, P=0.069; and TT versus TC, t = 3.34, P=0.044).The shape of the Begg’s funnel plots in genetic models seemed nearly symmetrical, indicating that no evidences for obvious publication bias were exhibited A–E. BaseLonger alleles of CR1 were found to be risk factors for the development of AD, based on the excessive inhibition of C3b or C4b and the decrease in C3b-mediated opsonization of the amyloid b42 (Ab42) peptide ,24,43. TP<0.009) [P=3.7 × 10−9 for combined data) [In a genome-wide association study, Lambert et al. found the SNPs of CR1, rs6656401A/G and rs3818361T/C, in AD patients . AnotherP<0.009) . An assoP<0.009) . In the ed data) .P=0.012) [I2  showed that the proportion of interstudy variability contributed to low heterogeneity. In addition, the results of sensitivity analysis based on the sequential removal of individual studies showed that no study had any effect on the pooled results in the above three models. So, the pooled results of the above three models were stable and credible.A prevalence study between 428 AD cases and 524 controls implicated a significant association of rs6656401A/G or rs3818361T/C with AD risk . Keenan P=0.012) . Other sP=0.012) ,27,31,54P=0.012) . These fP=0.012) . KlimkowP=0.012) . Hence, The current meta-analysis had some limitations. First, the sample size of included studies was small, which might contribute to possible limited strength of the statistics. However, the latest high quality studies (NOS score > 5), which met our stringent selection criteria, were included in the meta-analysis. Second, SAD has complex etiopathogenesis, and the gene–gene and gene–environment relationships were not analyzed due to lack of original data. Larger sample studies with multifactorial etiology should be conducted in the future. Finally, a possible publication bias might be explored by the results of the Egger’s linear regression test in rs3818361T/C genetic models (TT versus (TC+CC), TT versus CC and TT versus TC), it is possible that relevant unpublished articles with null results were not included. Although the shape of the visual Begg’s funnel plot appeared to be approximately symmetrical and the results of sensitivity analysis suggest these analysis models are stable and reliable, the results of rs3818361T/C should be applied with caution.Despite these limitations, the current meta-analysis suggested that the CR1 rs6656401 A/G or rs3818361T/C polymorphism might be a risk factor for SAD. The rs6656401 A/G or rs3818361T/C genetic polymorphism plays an important role in the development of SAD. A carrier of rs6656401A/G or T carrier of rs3818361T/C CR1 genetic polymorphism might be an increased factor for SAD.


PTPN22 [protein tyrosine phosphatase non-receptor type 22]-C1858T) might be related to increased sensibility to Mycobacterium tuberculosis and M. leprae infection. However, the results were inconclusive despite a high degree of similarity between both parameters. Herein, we carried out this meta-analysis to systematically summarize and articulate the correlation between PTPN22-C1858T polymorphism and mycobacterial infection. The susceptibility of PTPN22-C1858T carriers with autoimmune conditions receiving immunosuppressive therapy to M. tuberculosis and M. leprae infection was determined. A systematic retrieval of studies on relevance of PTPN22-C1858T polymorphism to susceptibility of M. tuberculosis or M. leprae infection was performed in Chinese National Knowledge Infrastructure, PubMed and Embase databases. We regarded Odds ratios (ORs) and 95% confidence intervals (CIs) as the determined effect size. Finally, four and two case-control studies on tuberculosis and leprosy, respectively, were included. In all genetic models, without indicated association between PTPN22-C1858T polymorphism and tuberculosis’s susceptibility. . A significantly increased risk of leprosy was perceived in patients with the PTPN22-C1858T polymorphism [C versus T: OR = 2.82 ]. While the PTPN22-C1858T polymorphism is irrelevant to higher susceptibility to the infection of M. tuberculosis in Caucasians and Asians, it is relevant to increased susceptibility to the infection of M. leprae. However, the results of M. leprae are supposed to interpreted with prudence owing to the limited quantity of studies and heterogeneity. Further well-designed studies with sufficient populations are required to verify our conclusions.It was previously published that single-nucleotide polymorphism rs2476601 ( Worldwide, tuberculosis is one of the principal lethal causes, ranking above human immunodeficiency virus infection/acquired immunodeficiency syndrome. Despite being a preventable and curable disease, the annual number of people died from tuberculosis is 1.5 million approximately. . By receMycobacterium tuberculosis and occasionally by other components of M. tuberculosis complex, and Mycobacterium leprae result in leprosy. M. tuberculosis and M. leprae are obligate pathogens with a similar morphology and high cell wall lipid content, which is responsible for their increased chromaticity, resistance, and pathogenicity. Moreover, these mycobacteria can cause chronic granuloma in most infected individuals.Tuberculosis and leprosy are caused by mycobacteria . In humaPTPN22) gene encodes the protein lymphoid tyrosine phosphatase (LYP), which regulates the activation of protein kinases to modulate intracellular tyrosine phosphorylation incidence and induce various biological effects. PTPN22-C1858T is the most talked about single-nucleotide polymorphism (SNP) in the field of autoimmunity , PubMed and Embase databases independently and systematically, which were updated on April 15, 2020. Retrieved items including “tuberculosis or (pulmonary tuberculosis) or (mycobacterium tuberculosis) or (tubercle bacillus) or (tubercle bacillus) or mtb)”, “leprosy or (leprosy bacillus) or (mycobacterium leprae) or (mycogerms leprae) or (wholemycobacterium leprae)”, “PTPN22 OR LYP”, “polymorphism OR poly-morphism” and susceptibility” were searched in the National Institutes of Health (PubMed) and European (Embase) databases without limitation. The key words “PTPN22基因多态性” and “结核” were searched in the CNKI database. The references in retrieved studies and related reviews were also under reviewing by two investigators without communications.PTPN22 polymorphisms and infection susceptibility were electronically retrieved. Thereafter, case-control studies were identified from their titles and abstracts. The full article of manuscripts fulfilled the inclusion criteria was perused. Inclusion criteria were as follows: (a) studies associated between PTPN22 polymorphisms and infection susceptibility; (b) the category of the study is case-control study among human; (c) original research with detailed explanation of the sample size; (d) with odds ratios (ORs) and its corresponding 95% confidence intervals (CIs); (e) with clear determination of genotype frequency; (f) genotype distribution in controls complying with Hardy-Weinberg equilibrium (HWE) law. Excluding criteria were as follows: (a) non-conformance to the inclusion criteria; (b) article type: abstract, review, comment, and letter; (c) studies with insufficient or no explanation of the sample size; (d) studies without genotype data; (e) repeated publications; (f) family-based studies. If several studies were with same population, the larger one will be included. According to the inclusion criteria and excluding criteria, two investigators screened out eligible literatures independently through titles, abstracts, and full-texts. We settled all dissents through discussion. The third researcher was consulted in the absence of an agreement. Finally, two studies were discussed and excluded after our discussions.All studies pertaining to PTPN22-C1858T genotype frequency and HWE. Therein, populations from all included studies were classified into two ethnic: Caucasians and Asians. Two investigators verified the withdrawn data and achieved agreements on the conclusive data. In the case of a disagreement, the original data was re-verified and re-discussed to reach consensus. If disagreements are still subsistent, we consulted for final judgement from a third investigator. In the end, a study was discussed through third investigator.Two investigators withdrawn the data from all included studies independently. The extracted data included the name of first author, year of publication, subject resource, ethnicity, infectious type, diagnostic criteria for infection, genotyping method, number of participants in the control and case groups, cases’ and controls’ characteristics, all subjects’ The Newcastle-Ottawa Scale (NOS) was applied to assess the quality of six eligible studies in meta-analysis by two independent investigators  (MethodsP < 0.05 was significant). ORs and its corresponding 95% CI is was applied to determine the extent of correlation between PTPN22-C1858T polymorphism and susceptibility to mycobacterial infection. We calculated the pooled ORs in allelic comparison (PTPN22: C versus T), the heterozygote model (PTPN22: CT versus CC), and the dominant model (PTPN22: CT+TT versus CC). P < 0.05 was significant according to Z-test. Heterogeneity was assessed by Q test (P < 0.1 was significant) and I-squared statistic  (P < 0.1 was considered significant) with pathogen (M. tuberculosis and M. leprae) and ethnicity and subgroup analysis stratified by pathogen and ethnicity. No deviation from HWE was shown among controls in all included studies, which are used for further meta-analysis. Additionally, we assessed publication bias by Begg’s funnel plots . Except for certain conditions defined a specific P value, a two-tailed P value < 0.05 was regarded as significant.The PRISMA checklist was followed throughout the course of this meta-analysis strictly. . The HWEnalysis) . Heterogel plots . An asymPTPN22, one was not related to tuberculosis or lepriasis, and two were not case-control studies. Finally, six case-control studies  polymorphism with M. tuberculosis and M. leprae infection is shown in  studies , 25–27 cPTPN22-C1858T polymorphism associates susceptibility to mycobacterial infection. After Q-test and I-squared statistics in various genetic models, it indicated significant heterogeneity. Therefore, we used the random-effects model in meta-analysis. No genetic model showed correlation between PTPN22-C1858T polymorphism and increased susceptibility to mycobacterial infection  ; CT versus CC: OR = 1.03 ; CT+TT versus CC: OR = 1.03 ] ; CT versus CC: OR = 1.03 ; CT+TT versus CC: OR = 1.03 ] (We explored that = 0.000) Figure 2PTPN22-C1858T polymorphism and M. tuberculosis infection in our included studies of M. tuberculosis infection. There was no genetic model supported significant correlation between PTPN22-C1858T polymorphism and increased possibility to M. tuberculosis infection  ] Table 2.M. tuberculosis infection on the four included studies according to ethnicity  (H = 0.474); TT+CT versus CC: OR = 0.21 ]  (H = 0.733); TT+CT versus CC: OR = 0.21 ] ] Table 2.PTPN22-C1858T polymorphism and increased possibility to M. leprae infection in Caucasian and Asian populations was investigated in two studies (P = 0.108 and I-squared = 61.2%) ] ] and dominant models [TT/CT versus CC: OR = 2.91 ] ] Table 2.M. tuberculosis/M. leprae) was able to account for the heterogeneity of the associations between mycobacterial infections and PTPN22-C1858T polymorphism.Ethnicity and pathogen were included in meta-regression model for heterogeneity analysis. The coefficient of ethnicity is -0.060 (P = 0.955) and the coefficient of pathogen is 2.560 (P = 0.060) in all patients with Mycobacterial infection Table 3,P = 0.734) or leprosy (P = 1.000) was reflected in Begg’s funnel plot. Meanwhile, we obtained a symmetrical funnel plots  might be related to raised susceptibility to tuberculosis. One study showed 788A allele was with higher frequency of in Moroccan patients with tuberculosis than in healthy donors  ] .PTPN22-C1858T polymorphism-induced immune dysregulation on delayed-type hypersensitivity of tuberculosis and leprosy has been extensively studied. Herein, we discussed the relevance of PTPN22-C1858T polymorphism and increased risk of tuberculosis and leprosy in humans  and promote type I IFN-dependent biological effects, causing immune cells to trigger a host defense response. In contrast, PTPN22-C1858T carriers show decreased TRAF3 K63-linked polyubiquitination and type I IFN production    might haPTPN22-C1858T polymorphism was uncorrelated with raised susceptibility to M. tuberculosis in Caucasians and Asians. In contrast, PTPN22-C1858T polymorphism related to increased susceptibility to M. leprae infection. However, the results of M. leprae are supposed to interpreted with. Further well-designed studies with sufficient populations are required to verify our conclusions.In conclusion, we manifested that this The original contributions presented in the study are included in the article/YC and SL conceived the topic and analyzed data. SL wrote this manuscript and YC modified it. JY provided statistical suggestions. SL and YZ evaluated the quality of the six included studies. SL, YZ, XW, and TC searched references.Y, ZJZ, and ZZ provided the overall direction of series studies and funding support. All authors contributed to the article and approved the submitted version.This work was supported by the 100 Top Talents Program of Sun Yat-sen University, National Natural Science Foundation of China , the Shenzhen Science and Technology Innovation Committee of Guangdong Province of China (Grant No. JSGG20180703155802047), and the Shenzhen Science and Technology Innovation Committee of Guangdong Province of China (Grant No. JCYJ20180307150634856).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.


To investigate the association between exposure to general anesthesia and the development of Alzheimer's disease (AD) and dementia by reviewing and integrating the evidence from epidemiological studies published to date.  We searched MEDLINE, EMBASE, and Google Scholar to identify all relevant articles up to April 2018 reporting the risk of AD/dementia following exposure to general anesthesia and finally updated in February 2020. We included patients older than 60 or 65 years who had not been diagnosed with dementia or AD before the study period. The overall pooled effect size (ES) was evaluated with a random-effect model. Subgroup analyses were conducted and possibility of publication bias was assessed. pχ2 < 0.001, I2 = 79.4). Although the overall analysis revealed a significant association, the results of the subgroup analyses were inconsistent, and the possibility of publication bias was detected.  A total of 23 studies with 412253 patients were included in our analysis. A statistically significant positive association between exposure to general anesthesia and the occurrence of AD was detected in the overall analysis , but with substantial heterogeneity (Trial registration. PROSPERO International prospective register of systematic reviews CRD42017073790.s. This meta-analysis demonstrated a significant positive association between general anesthesia and AD. However, considering other results, our meta-analysis must be interpreted with caution. Particularly, it should be considered that it was nearly impossible to discriminate the influence of general anesthesia from the effect of surgery itself on the development of AD. Further, large-scale studies devised to reduce the risk of bias are needed to elucidate the evidence of association between general anesthesia and AD.  With the development of medical technology and healthcare systems, life expectancy has increased worldwide. Accordingly, the number of surgeries performed in elderly patients has also been increasing . HoweverDementia is a progressive neurodegenerative disease characterized by multiple cognitive impairments that represent a decline from one's previous level of functioning. The global prevalence rate of dementia in people over the age of 60 ranges from 5–7%, and increases rapidly with age, to 20% in people over the age of 85 years , and it Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 60–80% of dementia cases . HoweverPrevious studies have suggested advanced age, female sex, family history of AD, cardiovascular disease, head trauma, depression, and lower educational level as potential risk factors , 14, 15.There have been several attempts to integrate the evidence from various epidemiological studies, such as the reanalysis of eight case-control studies  and two CRD42017073790) and published in a peer-reviewed journal [The protocol for this review has been registered in the PROSPERO network  the elderly (defined as more than 60 or 65 years old) from all countries and (2) those who had not been diagnosed with dementia or AD before the beginning of the study period. If the study's definition of the elderly was other than being older than 60 or 65 years of age, an attempt was made to contact the study authors to obtain the relevant information. When unsuccessful, we performed a pooled analysis including the data of that study first, and then, we performed a sensitivity analysis excluding the data. No restrictions were applied in terms of sex, race/ethnicity, or socioeconomic status.Exposure to general anesthesia for surgery, usually using inhalation anesthetics, was included. Intravenous anesthesia, spinal anesthesia, epidural anesthesia, and regional anesthesia were excluded. If an article reported on general anesthesia including intravenous, spinal, epidural, or regional anesthesia along with inhalation anesthesia, we tried to contact the study authors to obtain information on general anesthesia using inhalation anesthetics. When unsuccessful, we first analyzed the data on general anesthesia, including intravenous, spinal, epidural, or regional anesthesia, and then we performed sensitivity analysis excluding the data. The source of exposure assessment was also collected.Comparison groups included individuals with no history of general anesthesia. If a study only reported previous anesthesia history during the study period, we tried to contact the study authors for further information about previous anesthesia history prior to the study period. When unsuccessful, the reported information was used for our analysis. If a study investigated the associations of AD and general anesthesia using two or more comparison groups and reported each outcome separately, pooled estimates of associations for these groups were calculated and used for analysis.To cover as many AD cases as possible, we included not only AD cases but also dementia cases, of which AD cases comprise the largest portion, diagnosed by standard criteria such as the DSM or clinically diagnosed by a professional physician. Studies reporting effect size (ES) as odds ratio (OR), relative risk (RR), or hazard ratio (HR) of dementia/AD to general anesthesia exposure were included. In some studies, which reported only the number of individuals with and without AD instead of ES, we obtained the ES by calculation from the data provided. When the study reported only dementia cases without distinguishing AD –28, we aReference lists obtained as described above were imported into Endnote software , and duplicate articles were removed. The titles and abstracts identified through the search strategy were scanned independently by two investigators. To minimize data duplication as a result of multiple reporting, papers from the same author were compared. For reports determined to be eligible based on the title or abstract, the full paper was retrieved. Potentially relevant studies chosen by at least one investigator were retrieved and evaluated in full-text versions. Articles meeting the inclusion criteria were assessed separately by two investigators, and any discrepancies were resolved through discussion. In cases where agreement could not be reached, the disputes were resolved with the help of a third investigator.Using a standardized extraction form, the following data were extracted independently by two reviewers: study name ; region where the study was conducted; study design; source from which subjects were selected; age of subjects; exposure definition; method of data collection ; outcome definition; ES such as OR, RR, and HR with 95% confidence intervals (CIs); methods for controlling covariates and the confounding variables controlled for; number of cases/controls or cohort groups; and total number of participants. If information was missing, an attempt was made to contact the study authors to obtain the relevant information. When unsuccessful, missing information was calculated if possible from the relevant data in the study. As the ES was not reported or needed to be integrated because of the multiple groups, it was calculated in six studies , 29–31 uThe quality of the studies was independently assessed by two investigators using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) . The quaAll statistical analyses were performed using Stata SE version 15.0 .Q and Higgins's I2 statistics [p value of <0.10 for the χ2 statistic or an I2 greater than 50% was considered as showing heterogeneity, and data were analyzed using the Mantel–Haenszel random-effect model. Otherwise, we applied the Mantel–Haenszel fixed-effect model [Overall pooled ES and its corresponding 95% CI and 95% prediction interval were computed. Between-study heterogeneity was assessed using the Cochran's atistics . A p valct model .Subgroup analysis was carried out based on study design (case-control vs. cohort study), region of the study population, exposure assessment , outcome definition (AD vs. dementia), and method of case ascertainment .We conducted sensitivity analyses to evaluate the influence of individual studies on the overall effect estimate by excluding one study at a time from the analysis.p value < 0.1 from Egger's test was considered to indicate the presence of publication bias. If publication bias was detected, trim and fill analysis was performed.Publication bias was assessed by using contour-enhanced funnel plots and Egger's test . An asymn = 8), we reviewed the remaining articles (n = 2776); 2730 of the articles did not meet the selection criteria. The remaining 46 articles were selected for review of their whole content. The kappa value for selecting articles between the two reviewers was 0.756.A total of 2784 articles were obtained after searching the databases and references and through the manual search . After eOf the 46 studies selected for review of their whole content, 23 were excluded for the following reasons: One was a conference proceeding , 9 were The study characteristics are summarized in Overall risks of bias evaluated using the RoBANS are shown in Q test and I2 statistics suggested substantial heterogeneity  . However, results of the  = 79.4) . 95% preAs the heterogeneity for ES was considerable, metaregression was conducted to determine the origin of heterogeneity. According to metaregression, the study design, region, exposure assessment, case ascertainment, definition of dementia or AD, and year of publication were not likely to be a source of heterogeneity .pχ2 < 0.001, I2 = 88.5) and case-control studies  showed a significantly higher risk of AD in people who had been exposed to general anesthesia, but with substantial heterogeneity . However, negative association was detected from the subgroup of studies based on self- or surrogate-reported data   .pχ2 < 0.001, I2 = 90.6), but with considerable heterogeneity. However, the pooled ES among the studies with an outcome definition limited to only AD suggested decreased risk of AD in patients with general anesthesia exposure   .pχ2 < 0.001, I2 = 81.2). In contrast, an inversely negative association was observed among the studies using standard diagnostic criteria   .Sensitivity analysis was performed by excluding one study at a time; no change in statistical significance occurred.p = 0.096) and case-control studies   . Therefo= 0.088) .The effect of general anesthetics, especially inhalation agents, on neurocognitive function is currently controversial; it is unknown whether general anesthetics are neurotoxic or neuroprotective . RegardiNotably, this outcome was contrary to the results of two previous meta-analyses , 21 and Given the various designs and methods used in the involved studies, we performed subgroup analyses to better understand the results of our meta-analysis. In the subgroup analysis based on exposure assessment, an increased risk of AD following exposure to general anesthesia was observed in studies using medical records. Because medical records are more objective and reliable data source than self-reported data collected through interview, this result enhances the validity of the positive association between general anesthesia and AD observed in overall analysis. In addition, as shown in However, according to the subgroup analysis based on case ascertainment, a negative association was observed in studies using standard criteria. Standard criteria are usually considered more reliable diagnostic tool because it is less likely to involve physician's subjectivity compared to clinical diagnosis. This finding suggests that the results of the overall analysis must be interpreted with caution.Considering that AD cases comprise the largest portion of dementia cases (60–80% in one study) , and curOne of the factors important in outcome assessment is lag time, which means the latency period before the diagnosis of disease. In studies without including the lag time, the patients with incidental dementia not severe enough to be diagnosed may be misinterpreted as having dementia caused by general anesthesia exposure. As highlighted in the meta-analysis conducted to verify the association between dementia and benzodiazepine which was published in 2018 , analysiTherefore, although a significant association between general anesthesia exposure and AD was observed, the results of this meta-analysis should be interpreted with caution. The possibility of publication bias was demonstrated by contour-enhanced funnel plots and Egger's test. The statistical significance disappeared after trim and fill analysis. In addition, the 95% prediction interval computed from overall studies implied that any future study could alter the statistical significance of association between general anesthesia and AD. These findings support the need for prudence to properly interpret the results of this meta-analysis.Our study has some limitations. First, substantial heterogeneity was observed among the included studies. Although various approaches were attempted to reveal the origin of heterogeneity, they were not successful. Second, because of insufficient details on the context of anesthesia including number of exposure, the agent used for induction and maintenance, dose and duration of exposure, and intraoperative events or perioperative complications such as hemodynamic instability and hypoxia, we could not conduct analysis adjusting for these variables. Moreover, surgery itself might contribute to an increased risk of AD. Although there are no data on the risk of AD, high-risk surgeries such as cardiac surgery have been reported as raising the risk of cognitive impairment such as delirium and postoperative cognitive dysfunction , 68. HowAccording to the limitations discussed, additional well-designed studies are necessary to clarify the relationship between general anesthesia and dementia or AD. Future studies are recommended to be conducted with the following considerations: large-scale study with adequate statistical power; prospective cohort studies with long-term follow-up including lag time, ensuring the subjects free of dementia before exposure of anesthesia; using reliable data source such as medical records; reporting sufficient details on the characteristics of exposure such as number of exposure, agents, and doses used; adequate adjustments for confounding variables; and outcome assessment with standard diagnostic tool of dementia. Recent review published by American scholars reported a wide variety of diagnostic methods for dementia used in large cohort studies, while emphasizing the need for the development of well-described and reproducible methods for diagnosing dementia in epidemiologic studies . We beliDespite the limitations above, our systematic review and meta-analysis demonstrate the strengths of a rigorous methodology based on a published, preplanned protocol to provide evidence of the relationship between general anesthesia exposure and risk of AD. Furthermore, our study has a value of suggesting general anesthesia exposure as a potential risk factor of AD and raising the necessity of further related studies for better management of the elderly. Recently, there was a meta-analysis reported the significantly high mortality rates of the patients with dementia after undergoing hip fracture surgery, emphasizing the importance of perioperative care for dementia . AlthougIn conclusion, we observed a significant association between exposure to general anesthesia and an increased risk of AD. However, considering the substantial heterogeneity, evidence of publication bias, and inconsistent results of the subgroup analyses, the results of our meta-analysis should be interpreted with caution. Moreover, it was nearly impossible to discriminate the influence of general anesthesia from the effect of surgery itself on the development of AD. Further, large-scale prospective cohort studies designed to reduce the risk of bias considering lag time, using standardized methods and reliable data with adequate adjustments of confounding factors, are needed to elucidate the evidence of an association between general anesthesia and AD.


Arteriosclerosis has genetic correlation. Many studies have shown that angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism is highly associated with arteriosclerosis, but there is no evidence-based basis. The purpose of this study is to systematically evaluate the relationship between AT1R gene A1166C polymorphism and arteriosclerosis.The search time is set from the establishment of the database in December 2020 in this study. The search database include China National Knowledge Infrastructure (CNKI), Wanfang, VIP and China Biology Medicine disc (CBM), PubMed, EMBASE, Web of Science, and the Cochrane Library. The subjects are observational studies on the relationship between AGTR1 A1166C polymorphism and arteriosclerosis . The language is limited to English and Chinese. The data of the included study are extracted and the literature quality is evaluated by 2 researchers independently. The data are statistically analyzed by Stata 16.0 software.This study will use pulse wave velocity as an index to evaluate arteriosclerosis to explore the relationship between AT1R gene A1166C polymorphism and arteriosclerosis.This study will provide evidence-based medicine for elucidating the genetic tendency of arteriosclerosis.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.DOI 10.17605/OSF.IO/V6E2Y It is found that genetic factors play an important role in the occurrence and development of arteriosclerosis, which is not affected by blood pressure, heart rate, body weight, age, and other cardiovascular risk factors. Exploring the factors that affect the rhythm of arterial aging can help identify people who are at increased risk of cardiovascular disease.Arteriosclerosis is an independent risk factor for cardiovascular events. It is the earliest clinical monitoring of vascular wall structure and functional changes. AT1R gene is located at 3q21-25, including 5 exons and 4 introns. AT1R A1166C polymorphism is located in the 3 ’non-transcribed region of the gene, which can interact with miR-155 and affect the expression of AT1R.,6 Renin-angiotensin system plays an important role in regulating cell growth and differentiation, endothelial function, and cardiovascular homeostasis. Angiotensin receptor gene polymorphisms are widespread in the population. AT1R gene A1166C polymorphism (AGTR1 A1166C polymorphism) is due to the AT1R gene (located on the long arm of chromosome 3) 3’ the 1166th nucleotide in the noncoding region of the’ end was replaced by A-C.Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor, which mediates the physiological effects of vasomotor, water and salt metabolism, vascular smooth muscle cell proliferation and functional regulation, and is an important link in the role of angiotensin II. there have been a number of studies to explore the relationship between AGTR1 A1166C polymorphism and arteriosclerosis.,9,10 However, due to differences in sample size, test efficiency, gene or environmental background, the results are not consistent. Therefore, we adopt the method of meta-analysis to comprehensively analyze the existing data, in order to provide evidence-based medical evidence for elucidating the genetic tendency of arteriosclerosis.Since the emergence of the first study in 1996 on the effects of angiotensin converting enzyme and AT1R gene polymorphism on normal blood pressure and aortic sclerosis in patients with hypertension,22.1 Moreover, it has been registered on open science framework (OSF) on December 24, 2020 (Registration number: DOI 10.17605/OSF.IO/V6E2Y).This protocol of systematic review and meta-analysis has been drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P).2.2Since the program does not require the recruitment of patients and the collection of personal information, it does not require the approval of the Ethics Committee.2.3(1)The study evaluates the relationship between the AGTR1 A1166C polymorphism and arteriosclerosis;(2)The study is an observational study ;(3)The evaluation index of arteriosclerosis in the study is pulse wave velocity (PWV);(4)Allele or genotype distribution frequency data is available;(5)The distribution frequency of genotype conforms to Hardy-Weinberg's law.2.4(1)Repeated published research;(2)Articles in which the published literature is an abstract or review, the data of the article are incomplete or incorrect, and the complete data cannot be obtained after contacting the author;(3)The study on the failure to provide detailed data on the frequency of genotypes;(4)Literature without relevant outcome indicators;(5)The objects of studying are not from human beings.2.5Use “Angiotensin II type 1 receptor,” “Gene Polymorphism,” and “Arteriosclerosis” as Chinese search words in Chinese database, including CNKI, Wanfang data knowledge Service platform, VIP Chinese Journal Service platform (VIP), and China Biology Medicine disc (CBM). The English words “Angiotensin II type 1 receptor,” “AGTR1,” “Polymorphism,” “variant,” “arterial stiffness,” and so on will be searched in the English database, including PubMed, EMBASE, Web of Science, and the Cochrane Library. All the literature about the relationship between AGTR1 A1166C polymorphism and arteriosclerosis will be collected from the establishment of the database in December 2020. Take PubMed as an example, the retrieval strategy is shown in Table 2.6Two researchers independently complete the literature screening, exclude the studies that obviously do not meet the inclusion criteria, and further read the abstract and the full text to determine whether they meet the inclusion criteria. The data included in the literature will be extracted and cross-checked. In case of disagreement, consult with the third researcher and reach a consensus. The extracted data include: the first author, the number of years of publication, the country of publication, the race of the study population, the basic characteristics of the study population , the distribution of each phenotype of genes (whether obeying the law of Hardy- Weinberg equilibrium), the results of PWV and so on. The literature screening process is shown in Figure 2.7 including 3 columns and 8 items with a total of 9 points, and the evaluation criteria is ≥6 as high quality, while the cross-sectional study is evaluated with 11 standard items recommended by the Agency for Healthcare Research and Quality (AHRQ) to evaluate the cross-sectional study. Zero to three are classified as low quality, 4 to 7 as medium quality, 8 to 11 as high quality.The case-control study and cohort study will be evaluated by Newcastle-Ottawa Scale (NOS),2.82.8.12 will be used to test whether the genotype distribution in the control group is in accordance with Hardy-Weinberg genetic equilibrium (P ≥ . 05). Meta-analysis is carried out by using STATA.16 software, continuous variables will be expressed in the form of standard mean deviation and 95% confidence interval, the binary classification variables will be expressed as odds ratio and 95% confidence interval. Heterogeneity is analyzed by Q test and I2, and the heterogeneity is evaluated according to the I2 value. If P > .1, I2 < 50%, the heterogeneity among the included studies is small, so the fixed effect model is used for analysis; if P < .1 and I2≥ 50%, the heterogeneity between the included studies is obvious, and the sources of heterogeneity are analyzed. Random effect model will be used for analysis.Before evaluating the correlation between gene polymorphism and arteriosclerosis, χ2.8.2If the data of the required study are incomplete or not reported in the study, the researcher will contact the first author or other authors of the study by phone or email. If the required data are not available, we will use descriptive analysis instead of meta-analysis and exclude these studies if necessary.2.8.3In order to deal with the heterogeneity between different studies, subgroup analyses will be conducted according to ethnicity  and populations .2.8.4In order to test the stability of the meta-analysis results, we will use the one-by-one exclusion method to analyze the sensitivity of the results through Stata 16.0.2.8.5P < . 05, it is considered to have obvious publication bias.We will use a funnel chart to qualitatively identify publication bias, and use Egger and Begg tests to quantitatively evaluate publication bias. If the funnel diagram is asymmetrical and 2.8.6 The evaluation content includes bias risk, indirectness, inconsistency, inaccuracy and publication bias, and the quality of evidence will be rated as high, medium, low, or very low.For research that can realize meta-analysis, we will use Grading of Recommendation Assessment, Development, and Evaluation (GRADE) scoring method to grade the evidence of the outcome index.3 Studies have shown that the degree of arteriosclerosis is directly related to the severity of left ventricular insufficiency and can be used as an independent predictor of left ventricular diastolic function.,17 As an independent risk factor for cardiovascular events, the risk assessment of cardiovascular events is of great significance for early diagnosis, treatment, and primary prevention of cardiovascular events.Atherosclerosis can increase cardiac afterload, reduce coronary artery perfusion, cause mechanical fatigue of the arterial wall, lead to leaving ventricular hypertrophy, myocardial ischemia and heart failure, and promote the formation of atherosclerosis and ventricular aneurysm. There are many studies on the relationship between genes encoding various components of renin-angiotensin system and arteriosclerosis, but the results are lack of consistency due to differences in sample size and research methods. Angiotensinogen produces angiotensin I under the action of renin, and then produces active angiotensin II catalyzed by angiotensin converting enzyme. By binding to AT1R, angiotensin II regulates cell proliferation, extracellular matrix deposition, and inflammation, thus affecting the structure and function of large arteries. Although the AGTR1 A1166C polymorphism is located in the non-coding region of the AT1R gene, it is related to the density of AT1R. In recent years, there are more and more studies on the effect of A1166C polymorphism on arteriosclerosis, but the results are inconsistent. The reason for the inconsistency is that the research scheme itself is still affected by population characteristics or other factors. This study will explore the relationship between angiotensin II 1 receptor gene polymorphism and arteriosclerosis by means of systematic review and meta-analysis. PWV can reflect the elastic function of the artery as a whole, and it is widely accepted and used as the gold standard for evaluation of arteriosclerosis.,20 Therefore, in this study, we use PWV as the evaluation index of arteriosclerosis.Arteriosclerosis has a moderate genetic correlation. So far, many genes have been found to be related to the occurrence and development of arteriosclerosis.Due to the limitation of language retrieval, we will only include Chinese and English literature in this study, and other languages may be ignored. Different race, skin color, and disease and other factors may cause a certain degree of clinical heterogeneity.Data curation: Zhongping Shi, Jun Wang.Funding acquisition: Yiwei Huang.Resources: Jun Wang, Shanjiang Chen.Software: Shanjiang Chen, Haiyue Dai.Supervision: Shanjiang Chen.Writing – original draft: Zhongping Shi, Jun Wang.Writing – review & editing: Zhongping Shi, Yiwei Huang.


ADRB3, beta-3 adrenergic receptor, participated in lipolysis and thermogenesis in adipose tissue. Consequently, this gene has attracted an increasing number of genetic studies examining its association with coronary artery disease (CAD) in different ethnicities in recent years, but no conclusion has been reached so far. The aim of this study was to explore whether the well-studied locus ADRB3 Trp64Arg in this gene confers a race-specific effect to CAD by conducting a stratified meta-analysis involving 15 independent studies and 11,802 subjects.Previous studies demonstrated that Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. Publication bias was quantified and examined with Begg's funnel plot test and Egger's linear regression method. The overall meta-analysis or stratified meta-analysis by ethnicity was performed by using STATA 12.0 software.ADRB3 Trp64Arg polymorphism was significantly associated with an increased risk of CAD. Further stratified analysis by ethnicity revealed that ADRB3 Trp64Arg polymorphism was significantly associated with CAD in Asians , but not in Caucasians .A total of 15 eligible studies involving 5779 CAD cases and 6023 health controls were included in this meta-analysis. The pooled results indicated that ADRB3 Trp64Arg polymorphism confers a race-specific effect to CAD.This meta-analysis suggests that  It has been reported that its disease susceptibility involves a list of genetic polymorphisms.,3 In the past decades, the polymorphisms of several susceptibility genes for CAD  have been well examined by independent studies or a pooled analysis. In this study, we aimed to systematically assess its properties of the association of the β3-adrenergic receptor (ADRB3) gene polymorphism Trp64Arg with the risk of CAD in different ethnic backgrounds.Coronary artery disease (CAD) has become the most prevalent cardiovascular disease, which is one of the diseases with high mortality and has been recognized as the first killer of human health.ADRB3 is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. A previous human study found that it is closely related to obesity, which in turn can lead to insulin resistance and the end point events of insulin resistance syndrome including stenocardia, myocardial infarction, hypertension and/or other complications.ADRB3 Trp64Arg (rs4994) is a single nucleotide polymorphism (SNP) locus and its missense variation results in a change of amino acids (from tryptophan to arginine), thus altering the conformation of the first intracellular loop and possibly the movement of the receptor to the cell surface and G-protein binding.,8 Several studies,9 revealed that disruption in the signal transduction pathway may result in reduced ADRB3 activity, rendering that ADRB3 may play a significant role in controlling energy expenditure through the regulation of lipolysis and thermogenesis. Consequently, ADRB3 has been deemed to a hot candidate for genetic association with CAD.ADRB3 Trp64Arg polymorphisms and CAD in different racial populations, but no consensus regarding this locus has been reached. There are several reasons that may explain these inconsistent results, for examples, genetic heterogeneities across different ethnicities and limited sample sizes that can be provided by individual studies. Therefore, further large-scale stratified meta-analysis to explore the properties of the association of the ADRB3 Trp64Arg locus with the risk of CAD in different ethnic backgrounds is highly demanding.Up to date, more than 10 studies have been performed to examine the relationship between 22.1ADRB3 Trp64Arg polymorphism with CAD. With the purpose of getting as many potentially relevant publications, the following keywords were used in the search: “β3-AR or ADRB3 or rs4994 or C190T or Trp64Arg or β3-adrenergic receptor” and “polymorphism or genetics or mutation or variation or variant” and “CAD or CHD or coronary heart disease or coronary artery disease or ischemic heart disease or myocardial infarction or MI.” The references of previous meta-analyses and reviews were also manually searched to identify other studies.Major electronic literature databases were systematically searched, which included PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) database, and SinoMed database, up to September 2018, for all publications about the association of 2.2To select eligible studies in this meta-analysis, the following criteria for inclusion were defined:(i)ADRB3 Trp64Arg polymorphism and the CAD or MI;studies aiming to assess the associations between (ii)complete genotype data were available;(iii)case–control or cohort studies.P < .01) were also excluded.If there were multiple publications from the same study group, the most recent study was included in this meta-analysis. However, if the study was a review, lecture, editorial, correspondence letter, or without full text , it was excluded. Also, Hardy–Weinberg equilibrium (HWE) was checked for each study and the studies whose healthy control groups failed HWE the first author's name;(ii)the year of publication;(iii)the country and ethnicity of the participants;(iv)genotyping method;(v)the frequency of genotypes.Then, a group discussion was conducted to remedy any discrepancies in data collected by different reviewers.2.4 which is a star rating system. The NOS contains 8 items, categorized into 3 dimensions including selection, comparability and exposure. The NOS ranges between 0 and 9 stars. A full score is 9 stars and a score range of 5 to 9 stars is considered to be high quality while a score range 0 to 4 is considered to be a poor quality. Conflicting evaluations on the NOS score of the studies were resolved through a comprehensive reassessment by 2 reviewers.The quality of the eligible studies included in the meta-analysis was assessed by using Newcastle-Ottawa Scale (NOS) criteria,2.5ADRB3 Trp64Arg polymorphism and CAD: the allelic, homozygous, heterozygous, dominant, and recessive model, respectively. In order to assess the general or race-specific effect of this polymorphism locus, both pooled and stratified meta-analysis by ethnicity  were performed. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association between this polymorphism locus with CAD. The significance of OR was determined with the Z-test, and P < .05 was regarded as statistically significant. Heterogeneity among studies was examined with χ2-based Q statistic. If there was statistically significant heterogeneity among studies (P < .05 or I2 > 50%), a random effect model (Dersimonian-Laird method) was selected to merge data. Otherwise, a fixed effect model (Mantel-Haenszel method) was employed to analyze data. Then, publication bias was estimated by Begg's funnel plot test and Egger's linear regression test.,17 Finally, sensitivity analysis was performed to assess the influence of each individual study by omitting the individual study each round and calculating pooled ORs again. If the exclusion of any individual study did not alter the meta-analysis result, it indicated that the outcomes were robust. This study was approved by the Ethics Committee of Guangdong Medical University.This meta-analysis was performed with STATA statistical software (Version 12.0). Five genetic models were used to evaluate the association between 33.1ADRB3 Trp64Arg polymorphism, and because of publication types of review, and dissertation, etc. Next, 1 full-text article was found with incomplete genotypic frequency data, and thus removed. Finally, the remaining 15 studies,9,19–31 were subjected to quality assessment with NOS criteria, and all were deemed eligible for the following meta-analysis. For the detailed evaluations, see Table P > .01).A total of 107 relevant records were identified through database searching, and 1 was identified manually. The detailed screening process is shown in Figure 3.2ADRB3 Trp64Arg polymorphism and CAD was found in the whole population under allelic, homozygous, heterozygote, dominant, and recessive genetic models  . Careful scrutiny of the forest plots under these genetic models (data not shown) revealed that Asians were largely in opposite direction to Caucasians, judged by the line for the average risk of this polymorphism, thus demonstrating the high level of heterogeneity between the 2 ethnic populations. The only 1 African study showed that the risk of this polymorphism on CAD  was largely in between Caucasians and Asians, close to the average line.Nevertheless, significant heterogeneity was detected under allelic, heterozygous, and dominant genetic models , homozygous , dominant , and recessive  genetic models, however no significant association was found in any genetic models in Caucasian population  or African population . Forest plots of the association between CAD and ADRB3 Trp64Arg polymorphism under the 5 genetic models  are shown in Figures Therefore, the stratified analysis by 3 ethnicities  was performed. The results are shown in Table 3.4ADRB3 Trp64Arg polymorphism and CAD for A vs T allele is shown in Figure P-value for Begg's test of ADRB3 Trp64Arg polymorphism A vs T allele was .381, and the P-value for Egger's linear regression test was .165. The shape of the funnel plot was symmetrical at large, and there was no statistical significance based on the P-values of Begg's test and Egger's linear regression test. The results under other 4 models were very similar (hence data not shown), suggesting no evidence of publication bias among the included studies.Both the Begg's funnel plot and Egger's linear regression test were adopted to evaluate the publication bias of all 15 studies. The funnel plot of the association between 3.5Finally, sensitivity analysis was performed to assess the influence of individual studies. A leave-one-out procedure  was adopted to evaluate the contribution of a single study to the pooled OR value. This sensitivity analysis revealed that none of the studies influenced the pooled OR to any great extent. The leave-one-out OR estimates ranged from 1.25 (1.06–1.47) to 1.33 (1.13–1.56) for A vs T allele Fig. , genotyp4 Numerous genetic studies suggested that a large number of genes and their complicated interplays contributed to the development of CAD.–35 However, due to various limitations  inherent in a population based study, single individual study unlikely provides an accurate and robust estimate of genetic risk on CAD. For example, though many studies on the relationship between ADRB3 gene polymorphism Trp64Arg and CAD have been performed, no conclusion has been reached so far.CAD is a complex illness that affects human health and quality of life worldwide. The proportion of deaths from CAD in Asia, particularly China, has also gradually increased.ADRB3 gene is located in 8p11.1-p12 and has a full length of 3672 bp, containing 2 exons and 1 intron, encoding 408 amino acids. Previous studies demonstrated that ADRB3, beta-3 adrenergic receptor, participated in lipolysis and thermogenesis in adipose tissue. Trp64Arg polymorphism is the only functional variant of ADRB3 protein. The ADRB3 Trp64Arg locus acts as a “thrifty” gene and has already been reported associating with obesity, hypertension, diabetes mellitus, insulin resistance, and glycolipid metabolism. Logically, ADRB3 Trp64Arg locus may play an important role in the pathogenesis of CAD.Human ADRB3 Trp64Arg locus and CAD had been performed by Zafarmand et al in 2008. Their analysis included 10 studies, and did not find significant association for ADRB3 Trp64Arg polymorphism and CAD. In the current meta-analysis, more extensive and more recent literature of both English and Chinese had been sought for, and 15 studies were finally included, with 8 Asian studies, 6 Caucasian studies, and 1 African study. In addition to the pooled analysis for assessing the overall risk of ADRB3 Trp64Arg polymorphism on CAD, a stratified meta-analysis by ethnicity aiming to evaluate the race-specific effect of this locus was conducted. Compared to Zafarmand et al's study, our analyses were more informative and more comprehensive, and therefore our results were more objective and more convincing. Following these meta-analyses, we further evaluated the publication bias of the included studies. Both the roughly symmetrical shape of the funnel plots and the P-value of Begg's and Egger's test suggested that there was no evidence of publication bias. Moreover sensitivity analysis also confirmed the stability of our results. Overall, this data analysis revealed a marked difference in genetic diversity among different ethnicity groups. We viewed that the race-specific effect of ADRB3 Trp64Arg locus on CAD in Asians, but not in Caucasians was well supported, which did not agree very well with a previous meta-analysis that reported no significant association of this locus with CAD in the general population . Possible explanations accounting for this inconsistency may be due to genetic heterogeneities across different ethnicities or sampling variance.Prior to the present study, only 1 meta-analysis of the association between In short, our study had several merits. First, we significantly extended sample size, especially including more Asian studies published in Chinese, which rendered our findings more stable and more detailed. Second, we adopted the very strict inclusion and exclusion criteria. All the 15 studies were subjected to the NOS assessment, and had achieved high quality scores of 5 stars or more. Third, in order to fully assess the relationship between this polymorphic locus and CAD, we performed a comprehensive and stratified meta-analysis by ethnicity, under the 5 conventional genetic models, which demonstrated that this locus was of race-specific effect, and the most likely inheritance mode was recessive.We recognized several potential limitations of this study. First, the searched literature was limited to Chinese and English, which might miss some important studies published in other languages. Second, Asian studies were not further divided by either ethnicity or geographic areas, which may also have slight different genetic diversity. Finally, due to the lack of adequate information regarding the participants’ demographic and epidemiological factors , we did not perform any stratified analysis regarding these potentially confounding factors, which might bias our statistical estimates.ADRB3 Trp64Arg polymorphism confers a race-specific effect to CAD. Stratified analysis by ethnicity revealed that ADRB3 Trp64Arg polymorphism was significantly associated with CAD in Asians, but not in Caucasians.In conclusion, our results suggested that Conceptualization: Yingjian Chen, Yuanjun Liao.Data curation: Yingjian Chen, Yuanjun Liao.Formal analysis: Yingjian Chen, Yuanjun Liao, Shengnan Sun, Fan Lin, Rang Li Shujin Lan.Resources: Yuanjun Liao, Xiaolei Zhao, Jiheng Qin, Shaoqi Rao.Software: Yingjian Chen, Yuanjun Liao.Writing – original draft: Yingjian Chen, Yuanjun Liao, Shaoqi Rao.Writing – review & editing: Yingjian Chen, Yuanjun Liao, Shaoqi Rao, Xiaolei Zhao, Jiheng Qin.Shaoqi Rao: 0000-0001-7809-3700.


Absolute monocyte count (AMC) is often used to be assessed in cancer follow‐up, which has regained interest as a potential prognostic indicator in many solid tumors, though not consistently or comprehensively. In the present study, we set out to perform a comprehensive meta‐analysis of all available data regarding the prognostic significance of AMC in solid tumors. We also evaluated the association between AMC and clinical features in solid tumors.CI) or a p value (p) from eligible studies were extracted and subsequently pooled analyzed. Subgroup analyses and meta‐regression analyses were conducted according to the confounders of included studies. In addition, the relationships between AMC and clinical characteristics were also explored in the meta‐analysis.A hazard ratio (HR) and corresponding 95% confidence interval , disease‐free survival (DFS) , progressive‐free survival (PFS)  and cancer‐specific survival (CSS)  in non‐hematological tumors. Subgroup analyses according to each confounder further proved the consistent prognostic value of AMC in solid tumor outcomes. Moreover, elevated AMC was more likely to be observed in male group and patients with smoking history, and associated with longer tumor length and advanced T stage.Overall, ninety‐three articles comprising 104 studies with 32229 patients were finally included. The results showed that elevated AMC was associated with worse overall survival (OS) In short, the meta‐analysis found that elevated AMC might indicate poor long‐term outcomes in non‐hematologic cancers, thus AMC may be a valuable marker in the prognosis for patients with solid tumors. Elevated AMC indicates poor long‐term outcomes in solid tumors, which could be applied in the prognosis assessment. AMCabsolute monocyte countCCL2C‐C chemokine ligand 2CCR2the receptor for chemokine CCL2CIconfidence intervalCSScancer‐specific survivalDFSdisease‐free survivalHRhazard ratioMCP‐1monocyte chemoattractant protein‐1MDSCmyeloid‐derived suppressor cellNK cellnatural killer cellNOSNewcastle–Ottawa Quality Assessment ScaleORodds ratioOSoverall survivalPD‐L1programmed cell death ligand 1PFSprogressive‐free survivalPRISMAPreferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelinesRFSrecurrence‐free survivalROCreceiver operating characteristic curveSARsurvival after recurrenceSMDstandardized mean differenceTAMtumor‐associated macrophageTMEtumor microenvironmentVEGFvascular endothelial growth factor1Cancer remains one of the leading causes of death and a major health care challenge worldwide.In the last decade, there have been the paradigms of chemotherapy being transformed from empiric therapy to individual pharmacogenomics‐ and genetics‐based personalized medicine, coinciding with rapid technological advances and brilliant discoveries in many fields such as genetics and molecular biomarkers.With the increased understanding of tumor immunology, the dual interaction between cancer and the immune system has been recognized and the microenvironment in which the cancer cells grow has been highlighted.Tumor‐associated macrophages (TAMs), derived from the infiltrating bone marrow‐derived monocytes, are a major component in TME and therefore were considered as conspicuous stromal targets in many types of solid tumors.Therefore, we performed a meta‐analysis with in order to validate the role of monocyte as a predictor in solid tumors. In addition, we also integrated data to demonstrate the relevant clinicopathological factors in relation to peripheral monocyte count, which is of the essence to tailor the personalized cancer treatment strategy.22.1The present study was performed in accordance the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines (PRISMA).2.2Studies included in this meta‐analysis meet the following criteria: (1) patients with solid tumors were studied; (2) the prognostic impact of AMC on overall survival (OS), cancer‐specific survival (CSS), progressive‐free survival (PFS), disease‐free survival (DFS) and/or recurrence‐free survival (RFS) was evaluated; (3) a hazard ratio (HR) with 95% confidence interval (CI) could be extracted in univariate or multivariate analysis of Cox hazard model, or could be estimated by Parmar's method2.3p values) model of survival analysis (multivariate or univariate).Two investigators performed data extraction independently with a standard extraction form. The following data were extracted: first author's surname, publication year, country, region, patient sources, cancer type, study design, characteristics of cancer , characteristics of the study cohort , testing time of monocyte, cut‐off value defining low monocyte, method for the selection of cut‐off value, outcome measures .2.4p < 0.05 in data synthesis. Besides, we used the outcomes in multivariate analysis whenever the univariate and multivariate analyses were available. The heterogeneity of pooled studies was measured by Cochran's Q test and Higgins I‐squared (I2) statistic; p < 0.1 or I2 > 50% was defined as significant heterogeneity. The random‐effects model was used in the analysis. Subgroup analysis was performed based on region, sample size, cut‐off value, cancer type, distant metastatic status, TNM stage, testing time of blood, analysis method, and study quality to explore the heterogeneity sources. Then, meta‐regression analyses were conducted to determine the hazard effects of covariates. Publication bias was evaluated by Begg's and Egger's test. Sensitivity analysis was conducted to explore the influence on the pooled effect size after removing a single study each time. Two‐sided p < 0.05 was considered statistically significant.This meta‐analysis was performed with STATA version 14.0 . The survival data were measured by HR and 95% CI. The aggregated HRs and 95%CIs, either directly extracted or presented in the form of Kaplan‐Meier survival curves, were calculated to evaluate the prognostic value of AMC on the long‐term prognosis (OS/DFS/PFS/CSS) using low AMC group as a reference. The relationships between the AMC and certain clinical features of patients were also assessed with STATA version 14.0. Odds ratios (ORs) for dichotomous variables and standardized mean differences (SMDs) for continuous variables with their 95% CIs were regarded as summarized statistics, respectively. Statistical significance was indicated when 33.1The initial literature search identified a total of 6016 potentially relevant publications. After thoroughly screening the titles and abstracts by two investigators independently, the full‐texts of 173 potential studies were selected for further identification. Finally, 102 retrospective studies and 2 retrospective‐prospective studies from 93 eligible papers that met the inclusion criteria were included in this meta‐analysis.n = 59) and pre‐operative (n = 42), while one study was post‐treatment and two studies remained unknown. There were 65 studies estimated as high‐quality studies and 39 low‐quality studies. The endpoints OS, DFS, CSS PFS, and survival after recurrence (SAR) were addressed in 88, 41, 23, 10, and 1 studies, respectively. As shown in Table Of those 104 studies, 82 were based on Asians and 22 on non‐Asians. According to the types of cancer, 41 studies were on abdominal cancers, 30 studies on thoracic cancers, 14 studies on pelvic cancers, 12 studies on head and neck cancers, 6 studies on melanoma, and 1 study remained unknown. Based on the testing time of blood, majority of the included studies were pre‐treatment  . Subgroup analyses were performed based on the available data. The subgroup analyses revealed a significant association between higher AMC and unfavorable cancer prognosis in Asian patients, studies with large sample size, studies with low cut‐off value, studies with multivariate analysis, and low‐quality studies with decreased heterogeneity. Similar associations were seen in analyses stratified by TNM stage and distant metastatic status, as well as in pre‐treatment studies and pre‐operative studies. Considering various cancer types may lead to inconsistent results, a subgroup analysis according to cancer type was conducted. Most subgroups showed a negative prognostic effect of elevated AMC. This includes the subgroups of breast cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, head and neck cancer, lung cancer, melanoma, pancreatic cancer, and prostate cancer. Of subgroups stratified by cancer type, the highest effect on OS was found in cervical cancer  and no heterogeneity was found in the prostate cancer subgroup  .  . The analyses demonstrated that elevated AMC was positively related to pooled HR for DFS when stratified by region, sample size, cut‐off value, analysis method, and study quality. In subgroup analyses according to cancer type, studies on breast cancer, endometrial cancer, esophageal cancer, lung cancer, and melanoma also demonstrated the negative effect of high AMC on outcomes with consistency. In addition, we found poor DFS in studies with IV stage cancers, but the estimate was insignificant  , with moderate heterogeneity 2 , patients with colorectal cancer  and lung cancer , patients with stage IV cancer  with no heterogeneity. The adverse effect of higher AMC was also seen when stratified by sample size, cut‐off value, distant metastatic status, the time of blood testing, analysis method, and study quality  . When stratified by cancer type, distant metastatic status, and the time of blood testing, elevated AMC was associated with worse outcome in patients with colorectal cancer , distant metastatic cancer  and studies with pre‐operative AMC  without heterogeneity. The subgroup analyses also revealed that elevated AMC might be a potential biomarker in non‐Asian patients, studies with high cut‐off value, and studies with univariate analysis or low quality  Table . A relat3.6, microvascular invasion , macrovascular invasion  and larger tumor length . The pooled analysis revealed that the AMC of male with solid tumors was more likely higher . . Patients with elevated pre‐operative monocyte has lower albumin , while higher platelet   and Egger's test (p < 0.001) further confirmed that the asymmetry was mainly attributed to the publication bias. The “trim‐and‐fill” analysis was performed and no significant change in our results was found, further suggesting the stability of the meta‐analysis   and Egger's test (p = 0.001) showed publication bias. The adjusted random effect HR of 1.363  was obtained using the “trim‐and‐fill” analysis, which was consistent with the primary analysis. For PFS, there were no evidence of asymmetry, and no trimming was performed after applying the “trim‐and‐fill” analysis. For CSS, the results of Begg's test (p = 0.007) and Egger's test (p = 0.001) indicated publication bias, and there was no trimming performed after applying the “trim‐and‐fill” analysis.For OS, the funnel plot was visibly asymmetrical, indicating the presence of publication bias . In accord with the plot, the results of Begg's test In addition, sensitivity analysis was carried out and the results showed that the pooled HRs were not significantly affected by omitting an individual study.4To the best of our knowledge, we performed a comprehensive meta‐analysis for the first time to assess the prognostic value of AMC in various solid tumors. The systematic review and meta‐analysis involving data on 32,229 participants from 104 studies provided robust evidence that elevated the level of monocyte count might be an independent prognostic factor for poor OS, DFS, PFS, and CSS in non‐hematologic tumors. Subgroup analyses focused on clinical outcomes were conducted and further proved the predictor role of elevated AMC on long‐term cancer outcomes. In addition, we found a tendency that an elevated AMC was significantly associated with some clinicopathological characteristics including gender, T stage, vascular invasion, tumor length, and smoking, as well as higher platelet counts and lower albumin.Since Virchow described the role of inflammation in 1863, inflammatory response has gone beyond the marker of infection. It has been hypothesized that cancer arises from the background of inflammation, which has been supported by a multitude of evidence in the last decade.Of these immune cells, monocytes are a subset of circulating blood cell originated from myeloid progenitors in the bone marrow and subsequently can be attracted to peripheral tissues via bloodstream.highLy6C++CD43+ in mice, homologous to CCR2highCD14++CD16− in human), intermediate monocytes  and nonclassical patrolling monocytes . (The + denotes an expression level that is 10‐fold above the isotype control and ++ is 100‐fold above the isotype control).The exact underlying mechanisms of the association between elevated AMC and unfavorable outcomes have not been fully clarified and might be multifactorial. It is recognized that monocytes originate from mononuclear myeloid cells in bone marrow, which come into play in response to pathogenic stimuli such as cancer by myelopoiesis which largely manifest in the expansion of monocytes and neutrophils.In addition, the monocyte chemotactic factor monocyte chemoattractant protein‐1 /C‐C chemokine ligand 2 (MCP‐1/CCL2) secreted by tumor cells is a chemokine with potent monocyte chemotactic activity via binding to CCR2 (the receptor for chemokine CCL2), has been shown to directly or indirectly enhance immunosuppression and metastasis by vascular endothelial growth factor (VEGF) secretion and other tumor‐secreted factors like IFNγ in murine cancer models.It has been reported that a therapeutic regimen such as chemotherapy could modulate the pro‐tumor and anti‐tumor ability of monocytes/macrophages lineages.Our study possesses several strengths. Distinctively, we focused on all non‐hematological tumors and provided comprehensive evidence for the prognostic value of AMC, which might be a weighted one involved in the immunoscore system. Moreover, because of the diversity of cancer types and studies, the research into subgroup analysis were lucubrated. It is the first time that pre‐treatment AMC, pre‐operative AMC, and post‐operative AMC are compared. Based on subgroup analyses stratified by cut‐off values of monocytes, higher cut‐off values for OS and DFS seem to be more discriminative effective on prognosis, while inversely in PFS and CSS. Additionally, we studied the relationships between AMC and gender, T stage, tumor length, microvascular invasion, smoking, and other clinic parameters, which provide potential implications in clinical practice in the future.3 may enable us to better identify the poor outcomes in the present study, the optimal AMC cut‐off awaits standardization. Besides, as Walker SP said, “the unpredictability of the diseases undermined the ability to plan ahead.”Nevertheless, there were some limitations to the present study. A key limit was that cut‐off levels of AMC were set based on ROC, median value, previous studies or other methods, making the routine application less practical. Although the cut‐off >500/mm5In conclusion, our comprehensive meta‐analysis strongly supported that elevated AMC was remarkably associated with poor prognosis of patients with solid cancer. Monocyte, the relatively accessible low‐cost cancer biomarker, could have widespread clinical implications for surgical management, treatment strategy, and prognosis assessment. Further multicenter studies in a randomized and prospective manner with optimal AMC cut‐offs were warranted to refine our results and to advance the clinical applications of the monocyte counts in the future. Finally, given the different functions of monocyte subsets in TME, the monitoring of blood monocyte subpopulations could be further explored and applied to follow‐up treatment response.6This study reports a systematic review for which all data are already available within the public realm in the form of scientific publications, references for which are provided.The authors have declared no conflict of interest.Shu Wen, Ying Hu, and Liangzhi Xu conceived and designed the experiments; Litao Huang, Jin Peng, and Nan Chen collected the data; Meina Yang and Xiaoyang Shen analyzed the data; Shu Wen and Nan Chen contributed the materials/analysis tools and wrote the manuscript. Ying Hu and Song Yang revised the manuscript. All authors reviewed and approved the manuscript prior to submission.Fig S1Click here for additional data file.Fig S2Click here for additional data file.Fig S3Click here for additional data file.


To evaluate the association between apolipoprotein B gene polymorphism and coronary heart disease in some populations at home and abroad by means of meta-analysis.Using the strict exclusion criteria for primary screening of the literature and applying the Hardy-Weinberg equilibrium to test the genetic balance of the selected literature. The corresponding models were selected according to the results of the heterogeneity test. The Begg’s test and Egger’s test were used to evaluate publication bias, and meta-analysis was performed using Stata 12.0.P = 0.811,OR = 0.95, 95%CI = 0.62–1.46), recessive genetic models , or dominant genetic models . Subgroup analysis based on ethnicity showed allelic comparison , recessive genetic models , and dominant genetic models  in Asians, allelic comparison , recessive genetic models ,dominant genetic models  in Caucasian;The study included twelve articles. In the literature, a total of 1596 patients with coronary heart disease and 1431 controls.Meta-analysis results showed no statistical value in the following three genetic models: allelic comparison  XbaI locus is not a risk factor when it comes to the development of coronary heart disease in the domestic and international populations included in this paper. In Caucasians, people carrying the aa genotype may be less susceptible to CHD (coronary heart disease). The results of recessive genetic models have to take the effect of heterogeneity and sample sizes into account. Further research may require a larger and more rigorous research design. As countries grow richer, cases of coronary heart disease(CHD) also rise rapidly, and coronary heart disease patients are becoming younger and younger. CHD is a major cause of both death and disability in developed countries, responsible for about one-third or more of all deaths in individuals over the age of 35 –3. The 2ApoB XbaI (rs693) is a kind of single-nucleotide polymorphism (SNP) resulting in the change of amino acids, which is located in exon 26 of the ApoB gene. Many studies have been done on the correlation between ApoB XbaI gene polymorphism and CHD in different countries, however, their conclusions go different ways. Different studies at home and abroad have disputed the relationship between ApoB XbaI gene polymorphism and coronary heart disease, mainly because of the small sample size and genetic differences among different ethnic groups. Due to the limitations of a single study regarding research methods, number of studies, ethnicity of the study population and other aspects, it is important to summarize the results of these individual studies to be able to make reliable conclusions concerning XbaI gene polymorphism. The purpose of this meta-analysis is to integrate the results of these case-control studies to comprehensively assess the association between ApoB XbaI gene polymorphisms and CHD.http://www.ncbi.nlm.nih.gov/pubmed), Google Scholar(http://www.scholar.google.com),Web of Science (http://www.isiknowledge.com), Cochrane Library (http://www.thecochranelibrary.com),Chinese VIP database (http://www.cqvip.com),Chinese Wanfang database (http://www.wanfangdata.com.cn),China National Knowledge Infrastructure (CNKI) database (http://www.cnki.net). The search was limited to Chinese and English articles,for all publications about the association between ApoB XbaI gene polymorphisms and CHD, while excepting reviews and critical articles. The following key words were used while searching:apolipoproteins B/ApoB, ApoB XbaI polymorphisms, and coronary heart disease/coronary &disease/coronary disease &heart/ coronary atherosclerotic heart disease/CHD/CAD.We have conducted a comprehensive search through the computer system in the following databases up until April 2019:MEDLINE database(Articles were identified based on the inclusion criteria as follows: (1) The original study type was a well-designed case-control study with strict controls;(2) The studies should have exact genotypic and allelic data of ApoB XbaI;(3)Cases in the CHD group were diagnosed and cases in control group were excluded by coronary angiography, based on the World Health Organization (WHO) 1979 CHD Criteria;(4)The studies had comprehensive statistical indicators, such as odds ratio, confidence interval, etc. The genotypes of the case group and the control group in each study were in line with the Hardy-Weinberg equilibrium (HWE) to verify the representativeness of the study population, and if HWE-p was bigger than 0.05,which meant the research group met HWE, then it was included. The exclusion criteria of these articles were as followed:(1)The article was not a case-control study,but a lecture, review, correspondence, editorial letter,etc.;(2) Unable to extract exact genotype data from the article;(3) If the HWE-p was smaller than 0.05,which meant that the research group didn’t meet the Hardy-Weinberg equilibrium, it was excluded.The quality of these case-control studies was assessed by a star rating system, Newcastle-Ottawa scale (NOS), and evaluation of the NOS score of the studies was averaged by two independent reviewers. Full score is 9 stars,while a score range from 0 to 4 stars is considered poor quality , 6,and aData of selected studies was extracted by two independent reviewers in a standard data collection form, which included the following items:(1)the basic information of the included studies,such as the first author’s name,the publication year, etc.;(2)the region of the study population;(3) genotype data and allele frequency of ApoB XbaI for both CHD cases and control cases;(4) HWE-p in healthy control groups. In case of disagreement, we settle it through discussion or refer to a third party for help.P < 0.05 was considered a significant departure from HWE. At the same time, I2 statistics were used to test the heterogeneity of each piece of literature  and were used in this meta-analysis with a total of 1596 CHD patients and 1431 healthy control subjects. The detailed screening process was shown in Fig. A total of 66 abstracts both in English and Chinese from the last 20 years on the association between apolipoprotein B Xbal polymorphisms and CHD susceptibility were identified, including 9 in Chinese and 57 in English. Whenever two studies largely overlapped , 13, onl2 statistic was used to assess the heterogeneity respectively by using STATA12.0. In the three genetic models , significant heterogeneity was found: allelic comparison, recessive genetic models,dominant genetic models , recessive genetic models , or dominant genetic models . Next, subgroup analysis was conducted  and dominant genetic models , so therefore random effects model was used. While fixed effects model was used in recessive genetic models.No statistical association was found to be significant in any genetic models: allelic comparison , recessive genetic models , or dominant genetic models .In Caucasians,random effects model was conducted because of significant heterogeneity in any genetic models. Statistical significance was found in recessive genetic models ,which meant that ApoB XbaI gene polymorphism had a certain correlation with CHD. However, no statistically significant difference was found in the other two genetic models, dominant genetic models ). The above data showed that among Caucasians, those carrying the aa genotype may be less susceptible to CHD.Based on the statistically significant heterogeneity which was found for the analysis of allelic comparison, recessive genetic models, and dominant genetic models in this meta, the random effects model was employed to merge data. The combined OR values were calculated and the forest plot of the association between ApoB XbaI gene polymorphisms and CHD was made by D-L method, shown in Figs. p-value was 0.451,while the result of Eggers linear regression test showed that the p-value was 0.49 . In the three gene models studied in this paper we tested the heterogeneity, and they all showed significant heterogeneity. Therefore, we used random effect models to combine data, and we performed subgroup analysis according to ethnicity to explore the sources of heterogeneity. Interestingly, in the recessive genetic models, the heterogeneity between Asians and Caucasians was very different, seemingly indicating that this subgroup was a source of heterogeneity. However, we could also see that in the Asian subgroup,two piece of literature [Meta-analysis conducted a secondary analysis of descriptive data has a scientific and rational aspect, but it is also affected by a variety of factors including the amount of selected literature, the size of the total sample size, publication bias, and flaws in the analytical method itself. Through the foregoing description, this study has been proven to be heterogeneous through various methods of heterogeneity test. The significant positive correlation between plasma apolipoprotein B and LDL-C indicates that it is often an important predictor of CHD, and the risk-related relevance between its polymorphisms and coronary heart disease requires more large-scale original studies to be further validated.