Family and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations.Updating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria.ESR1 gene , rs12589592 at the FBLN5 gene , rs484389 in the PGR gene , and rs1800012 at the COL1A1 gene . Further credible novel variants have also been recently identified in genome-wide association studies.We screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the The genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice. The existence of inherited risk factors for pelvic floor disorders has been recognized for > 150 years –4 with aFamily studies, particularly those involving nuclear family members, provide limited information on heritability, as they do not control for shared exposure to environmental risk factors. Twin studies have been used to formally quantify the heritability of prolapse. In a sample of 16,886 Swedish twins aged > 50 years, heritability was estimated as 43% for prolapse surgery ) NOT mitral NOT carcinoma [Title] NOT cancer [Title] NOT “pelvic organ prolapse.”In this update we searched HuGE Navigator, also from January 1, 2015, to November 1, 2020, using the phenotype indexing term In addition, we searched conference abstracts for annual meetings of the American Society of Human Genetics, American Urological Association, American Urogynecologic Society, European Association of Urology, European Society of Human Genetics, International Continence Society, International Urogynecological Association, and Society of Gynecologic Surgeons 2005–2020.We developed standardized data forms for this study and conducted pilot screening and data extraction training exercises to achieve a high level of consensus between reviewers. All screening and data extraction were then performed independently and in duplicate by methodologically trained reviewers. Reviewers screened study reports by first screening titles and abstracts to select papers for full-text assessment and then screening full-text papers to confirm eligibility of the articles. Screening discrepancies were resolved by adjudication. We hand searched reference lists of all included articles, applying the same standardized screening process. When more than one report was identified for the same association in the same study population, we included the publication with the largest sample size.We contacted study authors by email, with a reminder after 1 month, for clarifications, additional information about methodology, and additional subgroup analyses where necessary. Data extracted included information on the setting for each study, details of the sampling strategy and sampled populations , the overall sample size and proportion genotyped, the outcome assessments used and phenotypic definitions, the genotyping method employed, and the genotyping quality control applied. Where possible we extracted or requested from authors full genotype frequencies among both cases and controls.2 statistic as a measure of between study heterogeneity. We recalculated the power of each study and retested for departure from Hardy-Weinberg equilibrium. We made assessments of risk of bias in phenotype definitions, genotyping, and population stratification. We used the Harbord test of funnel plot asymmetry and the significance chasing bias test [p < 0.05 as the criterion for significance, except in relation to GWAS, where p < 5 × 10−8 is accepted as the criterion for significance. Reporting of this review complies with recommendations of both the HuGE Handbook and the PRISMA statement.For polymorphisms assessed in ≥ 2 studies for the same phenotype and evaluated with similar case definitions, we conducted fixed or random effects meta-analyses as appropriate using the Metan package Stata 12.1). In situations where a proxy SNP had been selected for genotyping in one or more studies, in high linkage disequilibrium (defined as D′ ≥ 0.8) with another SNP of interest, these SNPs were considered as being equivalent for meta-analysis purposes; results are reported based on the original significant SNP identifier. Linkage disequilibrium was assessed between pairs of SNPs using the LDpair tool , 16 and 2.1. In sias test  to invesFor completeness of this review, we additionally provide summaries of the four genome-wide association studies (GWAS) reported to date. Where possible, significant GWAS findings have been included in meta-analyses. However suggestive and non-significant GWAS findings are typically not reported; hence, we are unable to include most null findings from GWAS in the meta-analyses.We screened 504 new abstracts for this review Fig. , eventuaESR1 gene, rs12589592 in the FBLN5 gene, rs484389 in the PGR gene, and rs1800012 in the COL1A1 gene  and could be included in meta-analyses [2 = 0.0%, Venice rating BAB). The risk variant is common in the populations assessed, and so despite the low total sample size (n = 339), this confers moderate epidemiological credibility.analyses , 20. In FBLN5 has been investigated as a candidate gene for prolapse as fibulins play a critical role in the assembly of elastic fibers, believed to provide strength and flexibility in the pelvic floor. Three studies from Brazil, Russia, and China assessed the same two variants (rs2018736 and rs12589592) of which two studies could be included in meta-analyses [2 = 36.3%, Venice rating BBB). The risk variant is common in the populations assessed, and so despite the low total sample size (n = 568), this confers moderate epidemiological credibility.analyses , 21, 22.PGR has been investigated as a candidate gene for prolapse, as it codes for the progesterone receptor, and changes in serum progesterone cyclically, during pregnancy, and after menopause are all observed to have an influence on prolapse. Two studies from China each assessed the same two common polymorphisms and could be included in meta-analyses [2 = 32.4%, Venice rating CBB). The risk variant is common in the populations assessed, but the low total sample size (n = 336) confers weak epidemiological credibility.analyses , 23. No COL1A1 has been investigated as a candidate gene for prolapse as it forms type 1 collagen, the most abundant human collagen. The rs1800012 was identified as a replicated locus in our earlier review, but we could now include six studies with a moderate protective effect with no heterogeneity  [n = 1264), this confers moderate epidemiological credibility.ing BAB) –28. The COL3A1 type 3 collagen (8 studies), COL18A1 collagen type 18 (3 studies), LAMC1 Laminin, gamma 1 (6 studies), ZFAT (3 studies), MMP1 matrix metalloproteinase 1 (3 studies), MMP3 matrix metalloproteinase 3 (4 studies), MMP9 matrix metalloproteinase 9 (4 studies), MMP10 matrix metalloproteinase 10 (2 studies), and four other variants identified from GWAS . None of these meta-analyses showed significant pooled effects. Results are summarized in Table We conducted further meta-analyses for variants in inase 10  studies,ZFAT replicating in one study [The first GWAS for POP involved 115 surgically treated, related POP cases who were part of high-risk POP pedigrees and 2976 population-based controls . The orine study , rs80277ne study , and rs1ne study , but witp < 10−6.A further GWAS using African American and Hispanic women from the Women’s Health Initiative Hormone Therapy study  includedThe largest POP meta-analysis of two GWA studies involved 3409 cases from Iceland and 131,444 controls and 11,601 cases and 209,288 controls from UK Biobank, all of which were of European ancestry , 36 TablFinally, a recently reported GWAS utilizing 1329 women with diagnosed and/or surgically treated prolapse and 16,383 hospital controls did not identify any variants meeting genome-wide significance . HoweverESR1 gene, rs12589592 in the FBLN5 gene, rs484389 in the PGR gene, and rs1800012 in the COL1A1 gene). In each meta-analysis we have at most moderate evidence in support of an association with POP. A much larger, recent prospective meta-analysis of two genome-wide association studies has identified eight variants significantly associated with POP [Given current evidence supporting a genetic predisposition for pelvic organ prolapse, we have identified four variants through meta-analysis of candidate gene studies significantly associated with POP (rs2228480 in the with POP , with rewith POP . As the


Although research indicates an association between hypertensive disorders of pregnancy (HDP) and congenital heart defects (CHDs) in offspring, consistency is still lacking. Therefore, we aimed to synthesize the updated published epidemiologic evidence to estimate the association of maternal HDP with the risk of total CHDs and its phenotypes in offspring.A systematic search of Web of Science Database, PubMed, and Embase were searched from inception through April 30, 2021 based on a preprepared protocol, and the reference lists were also manually searched. The combined risk estimates were calculated using either the fixed-effect models or random-effect models. Possible heterogeneity moderators were detected by subgroup, sensitivity analyses, and Galbraith plot.OR = 1.79, 95% CI: 1.50–2.13), gestational hypertension , and chronic hypertension , a significantly increased risk of total CHDs were still presented. Furthermore, a statistically significant increased association was found between maternal HDP exposure and most CHD phenotypes. Besides, relevant heterogeneity moderators have been identified by subgroup and sensitivity analyses.Twenty-four studies involving 477,839 CHDs cases among 40,394,699 participants were included in our meta-analysis. Mothers who had HDP exposure were significantly associated with an increased risk of total CHDs compared with non-exposure. When maternal HDP exposure was further subdivided into pre-eclampsia (Our study suggested that maternal HDP exposure may be associated with an increase in the risk of CHDs in offspring. These findings highlight the need for greater surveillance of pregnant women with HDP exposure to allow early prevention that may be good for reducing the risk of CHDs in offspring.www.ClinicalTrials.gov], identifier [CRD42021268093].[ Congenital heart defects (CHDs), defined as gross structural malformation of the heart or large blood vessels during the fetal period, are the most frequent congenital anomalies in newborns, affecting 8.6–10.3 per 1,000 live births , 5. Evidin utero environment, which may increase the risk of adverse pregnancy outcomes  (Hypertensive disorders in pregnancy (HDP) are a group of maternal disorders characterized by increased blood pressure during pregnancy, which include gestational hypertension, pre-eclampsia or eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension . It was d so on) , 13. Thed so on) –18.Until now, one meta-analysis has been published to discuss this question . This stTherefore, based on the above-mentioned situation, we synthesized the available published studies on the association between maternal HDP and the risk of CHDs in offspring in a systematic review and meta-analysis. The objective of this study is as follows: (i) to review and summarize the epidemiologic evidence on the association of maternal HDP on total CHDs and specific CHD phenotypes in offspring; (ii) to estimate the association of different types of HDP with total CHDs in offspring; and (iii) to identify potential sources of heterogeneity by subgroup, sensitivity analyses, and Galbraith plot.We conducted and reported this study by following the protocol of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement . Web of The exposures of interest were HDP, which was defined as a group of characteristic diseases that occur during the gestational period. HDP was usually divided into four categories: gestational hypertension, preeclampsia/eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension. The definitions of HDP of individual studies were guided by guidelines in place at the time of each study in our study. Traditionally, gestational hypertension was defined as new-onset elevated blood pressure (≥140/90 mmHg) after 20 weeks of gestation, and recovery before 12 weeks of delivery , 22. PreThe outcomes of interest were CHDs or specific CHD phenotypes including conotruncal defects (CTD), atrial septal defects (ASD), ventricular septal defects (VSD), atrioventricular septal defect (AVSD), tetralogy of fallot (TOF), transposition of the great vessels (TGA), coarctation of the aorta (COA), right ventricular outflow tract obstruction (RVOTO), left ventricular outflow tract obstruction (LVOTO), hypoplastic left heart syndrome (HLHS), and heterotaxia, which were confirmed by surgery and/or diagnosed by ultrasonography.Two authors (SMZ and TTW) independently initial screened titles and abstracts of all studies, and then reviewed full texts of relevant studies when necessary. Eligibility criteria for fulfilling in our meta-analysis included the following: (i) cohort or case-control studies; (ii) HDP were the exposure of interest including gestational hypertension, pre-eclampsia or eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension; (iii) CHDs or specific CHD phenotypes  were the outcomes of interest; (iv) the association between HDP and CHDs or specific CHD phenotypes were part of the main objective of the study ; (v) reported odds ratios (ORs) or relative risks (RRs), with corresponding 95% confidence intervals (CIs) , or complete four grid table data (2 × 2 tables) which is sufficient to calculate their OR value or RR value); (vi) published in English-language. On the contrary, exclusion criteria of studies were as follows: (i) reviews, meta-analysis, case reports, letters, and conference abstracts; (ii) without sufficient or clear data; (iii) duplicate publications . Additionally, we also excluded some studies that focused on the treatment of HDP or special populations .Two authors (SM.Z and TT.W) independently extracted data and assessed study quality for each included literature using a standardized data collection form. All discrepancies were resolved through discussion with third authors (X.Q) until consensus could be reached. Information extracted included the first author’s, year of publication, recruitment period, geographic region, study design, sample sources, sample sizes, the exposure of interest, the outcome of interest, whether confounding factors were adjusted, and quality assessment. Quality assessment of all included studies was conducted by using the Newcastle-Ottawa Scale . With thP < 0.10) and I2 statistic (significance level at I2 > 50%) were identified as a quantitative measurement index for detecting the heterogeneity between studies , we considered OR as RRs. Random-effect models were used to calculate the combined risk estimates when there is heterogeneity across studies, otherwise, the fixed-effect model was used . The Q s studies .P < 0.10)  . Data wen = 3,135) were further eliminated after screening titles and abstracts. Then 52 potential articles were carefully reviewed by full-text. Of these, 28 articles were further removed because they did not meet the inclusion criteria. Finally, a total of 24 articles  controlled for possible confounding factors when evaluating the association of maternal HDP with CHDs risk. Fifteen studies had a higher methodological quality; these studies devote most research participants. Additionally, based on the types of HDP, pre-eclampsia was reported in ten studies, gestational hypertension in six studies, chronic hypertension in twelve studies, and preeclampsia superimposed on chronic hypertension in one study.All included literature that was published from 1989 to 2021, with a summary of 477,839 CHDs cases among 40,394,699 participants, are provided in OR = 1.70, 95% CI: 1.46–1.98; P < 0.001) compared with those without HDP exposure. However, substantial heterogeneity was found in the present study .OR = 1.55, 95% CI: 1.33–1.79; P < 0.001), TOF , ASD ,HLHS , COA ,LVOTO ,and RVOTO . Nevertheless, there was no substantial heterogeneity except for ASD . Additionally, our results indicated that mothers with maternal HDP was not significantly associated with the risk of TGA , VSD , AVSD , and Heterotaxia . Nevertheless, obvious heterogeneity was observed for several above-mentioned phenotypes except for TGA  and Heterotaxia .The results of pooled estimates between maternal HDP and risk of CHD phenotypes are summarized in I2 = 90.0%), geographic region (TSD: I2 = 61.8%), sample sources (TSD: I2 = 63.0%), sample sizes (TSD: I2 = 61.5%), and quality assessment (TSD: I2 = 43.4%), were determined as potential heterogeneity moderators. However, a statistically significant difference was only found in different types of HDP  and geographic region , while different sample sources , sample sizes  and quality assessment  were not statistically different. Additionally, subgroup analyses showed that the risk of total CHDs also was significantly increased when data were restricted to specific HDP types , gestational hypertension , and chronic hypertension . Besides, our results showed that the risk of total CHDs was also significantly increased when restricted to specific preeclampsia types, e.g., mild preeclampsia , severe preeclampsia , early onset preeclampsia , and late-onset preeclampsia   .OR = 1.59; 95% CI: 1.34–1.89), but heterogeneity still exists . Further exclusion of four old studies (before 2010) also yielded similar results . Furthermore, removing nine studies that did not control any confounding factors still did not change the combined risk estimate , but heterogeneity cannot be ignored . Besides, removing any single study at a time still did not substantially affect the combined risk estimate . But, it is worth noting that there was an obvious decrease in heterogeneity (I2 decreased from 94.0 to 15.0%).Galbraith plot was performed to find the studies that bring about heterogeneity. Among 24 studies, nine studies were identified after Galbraith plot analysis . After eP = 0.608).Visual inspection of funnel plot showed a mild asymmetry , but EggOR = 1.55), TOF (OR = 1.35), ASD (OR = 1.78), HLHS (OR = 2.10), COA (OR = 1.73), LVOTO (OR = 1.33), and RVOTO (OR = 1.69). Third, the results of subgroup analyses indicated that the development risk of total CHDs in offspring had significantly increased when data were confined only to specific HDP types, such as pre-eclampsia (OR = 1.79), gestational hypertension (OR = 1.16), and chronic hypertension (OR = 1.68). Fourth, our results showed that the risk of total CHDs was also significantly increased when restricted to specific preeclampsia types, e.g., mild preeclampsia (OR = 1.33), severe preeclampsia (OR = 2.31), early onset preeclampsia (OR = 4.03), and late-onset preeclampsia (OR = 1.27). These findings indicated that early onset and severe preeclampsia had a higher risk of CHDs than late-onset and mild preeclampsia, respectively, and the increased exposure to the hypertensive disorder could generate more important complications. Besides, our results found that the association of maternal HDP with CHDs still exists after subgroup analyses, sensitivity analyses, and Galbraith plot, which indicated that our findings were credible.Our meta-analysis aimed to synthesize the published literature on the association of maternal HDP with the risk of CHDs in offspring. Four principal findings were obtained. First, our study suggested that mothers who had HDP exposure were associated with a 70% increased risk of CHDs in offspring compared with non-exposure. Second, our study indicated that maternal HDP exposure could significantly increase the risk of most CHD phenotypes in offspring including CTD , gestational hypertension (OR = 1.16), and chronic hypertension (OR = 1.68). Second, compared with the previous review , there are still many pregnant women who do not receive adequate antenatal and pregnancy care because of the limited medical service, and the incidence and mortality of HDP were relatively high in these countries. Moreover, the health awareness of pregnant women in these developing countries is relatively weak, which may lead to the diagnosis delay of HDP, and result in a lack of effective early clinical interventions for HDP. Besides, since the definition of HDP may change over time, bias on outcome detection is difficult to avoid, which may increase clinical heterogeneity between studies. Nevertheless, we should still view the results with caution as the heterogeneity cannot be ignored. Thirdly, both case-control and cohort studies were selected in our study. Case-control studies are widely acknowledged to be prone to recall and selection biases, which restrict the strength and quality of evidence. Although the exposure history of maternal HDP was confirmed through medical records and/or physician-diagnosed self-reporting, the potential bias was unavoidable.Fourth, considering that other subtypes of HDP were mostly diagnosed after organogenesis in addition to chronic hypertension, it is difficult to establish a causal link between pre-eclampsia or gestational hypertension and CHDs based on existing studies. Therefore, our study was mainly used to evaluate the association of maternal pre-eclampsia or gestational hypertension with CHDs in offspring, and could not explain the causal relationship. Fifth, of note, although our results found that early onset and severe preeclampsia had a higher risk of CHDs than late-onset and mild preeclampsia, respectively, the number of studies included in the analysis is limited, only three and four studies. In the future, more studies was needed to further explore the potential association between different types of preeclampsia and the risk of CHDs, which may contribute to improving the accuracy and reliability of risk estimates. Sixth, it is difficult to accurately evaluate the effect of the management of these disorders or the use of antihypertensive treatment on the occurrence of complications because of the limited information from original studies. Last but not least, the potential limitations including these studies (studies that were old or poor consideration of confounding factors) are inevitable. Although most of the included studies have tried to control for some potential confounding factors and restricting the analysis to studies that have controlled confounding factors did not substantially change the pooled risk estimate, the possible influences of confounding factors might not be completely omitted. Therefore, further studies with adequate adjustment of potential confounding factors are still warranted to clarify the association of HDP with CHDs in offspring.In conclusion, our findings have two implications significant for the public health of pregnant women. First, our study indicated maternal HDP exposure including pre-eclampsia, gestational hypertension, and chronic hypertension may be associated with an increase in the risk of CHDs. Second, our findings showed that maternal HDP exposure was significantly associated with the risk of most CHD phenotypes in offspring, such as CTD, ASD, and so on. These findings emphasize that maternal HDP exposure could seriously endanger the health of their babies, and lead to an increased risk of death in offspring. Therefore, for pregnancies, especially pregnant women at high risk of HDP, clinical workers should form a coalition of obstetricians, pediatricians, sonographers, and specialists in pregnancy-related hypertensive disease to conduct dynamic monitoring of these pregnant women, and increase cardiac developmental early screening of HDP-exposed infants in order to early intervention, so as to avoid missing the best treatment time and reduce the risk of death in children with CHDs. However, considering that the mechanisms involved in the association between maternal HDP and CHDs in offspring are unclear, further studies are essential to explore the potential mechanisms and find probable interventions.The original contributions presented in the study are included in the article/SZ, LZC, and YJ made substantial contributions concerning: conception and design, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published. XQ, TW, JL, JD, YL, LTC, and JQ made substantial contributions concerning: analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be published. LZC and YJ was the guarantor for the study. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hyperlipidemia plays an important role in the etiology of cardio-cerebrovascular disease. Over recent years, a number of studies have explored the impact of apolipoprotein genetic polymorphisms in hyperlipidemia, but considerable differences and uncertainty have been found in their association with different populations from different regions.P-values were less than 0.05.A total of 59 articles were included, containing in total 13,843 hyperlipidemia patients in the case group and 15,398 healthy controls in the control group. Meta-analysis of the data indicated that APOA5–1131 T > C, APOA1 -75 bp, APOB XbaI, and APOE gene polymorphisms were significantly associated with hyperlipidemia, with OR values of 1.996, 1.228, 1.444, and 1.710, respectively. All Meta-analysis of the data indicated that the C allele of APOA5 1131 T > C, the A allele at APOA1-75 bp, the APOB XbaI T allele, and the ε2 and ε4 allele of APOE were each a risk factor for susceptibility for hyperlipidemia. Hyperlipidemia can be categorized as hypercholesteremia, hypertriglyceridemia, mixed hyperlipidemia, and low-density lipoproteinemia, etc. Medical research has established that the mechanism of hyperlipidemia is not only determined by environmental factors, such as long-term consumption of large quantities of saturated fatty acids, cholesterol, and sugar, it is also influenced by genetic factors at gene loci. There are multiple academic reports that apolipoprotein (APO) gene mutations are closely related to disorders of blood lipid metabolism [Cardio-cerebrovascular disease is the leading cause of increased human mortality, globally . Recentltabolism . APO is tabolism Single nucleotide polymorphisms (SNPs) are changes to a single nucleic acid in a protein caused by the insertion, deletion, or substitution of a single nucleotide base in the gene sequence. Of the existing apolipoprotein candidate genes, researchers have correlated APOA1, APOA5, APOB, and APOE gene polymorphisms with hyperlipidemia. APOA1 and APOA5 genes are located in the long arm region of chromosome 11. APOA1 is located in the APOA1-C3-A4 gene cluster, the principal site controlling the expression of lipids and lipoproteins . APOA5 iOver recent years, there have been multiple studies that have explored the correlation between genetic polymorphism and hyperlipidemia for the apolipoprotein gene loci described above, but there are great differences and uncertainties in different populations from different regions. Therefore, in the present review, we systematically searched the literature and reviewed case-control studies of hyperlipidemia. A meta-analysis was conducted to explore the relationship between APOA , APOB , and APOE with hyperlipidemia so that an evidence-base can be provided for the prevention and control of hyperlipidemia.A total of 3706 articles were identified in the Chinese and English databases, of which 59 articles were finally selected, including 22 that analyzed APOA, 28 APOB, and 30 APOE. Three sites in the APOA gene were studied: A5–1131T > C was studied in 10 case-control studies that included 1211 cases and 1495 controls; A1-75bp was studied in 5 case-control studies that included 1284 cases and 1312 controls; and A1 + 83 bp was studied in 7 case-control studies that included 1452 cases and 1620 controls. The APOB gene was investigated at three sites: MspI was studied in 6 case-control studies that included a hyperlipidemia group, with 1155 cases and 1043 controls; XbaI was studied in 12 case-control studies that included 1900 cases and 1836 controls; and EcorI was studied in 10 case-control studies that included 1633 cases and 1686 controls. The APOE gene is co-coded by the three alleles, ε2, ε3, and ε4, for which 30 case control studies were studied that included 5208 cases in the hyperlipidemia group and 6406 cases in the control group. The NOS score of no study included in the review was less than 7. The comparison between case and control groups was highly credible. The specific process for literature retrieval is displayed in Fig. I2 = 73.9%, P < 0.001), so a random-effects model was used to analyze the combined effects. Individuals with the C allele had a higher risk of hyperlipidemia than those with the T allele, a difference that was statistically significant   and Caucasians  that had the C allele, using the allele model. Other gene models at this site displayed results that were consistent with this , and so a fixed-effects model was used to combine the effects. Individuals with the A allele had a higher risk of hyperlipidemia than those with the G allele, a difference that was statistically significant  . Other gene models at this site were consistent with this result, suggesting that the single nucleotide polymorphism APOA1-75 bp is associated with hyperlipidemia, the A allele being a risk factor for susceptibility to hyperlipidemia . Therefore, a fixed-effects model was selected to analyze the pooled effect. There was no significant difference in risk in individuals that carried the T allele compared with C . The P-values of other gene models at this locus were all higher than 0.05, suggesting that there was no significant difference. Thus, an association between APOA1 + 83 bp gene polymorphism and susceptibility to hyperlipidemia can be considered not to exist , and do a fixed-effects model was selected to analyze the pooled effects. No significant difference in risk was found in individuals carrying the M- compared with the M+ allele . The P-values of other gene models at this site were also greater than 0.05, indicating that there was no significant difference. Thus, no association between genetic polymorphism of APOB MspI and risk of hyperlipidemia was found  and so a random-effects model was used to analyze the pooled effects. The risk of hyperlipidemia in the T allele population was higher than that with the C allele, the difference of which was statistically significant  . However, no significant association was found in other gene models. We found that there was no significant association with risk of hyperlipidemia risk in Asians carrying the T allele using the allele model , other gene models displaying results consistent with those of the allele model , so the pooled effects were analyzed using a random-effects model. There was no significant difference in risk in individuals carrying the A or G alleles . The results of other gene models at this site were consistent with this conclusion, and so no association between the genetic polymorphism of APOB Ecor I and susceptibility to hyperlipidemia  and ε4  indicate that heterogeneity was present and so the pooled effects were analyzed using a random-effects model. The difference in risk between individuals with the ε2 and ε3 allele was not statistically significant . The risk of hyperlipidemia in individuals with the ε4 allele was higher than in those with the ε3 allele, a difference that was statistically significant   for those with ε2 compared with the ε3 allele, but the association was not significant for Caucasians   and Caucasians  with the ε4 allele than those carrying the ε3 allele  compared with carriers of the E3/E3 genotype in Asians, while Caucasians carrying the E3/E4, E4/E4 genotypes were statistically different from those carrying E3/E3  and hyperlipidemia were analyzed using the wild type E3/E3 genotype as a reference. The heterogeneity, and OR and 95% CI values of these data are displayed in Table P-values all > 0.05, indicating that publication bias was apparently not present.There was no apparent asymmetry in each Begg’s funnel plot Fig. , indicatP-values re-calculated. Exclusion of the study [OR = 1.800, 95% CI = 1.454–2.229, P < 0.001). The results indicated stability in the APOA1-75 bp and APOA1 + 83 bp allele models, with no literature having excessive deviation.For groups that deviated substantially in the analysis, meta-analysis was performed again after exclusion of the associated manuscripts, and OR and he study  for APOAOR = 1.365, 95% CI = 1.001–1.862, P = 0.049). Exclusion of the biased literature [OR = 1.351, 95% CI = 0.940–1.941, P = 0.104). Sensitivity analysis of the allele model of APOB Msp I was performed, the results of which were consistent with the original conclusions .For the APOB Xba I locus using the allele model, exclusion of the manuscript  with theOR = 1.150, 95% CI = 0.943–1.402, P = 0.167). Correspondingly, exclusion of the literature [OR = 1.657, 95% CI = 1.365–2.012, P < 0.001). To summarize, we conclude that there was no apparent inconsistency in the literature that would contradict our original conclusions, with good reliability.Exclusion of the manuscript  with theterature  with theThe present study found that allele C at APOA5–1131 T > C was a risk factor for hyperlipidemia, the A allele at AI-75 bp conferred susceptibility to hyperlipidemia, the T allele at APOB Xba I represents a preliminary pathogenic factor for hyperlipidemia in Caucasians, allele ε4 of the APOE gene is a risk factor for hyperlipidemia, and allele ε2 is a risk factor for hyperlipidemia in Asians.The APOE gene, located on chromosome 19, contains 4 exons and 3 introns, with 3 isomers, and the functions by of regulating plasma total cholesterol (TC) and lipoprotein metabolism. APOE3 is the most common phenotype. A principal function is to bind low-density lipoprotein receptor (LDL-R) and APOE receptor as the ligand . CompareAPOB is the principal protein component of LDL and plays a role in transportation of endogenous cholesterol to maintain its balance within the body. The APOB gene is located in region 23–24 of the short arm of human chromosome 2. The APOB gene plays a key role in the production, transport, and removal of LDL and VLDL from plasma and regulates the concentration of plasma cholesterol . The polThe APOA1 gene is located in the terminal region of the long arm of chromosome 11 and consists of 3 introns and 4 exons. APOA1 is the main apolipoprotein to create high-density lipoprotein (HDL), maintaining the stability and integrity of the HDL structure, and promoting the esterification of cholesterol (TC) . The APOA meta-analysis can effectively compensate for the lack of statistical efficacy and other problems within a single study. However, although the present review developed a scientifically-based and comprehensive search strategy with strict unified screening criteria, limitations still remain : (1) TheIn summary, the results of the present meta-analysis revealed that the C allele of APOA5 1131 T > C, the A allele at APOA1-75 bp, the APOB XbaI T allele, and the ε2 and ε4 alleles of APOE may represent genetic risk factors for susceptibility for hyperlipidemia. In addition, we found it is consistent with the present study on the pathological mechanisms of hyperlipidemia. However, there is a need for further large-scale studies, including larger case-control studies and analysis of other loci of the APO genes, to confirm our conclusions and elucidate the influence of gene-environment interactions.The Pubmed, Web of Science, ScienceDirect, the Chinese National Knowledge Infrastructure database, the Chinese Wanfang database, and Database of Chinese science and technology periodicals were searched to identify studies that evaluated the association of APO gene polymorphisms with the risk of hyperlipidemia, where publication date was prior to June 9, 2020. The keywords “apolipoprotein”, “APO”, “hyperlipidemia”, “dyslipidemias”, “hypercholesteremia”, “hypertriglyceridemia”, “mixed hyperlipidemia”, “low density lipoproteinemia”, “APOA”, “APOB”, “APOC”, “APOD”, “APOE”, “APOA5–1131 T > C”, “rs662799”, “APOA1-75 bp”, “rs670”, “APOA1 + 83 bp”, “rs5069”, “APOB MspI”, “rs1801701”, “APOB XbaI”, “rs693”, “APOB EcorI”, “rs1042031”, “gene”, “polymorphism”, and “genetic polymorphism” were searched. The references of all eligible studies were also searched manually in order to find other studies missed during the initial search activity. The analysis followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement .The inclusion criteria for the present meta-analysis were as follows: (1) studies that evaluated the association between APO and risk of hyperlipidemia; (2) studies with an appropriate statistical design and selection methods; (3) case-control and RCT studies; (4) diagnostic criteria for dyslipidemia that were clear and uniform ; (5) disTwo reviewers (XNZ and QS) independently conducted literature screening and evaluation. The following information was extracted from each study for inclusion in the review: first author, year of publication, area, age, source of control, sample size of controls and cases, genotyping method, Hardy-Weinberg equilibrium (HWE), and the distribution of genotypes and frequencies of alleles in cases and controls. Any disputes were resolved by discussion with a third investigator.The quality of the selected case-control studies was evaluated according to the Newcastle-Ottawa Quality Assessment Scale (NOS) , of whicI2 test was also used. Where homogeneity (I2 < 50%) was identified in the meta-analysis, a fixed-effects model was adopted; otherwise, a random-effects model was used to integrate the incorporated data. The data were assessed using Egger’s and Begg’s tests to evaluate publication bias. Sensitivity analysis was conducted by deleting, in turn, the data from individual studies that had large deviations as identified in the results, then recalculating the OR value. All P-values were two-sided, with a significance threshold set at α = 0.05.The included hyperlipidemia data were analyzed by meta-analysis using Stata 11 software. The correlation between apolipoprotein gene polymorphism and hyperlipidemia was expressed by odds ratio (OR) and 95% confidence intervals (CIs). In order to better evaluate the presence of heterogeneity between the studies, an To explore the source of significant heterogeneity, subgroup analysis of race was performed. A total of 7 sites were included, of which 3 sites  were evaluated by subgroup analysis of ethnicity, 2 sites  were analyzed by sensitivity analysis, as there was only one published study of different races in the literature that was not suitable for subgroup analysis. Race was not evaluated in 2 sites  by subgroup analysis due to the fact that the populations studied were the same race, and had no significant heterogeneity.


The aim of this meta-analysis was to evaluate the clinical significance of glutamine in the management of patients with colorectal cancer (CRC) after radical operation. Electronic databases, including PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), VIP medicine information system (VIP), and Wanfang electronic databases were comprehensively searched from inception to 30, July 2021. Prospective randomized trials with glutamine vs. routine nutrition or blank therapy were selected. The immune function related indicators , post-operative complications , and corresponding 95% confidence intervals (CIs) were assessed in the pooled analysis. Subsequently, the heterogeneity between studies, sensitivity, publication bias, and meta-regression analysis were performed. Consequently, 31 studies which contained 2,201 patients  were included. Results of pooled analysis indicated that glutamine significantly improved the humoral immune function indicators , and the T cell immune function indicators [including CD4+  and the ratio of CD4+/CD8+ ]. Meanwhile, the content of CD8+ was decreased significantly  followed by glutamine intervention. Pooled analysis of SSI , anastomotic leakage , and LOS  were decreased significantly in glutamine group compared with control group. Metaregression analysis revealed that the covariate of small-sample effects influenced the robustness and reliability of IgG outcome potentially. Findings of the present work demonstrated that glutamine ought to be applied as an effective immunenutrition therapy in the treatment of patients with CRC after radical surgery. The present meta-analysis has been registered in PROSPERO (no. CRD42021243327).Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO, Identifier: CRD42021243327. Colorectal cancer (CRC) is the most malignant tumors in digestive system and has become a serious threat to human health. Statistically, the global data showed that newly increased patients with CRC ~1,880,725 , and the fatality rate of CRC was estimated to be ~9.4%  Guidelines , 5 and EIncreasing evidences from clinical researches demonstrated that immunonutrition therapy was very likely to improve the immune function and decrease complications or recrudescence in patients after CRC surgery –20. GlutThese evidences were hard to match due to the heterogeneity of study designs, study populations, sample quantities, and systematic approaches based upon current clinical studies. To address those ambiguities and to evaluate the actual clinical significance of glutamine in patients with CRC, a meta-analysis of randomized, prospective clinical trials about glutamine applied in CRC patients who underwent radical surgery was conducted. This meta-analysis provided essential evidence of the effects of glutamine on immune functions and post-operative complications of patients with CRC.https://www.crd.york.ac.uk/PROSPERO).We have registered this protocol previously in PROSPERO in April 2021  the design of study was a prospectively randomized controlled trial (RCT); (2) patients with CRC  and undergone radical surgery; (3) glutamine was set as experiment group and routine nutrition or blank therapy (fluid supporting therapy) as control group; (4) at least one of the investigated outcomes was reported in original researches. The exclusion criteria were as follows: (i) irrelevant studies and duplicated literatures; (ii) unavailable data literatures; (iii) letters, reviews, comments, case-report, laboratory studies, and meta-analysis.The PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), VIP medicine information system (VIP), and Wanfang electronic databases were comprehensively searched up to July 30, 2021. The search terms were in the combination of medical subject headings (MeSH) terms and the following free words:  AND (glutamine/nutrition/immunenutrition) AND (complication/infection/leakage) AND (immune/immunity/IgA/IgG/IgM/CD4+/CD8+/CD4+/CD8+) AND . In addition, potentially relevant references were also obtained manually. The language of all the publications was not limited.All search results were combined in Endnote™, Version X8 (Thompson Reuters). Duplicates were removed manually. Two investigators (Tao Yang and Xuhong Yan) filtered the original studies independently. If the literature meets the eligibility criteria, the two investigators will further read the full text to screen the study. Any discrepancies were tackled by discussion or third-party consensus.All data were collected independently by two investigators (Tao Yang and Yibo Cao) from eligible RCTs using a standardized form. The following information were extracted including: (i) Study ID, including the name of the first author and publication year; (ii) study subjects, number of participants, and their ages; (iii) treatment regimens for the treatment and control groups; and (iv) the primary endpoint, the immune function related indicators  and the secondary endpoint, the post-operative complications . If insufficient details were reported, we would contact authors for further information. Disagreements between two investigators were tackled by discussion and consensus.The Cochrane Collaboration's tool for assessing risk of bias were employed for quality evaluation. Any disagreements during assessment were resolved by iteration, discussion, and consensus.Q-test and an I2-test before determining the pooled effect. A fixed effects model or a random effects model was based on the results of the Q-test and I2-test. A fixed effects model was adopted if I2 < 50% and p > 0.1. Otherwise, a random effects model was used. The primary endpoint was immune function related indicators  and LOS was a continuous variable. The pooled analysis of these indicators was expressed as standard mean difference (SMD). The SSI and anastomotic leakage were dichotomous variables, and the pooled analysis of these complications was expressed as relative risks (RR). The significance of pooled effects was determined using a Z-test; p < 0.05 was considered to indicate a statistically significant difference. Sensitivity analysis was utilized to investigate the influence of a high-risk study on overall meta-analysis. Possible publication bias and the detailed reasons underlying publication bias were determined by contour-enhanced funnel plot. Possible source of heterogeneity was explored by metaregression performing via random effect model, and the restricted maximum likelihood (REML) estimation method proposed by Harbord et al. . Heterogeneity amongst studies was assessed using a d et al.  was applA total of 444 relevant articles were retrieved ultimately. Among these, 304 were repeated articles. Totally, 84 literatures were excluded by screening the titles and abstracts due to reviews, conference abstract, animal experiments, case report, with 56 articles remaining. Then 25 articles were excluded by examining the abstracts or full-texts. Finally, this meta-analysis included 31 studies that fulfilled the inclusion criteria .Totally, 2,201 patients were involved in 31 studies , 30–57. Methodological quality assessment and outline of the included 31 studies were presented in I2-test = 89.3% and Q-test p = 0.000, I2-test = 65.2% and Q-test p = 0.000, I2-test = 89.9% and Q-test p = 0.000, Z = 5.27, p = 0.000; SMD = 1.15, 95% CI: 0.72–1.58; Z = 6.47, p = 0.000; SMD = 0.68, 95% CI: 0.48–0.89; Z = 5.34, p = 0.000; SMD = 1.10, 95% CI: 0.70–1.50; The pooled analysis of humoral immune function indicators  is presented in I2-test = 71.2% and Q-test p = 0.000, I2-test = 89.9% and Q-test p = 0.000, I2-test = 85.9% and Q-test p = 0.000, Z = 6.47, p = 0.000; SMD = 0.76, 95% CI: 0.53–0.99; Z = 2.44, p = 0.015; SMD = −0.50, 95% CI: −0.91 to −0.10; Z = 5.07, p = 0.000; SMD = 0.92, 95% CI: 0.57–1.28; Before pooled analysis of T cell immune function indicators , heterogeneity across studies was tested conventionally. Heterogeneity test results revealed there was moderate heterogeneity for CD4+  with significant heterogeneity (≥80%) across included studies. Results are shown in Sensitivity analysis p < 0.01, p < 0.05, p < 0.1 or p > 0.1) to funnel plots, was utilized to distinguish detail reasons of publication bias. Results of SSI (p > 0.1), which suggested that the origin of asymmetry may be more likely due to publication bias. Furthermore, results of IgA (p < 0.01), which indicated the origin of asymmetry was most likely to be due to undetected factors rather than publication bias. Subsequently, we traced the original researches again, speculating that studies with a small sample size, ITT analysis, and missing blinding in many studies may account for those undetected bias. These factors may influence our conclusions potentially.Contour-enhanced funnel plot, which added conventional milestones in levels of statistical significance . The remaining variable of total sample size had significant influences on the pooled effects of IgM  of glutamine; ② Tumor type ; ③ Total sample size (<100 or ≥100). Overall, univariate analysis indicated the administration route (PN or EN) of glutamine  and typeOverall, findings from this study illustrated that immune functions  can be improved significantly with glutamine in sufferers with CRC. Meanwhile, the main post-operative complications also reduced by glutamine in patients with CRC after surgery. The certainty of conclusion from current study is mainly reflected in the following three aspects. First of all, the critical indicators of humoral immune function, including IgA, IgM, IgG, were significantly increased followed by glutamine intervention. The results of integrated analysis revealed that IgA content  was increased significantly in glutamine group compared with the control group. Meanwhile, the indicator of IgM  and IgG were also significantly increased  in glutamine group. These results demonstrated that glutamine was able to improve the humoral immune function effectively for patients with CRC after radical operation. Secondly, results of integrated analysis revealed that glutamine could regulate T cell immune function effectively of CRC patients after radical surgery. On one hand, the content of CD4+  and index of CD4+/CD8+  were increased significantly in glutamine group compared with control group. On the other hand, the content of CD8+ was decreased significantly  in glutamine group. These results indicated that glutamine could regulate the disordered immune function of T cell. Thirdly, all indicators of post-operative complications were decreased by glutamine in patients with CRC after surgery. Pooled analysis of SSI , anastomotic leakage , and LOS  were decreased significantly in glutamine group compared with control group. All supporting evidence mentioned above demonstrated that glutamine should be applied as an effective immunenutrition therapy in the treatment of CRC patients after radical surgery.Immunenutrition support for patients who underwent radical surgery for CRC is widely accepted for reducing the incidence and severity of post-operative complications. However, appropriate assessment and application of immunenutrition therapies were largely neglected . Until tThis current work exerts more attention to the clinical benefits of glutamine in CRC patients after radical surgery. However, it is noteworthy that potential limitations of this integrated analysis should be emphasized. Thirty-one included trials were neither single nor double blinding design, which increases the risk of detection bias. Meanwhile, undetected bias predicted by contour-enhanced funnel plot showed studies with a small sample size and missing ITT analysis may account for potential bias. These factors may have a potential impact on final conclusions. Metaregression by univariate and multivariate analysis found sample size included in original studies was a potential covariate causing significant heterogeneity, and deescalating validity of results in this pooled analysis.All in all, this meta-analysis with 2,201 patients from 31 RCTs provide pivotal evidence that glutamine supplementation could improve immune function and decrease post-operative complications of CRC patients after radical surgery effectively. When accepting the conclusions of this study, the methodological limitations should be noticed at the same time. It is widely recognized that the management CRC in pre- or post-operative stages is very much needed in the participation of multiple disciplinary team (MDT) and requires long-term medication. Thus, increasing RCTs with larger scale and multidimensional efficacy and nutritional status assessment are extensively required to balance the risk-benefit profile of glutamine in the management of CRC.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.TY, XY, and YC performed the search and drafted the manuscript. TY and XY performed the data extraction and analyzed the data. YC, TB, and TX designed the study and amended the original draft. GL, SG, and KX equally involved and contributed into the study conduction. All authors contributed to the article and approved the submitted version.This research was financially supported by the Science and Technology Projects of Guizhou Province .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P-glycoprotein encoded by the ABCB1 gene constitutes a molecular barrier in the small and large bowel epithelium, and its different expression may influence susceptibility to inflammatory bowel disease (IBD). We aimed to assess the contribution of the C3435T polymorphism to disease risk in the Polish population. A total of 100 patients (50 Crohn’s disease (CD), 50 ulcerative colitis (UC)) and 100 healthy controls were genotyped for the single nucleotide polymorphism (SNP) C3435T by using the PCR-RFLP method. Patients were classified on the basis of disease phenotype and the specific treatment used. A meta-analysis was carried out of our results and those from previously published Polish studies. There was no significant difference in allele and genotype frequencies in IBD patients compared with controls. For CD patients, a lower frequency of TT genotype in those with colonic disease, a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease were observed, whereas for UC patients, a lower frequency of CT genotype was observed in those with left-sided colitis. A meta-analysis showed a tendency towards higher prevalence of CC genotype in UC cases. These results indicate that the C3435T variants may confer a risk for UC and influence disease behaviour. Inflammatory bowel diseases (IBD) are heterogeneous disorders that cause chronic inflammation of the gastrointestinal tract with possible extraintestinal manifestations. Two main subtypes, i.e., Crohn’s disease (CD) and ulcerative colitis (UC), can be distinguished . They haThe pathogenesis of IBD remains not fully understood, but may require an interaction between genetic predisposition and combination of persistent bacterial infection, defective mucous barrier and imbalance in the regulation of the immune system . GeneticP-glycoprotein (P-gp) is one of the most extensively studied human adenosine triphosphate (ATP)-binding membrane cassette transporters and is encoded by the multidrug resistance ABCB1 gene (previously known as MDR1). P-gp catalyses the translocation of its substrates against a concentration gradient by using the energy generated from the hydrolysis of ATP. It prevents uptake of drugs and toxins into the blood capillaries and limits the bioavailability of many orally administered drugs . In addiThe ABCB1 gene is an attractive candidate for the pathogenesis of IBD and perhaps response to therapy. Its role in IBD was investigated in a mouse knockout model (mdr1a-/-). These mice, previously healthy, spontaneously, even if maintained under specific pathogen-free conditions, developed colitis, which resembles UC in humans. The colitis was prevented and reversed by the administration of antibiotics, suggesting that the intestinal flora is necessary to initiate and perpetuate the inflammation . NeverthTherefore, we aimed to investigate the contribution of ABCB1 C3435T polymorphism to IBD susceptibility, the relationship between genotype and disease phenotype, as well as drug exposure, in a cohort of well clinically characterized patients originating from the Lower Silesia region in Poland, and to embed our association study results in the context of previous studies carried out in the Polish population.The study had a case–control design. The cases consisted of 100 patients, age 19–81 years, with IBD, recruited consecutively from the Department of Gastroenterology and Hepatology of Wroclaw Medical University, Poland in the period from September 2019 to December 2020. The diagnoses of CD and UC were made by a gastroenterologist based on endoscopic, radiological, and/or histopathological examinations in compliance with established clinical guidelines and criteria ,36. One ® Blood DNA Mini Kit  according to the procedure provided by the manufacturer at the Department of Clinical Pharmacology of Wroclaw Medical University, Poland.The genomic DNA samples of patients and controls were extracted from peripheral blood leucocytes with the use of E.Z.N.A.The determination of C3435T polymorphism in exon 26 of the ABCB1 gene was performed with the modified method of Siegmund and collaborators using Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP) . The PCRA thorough analysis of medical records was performed, and detailed phenotypic information was available for all patients from the study group. For both CD and UC, the Montreal classification was employed . For CD,In an attempt to evaluate the potential association of C3435T polymorphism of ABCB1 with IBD in a wider context, we carried out a meta-analysis of studies on Polish population. We performed systematic search of PubMed and EMBASE databases for articles published until 27th of March 2021. Our search strategy was as follows:  AND  AND  AND ([english]/lim OR [polish]/lim) AND [humans]/lim AND ([embase]/lim OR [medline]/lim). A total of 11 records were identified. A detailed review abstracts and full texts enabled inclusion of two studies. Three studies were excluded because of inadequate population , in one study different ABCB1 polymorphism  was analysed, another one was not a gene-association but gene-expression study, and four studies were review articles. Characteristics of eligible studies with the allele and genotype frequencies are shown in After these results were pooled with our own data, a total of 124 CD cases, 136 UC cases and 338 controls were included in the meta-analysis.The study was of case–control design. The distribution of individual characteristics was evaluated by simple descriptive statistics. Values were presented as mean ± SD. To determine whether the observed allele frequency distribution remained in the genetic equilibrium, the Hardy–Weinberg equation was tested via the Court lab-HW Calculator.xls.p-values. p-values were reported uncorrected for multiple testing and those <0.05 were considered statistically significant.Allele and genotype frequencies were compared between cases and controls, as well as between specific phenotypic disease subgroups (of at least 10 patients) and controls, through the use of chi-square tests. Odds ratios (ORs) were given with 95% confidence intervals (CIs) and 2-sided 2 statistic. In all comparisons, the hypothesis about the homogeneity of the studies could not be rejected (p > 0.05 and I2 < 50%); however, both fixed- and random-effects models were employed. Computations were made using the R-package version 4.0.3 software and the “meta” package version 4.19.0 for meta-analysis purposes.In meta-analysis for any individual study, ORs and 95% Cis were calculated and T and C allele as well as CC, CT and TT genotype frequencies were compared across studies. Statistical heterogeneity was evaluated with Cochran’s Q-statistic and quantified with the IA total of 50 CD cases, 50 UC cases, and 100 healthy controls were genotyped for C3435T. The proportion of males was higher in UC (64%) than CD (50%). The mean age at diagnosis for CD and UC patients was 27.6 and 29.3 years, with a mean duration of follow-up of 8.2 and 9.2 years, respectively. Detailed phenotypic information was available on all IBD cases. The proportions of CD patients with different disease location and behaviour, of UC patients with different disease extent and having severe disease, and of IBD patients as a whole requiring 5-ASA, immunosuppressants, corticosteroids and anti-TNFs, as well as of those who have undergone IBD surgery, are shown in Control and IBD case genotypes were in Hardy-Weinberg equilibrium. No statistically significant differences were found between either CD or UC patients and the control group for the frequency distribution of T and C alleles as well as of CC, CT and TT genotypes .Frequencies of the C3435T variants in the different IBD phenotypic subgroups were compared with their frequencies in the control group. In the group of CD patients there was a lower frequency of TT genotype  in those with colonic location, a higher frequency of allele C  and a lower frequency of allele T  in those with only luminal disease, as well as a trend toward a higher frequency of allele C  and a lower frequency of allele T  in those with colonic location .In the group of UC patients, there was a lower frequency of CT genotype  in those with left-sided colitis, together with a trend toward a higher frequency of allele C  and CC genotype  and a lower frequency of allele T  in those with severe disease .p = 0.06, for random-effects model)  was noted in two studies and the pooled OR for CC genotype in UC tended to be statistically significant  .Inflammatory bowel disease is considered a complex polygenic trait with several genes involved. Linkage analysis, the candidate-gene approach, and genome-wide association studies (GWAS) have all been used to identify IBD susceptibility genes ,42. On tp = 0.049, OR = 1.4; p = 0.005, OR = 2.1, respectively) [p = 0.02, OR = 1.28) and the TT genotype  [p = 0.02, OR = 2.12) [Based on the assumption that interindividual variability of P-gp expression in intestines is linked to the ABCB1 C3435T SNP, attempts have been made to explain whether TT genotype, associated with low intestinal P-gp expression, can predispose to IBD. In the initial case–control study by Schwab et al. (Germany), an increase in the frequency of T allele and TT genotype was confirmed in 149 UC patients, but not in CD patients (ctively) . This fi = 1.60) , as well = 2.12) . SimilarIn this study, carried out in an IBD population originating from the Lower Silesia region in Poland, we were not able to corroborate the association between the C3435T polymorphism of ABCB1 gene and IBD. The frequency distribution of T and C alleles and CC, TT and CT genotypes was not different between CD and UC patients and the control group. Our results are in line with those of large studies coming from Germany and Great Britain , North Ap = 0.06). This is in contradiction with the previously cited studies, which either found that T allele or TT genotype may increase the risk of UC, or did not confirm a significant influence of the C3435T polymorphism on the risk of IBD in general. A summary effect size was assessed in two meta-analyses from 2006; Annese et al. found a significant association of 3435T allele and 3435TT genotype with UC  and no association with CD [p = 0.013) but not with CD [p = 0.007), recognizing the 3435C allele as a risk factor for CD [Divergent results of the above-mentioned studies may be driven by population heterogeneity, sample size, selection of the control population and lack of statistical power to detect small or moderate effect size. A significant variation of the C3435T allele frequency in different populations has been proven. For example, the frequency of the C3435 allele has been reported as 43–54% in Caucasians, 34–63% in Asians and 73–90% in Africans . Therefo with CD , and Onn with CD . Urcelayr for CD .The results of our study, although we did not obtain statistical significance, seem to question the current state of knowledge, i.e., that a reduced intestinal barrier function initially linked to low P-gp expression and 3435TT genotype increases the risk of developing UC. They should be approached with great caution. First, our sample was relatively small, as was the total number of Polish cases included in the meta-analysis. Secondly, the effect size of an association between C3435T and UC is rather modest (estimated previously at 12–17%) ,33.p = 0.04) and UC , what was not true for each of these SNPs analysed separately [Of note, 3435C→T mutation in exon 26 is a synonymous SNP . There is a linkage disequilibrium between SNPs in exon 26 (C3435T) and exon 21 (G2677T/A), suggesting that initially attributed to the exon 26 SNP different P-gp expression, may result from the associated tri-allelic polymorphism in exon 21. The latter is a non-synonymous SNP  . A synonparately . Last buparately , which wparately . It is eTo investigate the possibility that C3435T associations were limited to specific disease phenotypes, we classified our cases into clinically well-defined subgroups. In the group of CD patients, we found a lower frequency of TT genotype in those with colonic disease (L2), a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease (B1). In the group of UC patients we found a lower frequency of CT genotype in those with left-sided colitis (E2). No association was seen of C3435T with groups distinguished as per the pharmacotherapy used or the need for surgery. Once again it is necessary to underline that our results should be regarded with caution, given the small sample size, particularly when it comes to subgroup analysis.In a genotype–phenotype analysis by Ho et al., the risk of UC with the proximally spreading lesions was estimated as 1.70 (p = 0.009) and 2.64 (p = 0.003) for the 3435T allele and the 3435TT genotype, respectively . ArdizzoIt is very difficult to interpret these results, which are so divergent, and associate specific C3435T alleles or genotypes with a specific disease phenotype or response/non-response to treatment. However, due to the heterogeneity of inflammatory bowel disease and the fact that sometimes it can hardly be possible to predict the course of the disease in a given patient, it is always worth looking for the relationship between the phenotype and genetic factors. We acknowledge several limitations of our study: the sample was relatively small; we tested only one ABCB1 polymorphism, and therefore haplotype analysis was not possible; we did not examine the expression of the ABCB1 gene in the duodenum; and we did not correlate that expression with the expression of, e.g., CYP3A4, another known molecular barrier component in the small intestinal epithelium.The strengths of our study are the association of C3435T variants with different IBD phenotypes and treatment response (revised for the first time in the Polish population) and the embedding the results of current case–control study in the context of other studies in the Polish population. An intriguing conclusion is the predominance of C allele in patients with both CD and UC , as well as the predominance of CC genotype in UC patients, striving for statistical significance. An absolutely principal question that arises here relates to the level of expression of the ABCB1 gene with respect to its variants (considering opposite results yielded by German and Japanese authors), and whether this level shows differences depending on the studied population . Indeed, in order to dispel some of the uncertainties that arose in the course of the current study, we have already planned its continuation with another SNPs (C1236T and G2677T/A) in addition to C3435T being assessed, enterocolonic biopsies being taken and tissue P-gp expression being measured.


ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞  and Cmax  than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.Although several studies have revealed the association between rosuvastatin pharmacokinetics and the  Rosuvastatin, a potent 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitor , markedlSLCO1B1) and the ATP-binding cassette superfamily G member 2 (ABCG2), respectively. [SLCO1B1 and rosuvastatin pharmacokinetics has been studied extensively, while little is known about the relationship between ABCG2 and rosuvastatin pharmacokinetics. It has been reported that interindividual variation in exposure to rosuvastatin is associated with the polymorphisms of OATP1B1 and BCRP, which are encoded by the solute carrier organic anion transporter family member 1B1 , one of the most frequent polymorphisms in the ABCG2 gene [ABCG2 efflux activity [ABCG2 substrate, the ABCG2 421C>A polymorphism can affect rosuvastatin pharmacokinetics and its therapeutic efficacy. Although several studies reported the association between rosuvastatin pharmacokinetics and ABCG2 421C>A polymorphism [ABCG2 421C>A polymorphism in rosuvastatin pharmacokinetics that may affect its efficacy and side effects.The CG2 gene , decreasactivity . As rosumorphism , most stABCG2 OR  OR (ATP-Binding Cassette Superfamily G member 2) OR BCRP OR BCRP1 OR (Breast cancer resistance protein) OR MRX OR MXR OR MXR1 OR MXR-1 OR CD338 OR CDw338) AND . This meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist . Two resAfter removing duplicates, two researchers independently screened the titles and abstracts of all records to identify potentially eligible studies. Then, a full-text review was performed to determine the final inclusion according to the eligibility criteria. In cases of disagreement, a consensus was reached by discussion.ABCG2 421C>A polymorphism with rosuvastatin pharmacokinetic parameters, and (ii) included healthy adult volunteers receiving a single dose of rosuvastatin. Studies were excluded if they were (i) non-original articles, (ii) performed on subjects receiving concomitant drugs, (iii) unable to extract data, (iv) overlapping papers, and (v) not written in English. Only the most recent and comprehensive data were included in the meta-analysis in the case of overlapping data.Studies were included if they (i) evaluated the association of the ABCG2 421C>A were also extracted from the studies. The primary outcomes were the area under the plasma concentration–time curve from 0 h to infinity (AUC0-∞) and the peak plasma concentration (Cmax); the secondary outcomes were the time to reach Cmax (Tmax) and the half-life.Two researchers independently extracted data, and the discrepancies were resolved by consensus. The extracted data included the following information: the name of the first author, publication year, nation, race, number of patients, percentage of males, age, body mass index, rosuvastatin dose, studied pharmacokinetic parameters, type of mean values, and genotyping and quantitative methods. In addition, the pharmacokinetic parameters of rosuvastatin impacted by Two researchers assessed articles based on the Newcastle–Ottawa Scale (NOS) , evaluatABCG2 421C>A polymorphism with rosuvastatin AUC0-∞ and Cmax. The arithmetic mean difference (AMD) and their corresponding 95% CIs were used for determining the Tmax and half-life. If the administered rosuvastatin dose was different from 20 mg, the mean and standard deviation (SD) were adjusted, given that AUC0-∞ and Cmax were reported to increase proportionally with the dose [The meta-analysis was conducted using Review Manager , using inverse variance weighting. The log geometric mean difference (lnGM) and their corresponding 95% confidential intervals (95% CIs) were used to identify the relationship of the the dose . To poolthe dose .lnGM=lnlnGM). The heterogeneity across studies was estimated using a chi-square test and an 2I statistic [2I > 50%); otherwise, the fixed-effects model was applied [p-value < 0.05 was considered statistically significant.The magnitude of the association was interpreted as the antilogarithm of a natural logarithm , an in vitro or animal study (n = 1), studies performed on subjects receiving concomitant drugs (n = 5), studies without pharmacokinetic parameters (n = 3), studies on other genes (n = 3), a study on other drugs (n = 1), studies unable to extract data (n = 9), and studies not written in English (n = 1). Finally, a total of eight studies were selected for meta-analysis [A detailed flow chart of the study selection process is presented in ters n = , studiesanalysis ,21,22,23The characteristics of the included studies are presented in ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetic parameters  (max (p > 0.05)  , but not > 0.05) .0-∞ (lnGM range 0.42–0.45) and Cmax (lnGM range 0.39–0.44) and AMD for Tmax (AMD range −0.12–0.15), and half-life (AMD range −0.57–0.21) were similar to the main results .The ulations . However0-∞ and Cmax of rosuvastatin between GM and AM  was also associated with ABCG2 421 C>A. According to Zhang et al. [In addition to AUCg et al. , CL/F  [Our results with healthy volunteers were similar to previous results with hypercholesterolemia patients. Lee et al. revealed that in Chinese patients with hypercholesteremia, the mean plasma concentrations of rosuvastatin and its metabolite were higher in subjects with the genotype . In addi < 0.05) . p <10−5) [Several studies reported that 421 C>A affected not only pharmacokinetic properties, but also drug responses of rosuvastatin. According to Lee et al., % changes in LDL-C were significantly different among 421 C>A genotypes in rosuvastatin-treated patients  . Similarp <10−5) ,27. In tp <10−5) . ABCG2 421 C>A [ABCG2 poor function due to the high exposure. In line with its recommendation, this study provided quantitative evidence for the associations between ABCG2 421 C>A and increased AUC0-∞ and Cmax of rosuvastatin by pooling the results of related articles identified by systematic review through the meta-analysis.Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) conducted a systematic review and published the guideline for statin-associated with musculoskeletal symptoms, including  421 C>A . AccordiABCG2 421C>A polymorphism decreases the plasma membrane expression or transporter ATPase activity of ABCG2 [It has been reported that the of ABCG2 ,30,31,32of ABCG2 .ABCG2 421C>A polymorphism and drug responses. For example, a meta-analysis of the association between ABCG2 421C>A polymorphism and imatinib response in patients with chronic myeloid leukemia revealed that the A allele was significantly associated with an increased rate of overall response [ABCG2 in A allele carriers appears to be the reason for this low efficacy.Several meta-analyses have shown the association between the response . Similarresponse . ReducedSubgroup analysis by ethnicity showed that, regardless of ethnicity, 421 A allele increased the rosuvastatin exposure by 50%. As the allele frequency of 421 A was higher in Asians than Caucasians (0.29 vs. 0.15) , Asians Another subgroup analysis by reported type of mean values showed that the GM method and AM method showed similar results, supporting the idea that the Higgins conversion equation  could prmax and half-life was relatively small. Despite those limitations, this meta-analysis revealed that A allele carriers showed increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Thus, as there might be interindividual variations in rosuvastatin efficacy and toxicity, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.This study has some limitations. First, we conducted a meta-analysis on healthy volunteers, not patients, which may result in low external validity. Second, we could not consider other intrinsic or extrinsic factors that could affect rosuvastatin pharmacokinetics. Third, the number of studies for T


BAX -248 G>A and BCL2 -938 C>A with different cancers created conflicts. We studied the correlation and the effect of these polymorphisms in patients with Nasopharyngeal Carcinoma (NPC). The association of PCR-RFLP and Sanger sequencing were used to detect polymorphisms. Statistical analysis including forest plot and Kaplan-Meier Log-rank test was conducted to investigate the association and effect of these SNPs on the NPC patients’ survival. The computational study was performed to investigate the possible regulatory role between these polymorphisms and the poor survival of NPC patients. Meta-analysis was executed to check the tissue-specific association of these polymorphisms in the context of global cancer prognosis. BAX -248 G>A , and BCL2 -938 C>A  with the risk of NPC. Also, these SNPs were strongly correlated with poor survival in NPC patients . The computational study showed that these SNPs altered the binding affinity of transcription factors HIF1, SP1, PAX3, PAX9 and CREB towards promoter (Lower p indicates strong affinity). The meta-analysis revealed the tissue-specific association of these polymorphisms. BAX -248 G>A showed a significant correlation with carcinomas , and BCL2 -938 C>A with other malignancies . We observed an increased and significant association of BAX -248 G>A and BCL2 -938 C>A was associated with poor survival in NPC patients. It may increase cancer susceptibility through transcriptional regulation. Moreover, these SNPs’ effects could be tissue-specific. SNP) and structural alteration in the individual organism . SNP is the most studied form of sequence variation, which sometimes may enhance disease susceptibility including cancers . It is detected in different parts of a gene covering from the untranslated regions to the functional regions. Thus, the effect of SNPs in susceptibility towards diseases may vary depending on the location of such alterations. SNP in the promoter region may alter gene expression either by altering transcription factor (TF) binding, DNA methylation, or histone modifications. However, the functional consequences of SNPs are more challenging to predict and validate, because the regulatory code is much more complex than the genetic code . Genetic polymorphisms make up the basics of phenotypic diversity. Increasing evidence showed substantial sequence abnormalities such as single nucleotide polymorphism . BAX and BCL2 are the members of the BCL-2 family that regulates apoptosis differently. BAX  is a pro-apoptotic protein, promotes apoptosis via mitochondrial-mediated pathway. BCL2 (OMIM 151430), on the other hand, is categorized as an anti-apoptotic protein that inhibits apoptosis by inhibiting BAX. Though, two proteins are located in different chromosomes (BAX on19q13.33 and BCL2 on 18q21.33), they functionally bind with each other to regulate cell proliferation. Evidence suggested that the expression of these proteins is regulated individually by many other cellular components and that the ratio of their relative levels determines the cell fate . Thus, any aberration in their expression level may lead to an increase in cell proliferation.So far, promoter polymorphism of BAX promoter polymorphism altered its expression in chronic lymphocytic leukemia and significantly shortened the patients’ survival in many cancers . Similar results were found in the case of BCL2 . However, SNP observed in specific characteristics may not unavoidably the causative change . Thus, preliminary data based on the computational study is required to produce an assumption about the regulatory mechanism involved. Moreover, further evidence demonstrated the ethnicity-specific association of these SNPs, as the Asian population is exhibited a significant correlation compared to Caucasians . Besides the correlation with cancer susceptibility, negative associations are also reported in some malignancies. Hence, conflicts are still there about the association of these polymorphisms with cancer susceptibility. Early evidence suggested that the effect of some SNPs could be Tissue-specific. So far, no such association was reported in BAX -248 G>A and BCL2 -938 C>A polymorphism. Thus for better rationalization, the association and the effect of these polymorphisms on different cancer susceptibility need to be inspected in any ethnicity-specified and tissue-specific cancers. Some findings suggested that these SNPs increased the risk of cancer by altering their gene expressions and lowering the survival in patients with malignancies . For example, BAX -248 G>A and BCL2 -938 C>A SNPs on nasopharyngeal carcinoma (NPC) patients’ survival. Further, the impact of these polymorphisms in different tissue-specific  cancers was investigated. NPC was chosen for several reasons, unlike other cancers, the occurrence and distribution of NPC depend on the ethnic variation. In Asia, it is uniquely prevalent in southern China, Indonesia, and Northeastern India (NEI) . Moreover, about 20% to 30% of the NPC patients with the same stages, receiving similar treatment, showed local relapse or distal metastasis, indicating the involvement of genetic factors . Moreover, the correlation of these SNPs with NPC prognosis is still unknown. Therefore, in our present study, efforts were made to explore the correlation and effect of Study selectionNPC samples (n=100) were collected from different state hospitals of NEI between 2014 and 2018. For each subject, epidemiological and clinicopathological information was verified and considered for the study. Based on the instructions of the World Health Organization (WHO), clinical examinations of all cases were confirmed . NPC stages were determined according to the AJCC (American Joint Committee on Cancer) classification system . For the control group, samples were collected (n=70) from the age and sex-matched healthy volunteers of the same ethnic background. According to the research review committee guideline, informed consent was obtained from all subjects. The characteristics of NPC patients and controls are described in supplementary table S1. The present study was approved by the Institutional ethics committee. Also, ethical approval was obtained from all the participating institutes.Detection of genotypes by PCR-RFLP and SequencingBAX and BCL2 were amplified by PCR with specific primers as previously reported . For restriction fragment length polymorphism (RFLP), PCR products were purified and half of the volume was digested by TauI  and BccI  to identify genotypes of BAX and BCL2 respectively . Another half of the purified PCR products were sent to the service provider  for Sanger sequencing to cross-check the previous analysis result. After the sequencing, sequences were aligned with the reference sequence for BAX (rs 4645878) and BCL2 (rs2279115) using the CLUSTALW  to check sequence similarity.Genomic DNA was extracted from each sample using the genomic DNA extraction kit  following the manufacturer’s instructions. Initially, eight NPC samples were removed from the study due to poor DNA content. A total of 92 NPC samples and 68 healthy controls were used to identify BCL2 -938 C>A. After the first analysis, 22 samples containing an insufficient amount of DNA were eliminated and 70 NPC samples and 70 healthy controls were considered further for the detection of BAX -248 G>A. Gene symbols were verified according to the nomenclature guidelines of the Human Genome Variation Society (HGVS) . Promoter regions of both Study the genetic association and NPC patients’ survivalBAX -248 G>A, and BCL2 -938 C>A polymorphism with the risk of NPC . Odds ratio (OR) was calculated for each genetic model to show the association between the exposure and outcome, 95% of Confidence Interval (CI) was analyzed to determine the population mean precisely, and the p-value was measured for the level of significance, where P<0.05 was considered as significant. A fully nonparametric Kaplan-Meier analysis was conducted to test the survival probability due to SNPs. Log-Rank test was used to estimate if there were a statistically significant difference in the cumulative proportions across groups. All the patients’ data was arranged according to the genotype combination. Endpoint or censored information of each patient was obtained from the hospital cancer registry. MedCalc Statistical Software, version 18.1 , and R studio (Version 1.3) were used for the statistical calculation . The allele and genotype frequencies in NPC cases and healthy controls were calculated manually . Linear regression was measured by Fisher’s exact test to investigate the association of Functional analysis of BAX -248 G>A and BCL2 -938 C>AThe computational approach was performed to investigate the possible regulatory mechanism involved due to these polymorphisms in terms of transcription factors (TFs) binding to the specific polymorphic region. The difference of TFs’ binding affinity was measured using the online available tool named sTRAP (http://trap.molgen.mpg.de/cgi-bin/trap_two_seq_form.cgi), which predict TFs binding affinity changes to a region . The sTRAP is an affinity-based method, uses both TRANSFAC and JASPAR databases to search the query. It has several advantages over other hit-based approaches that use position-specific scoring matrices (PSSMs) . After initial analysis for the TFs, weight scores were measured from the prior chosen weight matrices. Then total affinity of a sequence for a TF was calculated by affinity values , where a lower p-value indicated a strong affinity .Study the impact of BAX and BCL2 SNPs on tissue-specific malignanciesMeta-analysis was conducted to investigate if there is any impact of these SNPs on tissue-specific cancers. Qualified publications were retrieved from publicly available Medline databases (PubMed), EMBASE, Science Direct, and Wiley online library until October 2018. To assess the quality of the meta-analysis, the method of each study was considered independently following the PRISMA statement . Initially, 766 reports were identified from various databases and 3 articles from other sources were included to make our search inclusive. Following the removal of duplicates, 312 records were identified. After a full-length screening, studies containing irrelevant data, missing information, etc. were excluded, and eventually, 29 studies were considered. Our current case-control study was also included, to increase the study size . Hardy–Weinberg equilibrium (HWE) was calculated to detect a deviation in genotype distribution of the control groups using the web-based tool . P >0.05 was considered as no deviation from the Hardy–Weinberg equilibrium. Forest plot analysis was performed to evaluate the association in 5 different models, i.e. allelic (A vs G/A vs C); homozygous (AA vs GG/AA vs CC); heterozygous (GA vs GG/CA vs AA); dominant (AA+GA vs GG/ AA+CA vs CC) and recessive model (AA vs GG+GA/ AA vs CC+CA). Detection of BAX -248 G>A and BCL2 -938 C>A and association with NPC patients’ survival BCL2 -938 C>A polymorphism and NPC was found in the genotype CA, AA, CA+AA and the allele A . BAX GA+ BCL2 CA dual positive genotype was also observed in seven (10%) NPC cases and one (1.42%) healthy control. Genetic association study showed that dual positive heterozygote was not significantly associated with the risk of NPC (The results of the PCR-RFLP and sequencing for the detection of BAX and BCL2 genotypes is shown in k of NPC . BAX (GA+AA) and BCL2  polymorphisms are the independent predictors for the lower survival in patients with NPC. Likewise, the dual positive heterozygote of BAX and BCL2 have demonstrated decreased survival. Also, the same genetic models for BAX, BCL2, and dual positive heterozygote showed the lowest Proportion of Surviving at 5 years. Due to the detection of only one AA genotype in BAX G>A, the true effect of GA vs AA vs GG on survival was not observed ; SP1: ]. On the other hand, BCL2 -938 C>A polymorphism changed the binding affinity of PAX3, PAX9 and CREB to the promoter   of BAX -248 G>A SNP and cancer risk were included in the meta-analysis . The res<0.001)] . The res<0.001)] . HWE anaThe impact of BCL2 -938 C>A (Rs2279115) on tissue-specific malignancies BCL2 -938 C>A polymorphism on global cancer susceptibility in both overall and stratified analysis. 16 studies  were identified for the study  in the overall studies for BAX (rs 4645878) and BCL2 (rs2279115). Genetic models A vs G, GA vs GG, and AA+GA vs GG for BAX (rs 4645878) showed a significant source of heterogeneity (p< 0.05). Likewise, a significant level of heterogeneity was observed in any of the five genetic models of the overall study in BCL2 (rs2279115). Identification of the source of heterogeneity in the subgroup analysis was difficult due to the effect of a small number of studies (Supplementary Table S4 and S6). To assess the stability of the results, the sensitivity analysis was performed individually for BAX and BCL2 polymorphisms in the overall meta-analysis by ignoring one study at a time and then computing the pooled ORs again . The result pointed out that the meta-analysis was not influenced by any single study in any of the five genetic models of the BAX polymorphism in the overall study . Similar finding was observed in the case of BCL2 polymorphism , thus our analysis was robust and stable. Funnel plot and Egger regression analyses were performed to designate the publication bias for each of the five genetic models of the overall study. Eggers test revealed that all p values were >0.05 and funnel plots were relatively symmetrical in any of the genetic models of the meta-analysis which indicated the absence of publication bias in the current study . Statistical post hoc power was calculated assuming a small effect size (w=0.15) to measure the probability of the presence of any small effect in the study. Results depicted that studies containing low study size shown weak power (<0.5) to detect mild effects of the polymorphisms on disease susceptibility  was calculated for each of the studies to rationalize the difference between common and rare variants (supplementary Table S5 and S7). Heterogeneity with Q value, P-value, and I square statistics were assessed for the individual model. The random (Der Simonian and Laird method) or ﬁxed (Mantel–Haenszel’s method) model was used to calculate the combined OR and 95% CI based on heterogeneity or homogeneity among studies. The random-effect model was chosen if the Q statistic was significant (p <0.05). In the meta-analysis, Substantial heterogeneity was observed  and rare homozygote (AA) was shown to be associated with higher NPC prognosis. Our study was consistent with previous ethnicity-based studies. Further, the presence of both SNPs in the same patient with a higher proportion was noted. Survival curve analysis by Kaplan-Meier and log-rank test suggested that combined dominant genotypes of BAX -248 G>A and BCL2 -938 C>A decreased NPC patients’ survival. The presence of dual SNPs also exhibited the equivalent result.BAX promoter polymorphism might alter the binding affinity of Hypoxia Inducing factor 1 (HIF1) and SP1. HIF1 has a complex role in hypoxia-induced apoptosis by either the activation of p53-mediated cell death or by inducing BNIP3 mediated apoptosis . HIF1 down-regulates the BAK and BAX in the tumor through p53 dependent and independent manner . Unlike HIF1, the interaction of SP1 with the BAX promoter element was investigated, which discovered one additional GC rich SP1 binding site of about six base-pair. Further, mutation analysis in the GC box confirmed that this region is essential for p53 dependent activation . Computational analysis showed that BAX -248 G>A and BCL2 -938 C>A may lead to the changes in transcription factor binding towards the promoter, resulting in the altercation of gene expressions, which could be correlated with poor prognosis of the NPC patients’ survival. From the overall study, we established a hypothetical model, which described the effect of these polymorphisms on the onset of NPC prognosis . Another TF, called cAMP response element-binding protein (CREB) binds at the upstream promoter of BCL2 and up-regulates its expression . Thus, polymorphisms in rognosis . BAX -248 G>A and BCL2 -938 C>A polymorphisms in the context of the global cancer prognosis. In Meta-analysis, no significant association in the overall study was found. Subgroup analysis of rs 4645878 explored that four genetic models under carcinomas showed a significantly increased risk of cancer than other subgroups. An opposite result was observed in the case of rs2279115, where the subgroup other malignancies displayed a significant association with cancer risk than other subgroups. Previously reported meta-analysis suggested that BAX -248 G>A and BCL2 -938 C>A are not directly associated with the overall cancer susceptibility but the correlation could be ethnicity-specific, which probably contributes to increasing adverse prognosis of cancer . Early reports indicated the tissue-specific effect of several SNPs, but the impact of these two polymorphisms in different cancer types was still unknown. Our study was reliable with the tissue-specific association of Though our study was stable as compared to the early findings, some limitations still exist. First, relatively low sample size was used, which might affect the statistical analysis. Second, somewhat few studies were included in the meta-analysis i.e. only case-control reports were considered. Therefore, we could not able to calculate the heterogeneity and publication bias of the subgroup. Finally, due to the unavailability of suitable computational tools, a single web-based tool was used for computational analyses. No other techniques were involved for the cross-validation, even though this is our first prediction and a well-referred tool was used for the approach . BAX -248 G>A and BCL2 -938 C>A polymorphisms were significantly associated with the susceptibility towards NPC and it lowers NPC patients’ survival. The computational study pointed out that these polymorphisms might affect TFs’ binding. Meta-analysis explained the tissue-specific association of these polymorphisms in regards to the global cancer prognosis.In conclusion, our findings indicated that Koustav Chatterjee: Conceptualization; Data curation; Formal analysis; Methodology; Resources; Software; Validation; Visualization; Roles/Writing - original draft. Saikat De: Data curation; Formal analysis. Sankar Deb Roy: Resources. Arindom Chakraborty: Software, Formal analysis, Roles/Writing - original draft. Sandeep Ghatak: Formal analysis, Writing - review & editing. Sushil Kumar Sahu: Methodology, Writing - review & editing. Nilanjana Das: Data curation. Sudipa Mal: Formal analysis. Nabanita Roy Chattopadhyay: Writing - review & editing, Piyanki Das: Writing - review & editing. R Rajendra Reddy: Resources, Data curation. Syamantak Mukherjee: Data curation; Formal analysis. Ashok Kumar Das: Resources. Zoreng puii: Resources. Eric Zomawia: Resources. Y Indibor Singh: Resources. Sam Tsering: Resources. Komri Riba: Resources. Shanmugam Rajasubramaniam: Resources. Amol R Suryawanshi: Resources. Tathagata Choudhuri: Funding acquisition; Investigation; Methodology; Project administration; Supervision; Validation; Visualization; Writing - review & editing.