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This study aimed to modify screen-printed carbon micro-electrode surfaces by coating them with multiwall carbon-based nanotubes conjugated with chitosan and then validated the formed multiwall carbon-based nanotubes-chitosan coated screen printed carbon micro-electrode for the detection of homocysteine, a biomarker analyte known as a risk indicator in cardiovascular disease. The microstructure surface and crystallographic structure stability of the formed multiwall carbon-based nanotubes-chitosan obtained at formed multiwall carbon-based nanotubes per chitosan ratios of 1:1, 2:1, 3:1, and 4:1 were examined via field emission scanning electron microscopy, X-ray radiation, Raman spectroscopy, surface area and pore size, and thermogravimetric analyses. Homocysteine solutions at 30–100 µM were measured by cyclic voltammetry using the different formed multiwall carbon-based nanotubes-chitosan compositions as sensor electrodes. That with an optimal formed multiwall carbon-based nanotubes per chitosan ratio of 4:1 showed the highest crystallinity and electrical conductivity and gave a high coefficient of determination (R2 = 0.9036) between the homocysteine concentration and the oxidation current detection over an operating range of 30–100 µM. This new composite microelectrode for detecting homocysteine concentration makes it a promising candidate for clinical applications.

Abstract Background Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription. Methods In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins. Results Here, we have shown that the high enzymatic activity genotype of CCND1High (AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMTMedium (MetVal) and the high enzymatic activity of COMTHigh (ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMTHigh (ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: 2.22, 95%CI (1.49–3.28)] and Finland [OR: 1.73, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity. Conclusion Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.

Allergic inflammation, which is the pathogenesis of allergic rhinitis and asthma, is associated with disruption of the airway epithelial barrier due to the effects of type 2 inflammatory cytokines, i.e. interleukin-4 and interleukin-13 (IL-4/13). The anti-allergic inflammatory effect of β-eudesmol (BE) on the tight junction (TJ) of the airway epithelium has not previously been reported. Herein, the barrier protective effect of BE was determined by measurement of transepithelial electrical resistance and by paracellular permeability assay in an IL-4/13-treated 16HBE14o- monolayer. Pre-treatment of BE concentration- and time- dependently inhibited IL-4/13-induced TJ barrier disruption, with the most significant effect observed at 20 μM. Cytotoxicity analyses showed that BE, either alone or in combination with IL-4/13, had no effect on cell viability. Western blot and immunofluorescence analyses showed that BE inhibited IL-4/13-induced mislocalization of TJ components, including occludin and zonula occludens-1 (ZO-1), without affecting the expression of these two proteins. In addition, the mechanism of the TJ-protective effect of BE was mediated by inhibition of IL-4/13-induced STAT6 phosphorylation, in which BE might serve as an antagonist of cytokine receptors. In silico molecular docking analysis demonstrated that BE potentially interacted with the site I pocket of the type 2 IL-4 receptor, likely at Asn-126 and Tyr-127 amino acid residues. It can therefore be concluded that BE is able to prevent IL-4/13-induced TJ disassembly by interfering with cytokine-receptor interaction, leading to suppression of STAT6-induced mislocalization of occludin and ZO-1. BE is a promising candidate for a therapeutic intervention for inflammatory airway epithelial disorders driven by IL-4/13., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tharabenjasin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Zingiber cassumunar Roxb. (Phlai) has been used for the treatment of allergies including allergic rhinitis (AR). Although the anti-histamine effects have been reported, assessment of nasal cytokine and eosinophil production had not been investigated., Objective: This study aimed to examine the effect of Phlai on alterations in nasal pro-inflammatory cytokine levels and eosinophil counts in nasal mucosa., Methods: This was a randomized, double-blind, three-way crossover study. Nasal concentrations of cytokines, namely interleukin (IL)-4, IL-5, IL-13 and interferron-gamma (IFN-γ), nasal smear eosinophilia as well as total nasal symptom score (TNSS) were evaluated before and after a 4 weeks treatment with 200 mg Phlai capsules or placebo in 30 AR patients., Results: We observed significant (p < 0.05) reduction in IL-5, IL-13 as well as the number of eosinophils in subjects given Phlai. The degree of improvement of TNSS after Phlai treatment was initially manifested in week 2 with the greatest effect in week 4. In contrast, there were no significant differences in all nasal cytokines, eosinophil counts or TNSS between before and after receiving placebo., Conclusions: These findings provided the first evidence for the anti-allergic effect of Phlai which possibly involved inhibition of nasal pro-inflammatory cytokines production and eosinophilic recruitment. Phlai thus represents a promising herbal medicine for alleviating inflammation and AR symptoms.

The multifactorial pathogenesis of severe malaria is partly attributed to host genes, such as those encoding cytokines involved in complex inflammatory reactions, namely tumor necrosis factor-alpha (TNF-α). However, the relationship between TNF-α -308G >A gene polymorphism (rs1800629) and the severity of Plasmodium falciparum (P. falciparum) malaria remains unclear, which prompts a meta-analysis to obtain more precise estimates. The present meta-analysis aimed to better understand this correlation and provide insight into its association in populations with different ethnicities. Literature search outcomes included eight eligible articles in which TNF-α -308G >A polymorphism was determined in uncomplicated malaria (UM) and severe malaria (SM) of P. falciparum as represented in the case and control groups. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated in standard homozygous, recessive, dominant, and codominant genetic models. Subgroup analysis was based on ethnicity, i.e., Africans and Asians. The analyses included overall and the modified outcomes; the latter was obtained without the studies that deviated from the Hardy-Weinberg Equilibrium. The significant data also underwent sensitivity treatment but not publication bias tests because the number of studies was less than ten. Interaction tests were applied to differential outcomes between the subgroups. Overall and HWE-compliant analyses showed no significant association between the TNF-α -308G >A polymorphism and susceptibility to P. falciparum SM (ORs = 1.10-1.52, 95%CIs = 0.68-2.79; Pa = 0.24-0.68). Stratification by ethnicity revealed that two significant associations were found only in the Asians favoring SM for dominant (OR = 1.95, 95% CI = 1.06-3.61, Pa = 0.03) and codominant (OR = 1.83, 95% CI = 1.15-2.92, Pa = 0.01) under the random-effects model, but not among the African populations. The two significant Asian associations were improved with a test of interaction with P-value of0.02-0.03. The significant core outcomes were robust. Results of the meta-analysis suggest that TNF-α -308G >A polymorphism might affect the risk of P. falciparum SM, particularly in individuals of Asian descent. This supports ethnicity as one of the dependent factors of the TNF-α -308G >A association with the clinical severity of malaria. Further large and well-designed genetic studies are needed to confirm this conclusion., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kongjam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Reported associations of the cannabinoid receptor 1 (CNR1) single nucleotide polymorphisms (SNPs) with alcohol dependence (AD) have been inconsistent, prompting a meta-analysis to obtain more precise estimates., Methods: A Boolean search of 4 databases (PubMed, Scopus, Google Scholar, and Mednar) sought articles that evaluated the association between CNR1 polymorphisms and risk of AD. We selected the articles with sufficient genotype frequency data to enable calculation of odds ratios (ORs) and 95% confidence intervals (CIs). Using the Population Intervention Comparators Outcome elements, AD patients (P) were compared by genotype data between AD-participants (I) and non-AD-participants (C) in order to determine the risk of AD (O) attributed to the CNR1 SNPs. Analyzing 4 SNPs (rs1049353, rs1535255, rs2023239, and rs806379) using standard genetic models, we examined associations where multiple comparisons were Holm-Bonferroni corrected. The pooled ORs were assessed for aggregate statistical power and robustness (sensitivity analysis). Subgroups were Caucasians and African-Americans., Results: From 32 comparisons, 14 were significant indicating increased risk, from which 5 outcomes (P-value for association [Pa] = .003 to <.001) survived the Holm-Bonferroni-correction, which were deemed robust. In the rs1535255 outcomes, the codominant effect (OR = 1.43, 95% CIs = 1.24-1.65, Pa < .001) had greater statistical power than the dominant effect (OR = 1.30, 95% CI = 1.08-1.57, Pa = .006). In contrast, the rs2023239 codominant outcome was underpowered. Significance of both rs806379 Caucasian outcomes (ORs = 1.20-1.43, 95% CIs = 1.07-1.57, Pa = .003) contrasted with the null effects in African-Americans (ORs = 0.98-1.08, 95% CIs = 0.70-1.53)., Conclusions: Three CNR1 SNPs (rs1535255, rs2023239, and rs806379) were implicated in their associations with development of AD: based on aggregate statistical power, rs1535255 presented greater evidence for associations than rs2023239; rs806379 implicated the Caucasian subgroup. Multiple statistical and meta-analytical features (consistency, robustness, and high significance) underpinned the strengths of these outcomes. Our findings could render the CNR1 polymorphisms useful in the clinical genetics of AD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Oriental herbal medicine with the two bioactive constituents, β-eudesmol (BE) and atractylodin (AT), has been used as a remedy for gastrointestinal disorders. There was no scientific evidence reporting their antidiarrheal effect and underpinning mechanisms. Therefore, we aimed to investigate the anti-secretory activity of these two compounds in vitro. The inhibitory effect of BE and AT on cAMP-induced Cl - secretion was evaluated by Ussing chamber in human intestinal epithelial (T84) cells. Short-circuit current (I SC ) and apical Cl - current (I Cl -) were measured after adding indirect and direct cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activator. MTT assay was used to determine cellular cytotoxicity. Protein-ligand interaction was investigated by in silico molecular docking analysis. BE, but not AT concentration-dependently (IC 50 of ~1.05 µM) reduced cAMP-mediated, CFTR inh -172 inhibitable Cl - secretion as determined by transepithelial I SC across a monolayer of T84 cells. Potency of CFTR-mediated I Cl - inhibition by BE did not change with the use of different CFTR activators suggesting a direct blockage of the channel active site(s). Pretreatment with BE completely prevented cAMP-induced I Cl -. Furthermore, BE at concentrations up to 200 µM (24 h) had no effect on T84 cell viability. In silico studies indicated that BE could best dock onto dephosphorylated structure of CFTR at ATP-binding pockets in nucleotide-binding domain (NBD) 2 region. These findings provide the first evidence for the anti-secretory effect of BE involving inhibition of CFTR function. BE represents a promising candidate for the therapeutic or prophylactic intervention of diarrhea resulted from intestinal hypersecretion of Cl ., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Myopia prevalence mostly affects young people, particularly in Asia. Of the several recommendations addressing the myopia epidemic, auricular acupoint stimulation (AAS) has been proposed and investigated. However, reported outcomes have been inconsistent, prompting a meta-analysis to obtain more precise estimates. Materials and Methods: Twelve articles were included in a meta-analysis, wherein each article was evaluated for risk of bias. Summary effects were calculated using odds ratios ( ORs ) and 95% confidence intervals (CIs). Outlier and sensitivity treatments as well as publication bias assessment were applied. Results: Risk of bias among the articles was low in random sequence but generally unclear judgments for the other bias criteria. AAS outcomes were significant ( P a [ P -value for association] <0.00001-0.003) when random and fixed effects favored the treated groups ( ORs: 2.87-3.42; 95% CIs: 1.44-5.75). Conclusions: This meta-analysis showed evidence of AAS being effective for controlling myopia. Substantial magnitude (up to 3.4-fold), robustness, and lack of bias strengthened this effect., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

INTRODUCTION The relationship between circumcision and prostate cancer has been controversial. A recently published meta-analysis contradicted previous meta-analyses of male circumcision and prostate cancer risk. Our aim was to conduct a de novo meta-analysis and critically evaluate this recent paper published by Van Howe., Materials and Methods: We retrieved data from each of the 12 source studies Van Howe used, then performed a random effects meta-analysis of those data. We critically examined the data and other information in Van Howe's study., Results: Using the same values as Van Howe, we confirmed his finding of a positive association of circumcision with prostate cancer (random effects summary OR = 1.14; 95% CI 0.99, 1.31). However, our independent meta-analysis found a negative association of circumcision with prostate cancer (random effects summary OR= 0.87; 95% CI 0.76, 1.00; p = 0.05). The reason for this critical discrepancy was Van Howe's erroneous transposition of values for circumcised and uncircumcised men in his Table columns, leading to inversion of the result. We further critically evaluated a geographical analysis and cost analysis of circumcision and prostate cancer, as well as claims denying a role for sexually transmitted infections in prostate cancer etiology, finding these too to be misleading., Conclusions: Van Howe's 2020 meta-analysis was based on erroneous data transposition leading to an inverted outcome. The journal concerned recently corrected his Table. Van Howe's claim of a positive association of circumcision with country-level-age standardized prostate cancer prevalence and his cost analysis were found to be questionable. Our meta-analysis showed that circumcision is associated with lower prostate cancer risk.

Background: The aim of this study was to investigate associations between polymorphisms in the Lysyl oxidase ( LOX ) gene with susceptibility to cancer. The role of LOX in carcinogenesis prompted several association studies in various cancer types; however the outcomes of these studies have inconsistent. Thus, we performed a meta-analysis to obtain more precise estimates. Materials and Methods: A literature search yielded 14 articles from which we examined five cancer groups: breast, bone, lung, gastrointestinal, and gynecological cancers. For each cancer group, pooled odds ratios (ORs) and confidence intervals (95% CIs) were calculated using standard genetic models. High significance ( p -value for association [ p a ] < 0.00001), homogeneity ( I 2  = 0%), and high precision of effects (CI difference [CID] <1.0 [upper CI - lower CI]) comprised the three criteria for strength of evidence. We used sensitivity analysis to assess robustness of the outcomes. Results: We generated 28 comparisons from which 13 were significant ( p a < 0.05), indicating increased risk, (OR >1.00) found in all cancer groups except breast ( p a  = 0.10-0.91). Of the 13, three met all criteria (core) for strength of evidence ( p a < 0.00001, CIDs 0.49-0.56 and I 2  = 0%), found in dominant/codominant models of gynecological cancers (ORs 1.52-1.62, 95% CIs 1.26-1.88) and codominant model of lung cancer (OR 1.44, 95% CI 1.19-1.74). These three were deemed robust. Conclusion: Based on the three core outcomes, associations of LOX 473G/A with lung, ovarian, and cervical cancers indicate 1.4-1.6-fold increased risks, underpinned by robustness and high statistical power at the aggregate level.

Background: The reported association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains controversial despite the publication of four meta-analyses on this topic. Here, we updated the meta-analysis with more studies and additional assessments that include adults and children within the context of the coronavirus disease 2019 (COVID-19) pandemic., Methods: Sixteen articles (22 studies) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using three genetic models (allele, recessive and dominant), in which ARDS patients were compared with non-ARDS patients (A1) and healthy controls (A2). Mortality outcomes were also assessed (A3). The influence of covariates was examined by meta-regression. Bonferroni correction was performed for multiple pooled associations. Subgroup analyses based on ethnicity (Asians, Caucasians) and life stage (adults, children) were conducted. Heterogeneity was addressed with outlier treatment., Results: This meta-analysis generated 68 comparisons, 21 of which were significant. Of the 21, four A1 and three A3 highly significant (P a  = 0.00001-0.0008) outcomes withstood Bonferroni correction. For A1, allele and recessive associations were found in overall (OR 0.49, 95% CI 0.39-0.61), Caucasians (OR 0.46, 95% CI 0.35-0.61) and children (ORs 0.49-0.66, 95% CI 0.33-0.84) analyses. For A3, associations were found in overall (dominant: OR 0.45, 95% CI 0.29-0.68) and Asian subgroup (allele/ dominant: ORs 0.31-0.39, 95% CIs 0.18-0.63) analyses. These outcomes were either robust, or statistically powered or both and uninfluenced by covariates., Conclusions: Significant associations of the ACE I/D polymorphism with the risk of ALI/ARDS were indicated in Caucasians and children as well as in Asians in mortality analysis. These findings were underpinned by high significance, high statistical power and robustness. ACE genotypes may be useful for ALI/ARDS therapy for patients with COVID-19., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Reported associations of allograft rejection in kidney transplant patients with VEGF single nucleotide polymorphisms (SNPs) have been inconsistent between studies, which prompted a meta-analysis to obtain more precise estimates. Methods: Using the PICO elements, kidney transplant patients (P) were compared by genotype data between rejectors (I) and non-rejectors (C) in order to determine the risk of allograft rejection (O) attributed to the VEGF SNPs. Literature search of four databases yielded seven articles. To calculate risks for allograft rejection, four SNPs were examined. Using the allele-genotype model we compared the variant ( var ) with the wild-type ( wt ) and heterozygous ( var - wt ) alleles. Meta-analysis treatments included outlier and subgroup analyses, the latter was based on ethnicity (Indians/Caucasians) and rejection type (acute/chronic). Multiple comparisons were corrected with the Bonferroni test. Results: Five highly significant outcomes (P a < 0.01) survived Bonferroni correction, one of which showed reduced risk for the var allele (OR 0.61, 95% CI 0.45-0.82). The remaining four indicated increased risk for the wt allele where the chronic rejection (OR 2.10, 95% CI 1.36-3.24) and Indian (OR 1.44, 95% CI 1.13-1.84) subgroups were accorded susceptibility status. Conclusions: Risk associations for renal allograft rejection were increased and reduced on account of the wt and var alleles, respectively. These findings could render the VEGF polymorphisms useful in the clinical genetics of kidney transplantation., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Eiamsitrakoon T et al.)

Background: Etiology of polycystic ovary syndrome (PCOS) is attributed to genetic and environmental factors. One environmental factor is oxidative stress. Paraoxonase 1 (PON1) is an antioxidant high-density lipoprotein-associated enzyme encoded by the PON1 gene. The PON1 gene has been implicated in the risk for PCOS, the influence of which appears to come from single nucleotide variants (SNVs) at multiple genetic loci. However, association study reports have been inconsistent which compels a meta-analysis to obtain more precise estimates., Methods: From 12 publications, extracted genotype data were used in two genetic procedures. First, linkage disequilibrium (LD) was used to group eight PON SNVs into three: LD1, LD2 and LD3. Second, frequencies of the variant (var), wild-type (wt) and heterozygous (het) genotypes were used for genetic modeling (allele-genotype for LD1 and standard for LD2 and LD3). Risk associations were expressed in terms of pooled odds ratios (ORs), 95% confidence intervals (CIs) and P a -values. Evidence was considered strong when significance was high (P a  < 0.0001) and heterogeneity absent (I 2  = 0%). Pooled effects were subjected to modifier (power), subgroup (Asian/Caucasian), outlier, sensitivity and publication bias treatments. Multiple comparisons were Bonferroni-corrected., Results: This meta-analysis generated 11 significant outcomes, five in LD1, six in LD2 and none in LD3. All six LD2 outcomes did not survive the Bonferroni-correction but two of the five in LD1 did. These two core LD1 findings conferred greater odds of PCOS to the var allele in the highly significant (P a  < 0.0001) overall (OR 1.44, 95% CI 1.24-1.67) and Asian (OR 1.41, 95% CI 1.20-1.65) outcomes. Of these two core outcomes, the Asian effect was homogeneous (I 2  = 0%) but not the overall (I 2  = 29%)., Conclusions: Of the eight PON SNVs examined, two (rs854560 and rs662) were associated with PCOS risk. These 1.4-fold increased risk effects rendered Asians susceptible to PCOS. High statistical power, high significance, zero to low-level heterogeneity, robustness and lack of bias in the core outcomes underpinned the strong evidence for association.

Purpose: Reported associations of interleukin-18 (IL-18) single-nucleotide polymorphisms (SNPs) with allergic rhinitis (AR) have been inconsistent, prompting a meta-analysis to obtain more precise estimates., Methods: We synthesized data from 8 articles and examined 3 IL-18 SNPs. Two SNPs (rs360721 and rs187238), in linkage disequilibrium, were combined and termed RS1. The rs1946518 SNP was analyzed separately (termed RS2). The recessive, dominant, and codominant (multiplicative) genetic models were used to estimate ORs and 95% CIs. Subgroup analysis was ethnicity-based. Sources of heterogeneity were investigated with outlier treatment. Sensitivity analysis was used to assess robustness of the associative effects. Multiple comparisons were Holm-Bonferroni corrected., Results: All significant (pa < 0.05) outcomes indicating increased risks were found in the dominant/codominant models in RS1 and RS2. Five aspects of differences marked the significant African (RS1) and overall (RS2) outcomes: (i) magnitude of effect (ORs): greater (3.01-5.15) versus less (1.20-1.47); (ii) precision of -effects (95% CIs): less (1.07-21.52) versus more (1.01-1.89); (iii) outlier treated: no versus yes; (iv) sensitivity outcomes: nonrobust versus robust (dominant model only); and (v) greater evidential strength for RS2 (pa = 0.002) compared to RS1 (pa = 0.02) rendered RS2 our core finding. These levels of statistical significance for RS1/RS2 enabled both to survive the Holm-Bonferroni correction., Conclusions: The core outcome indicating a 1.5-fold increased risk could render the IL-18 polymorphisms useful in the clinical genetics of AR. Future studies that could focus on other IL-18 SNPs may find deeper associations with AR than what we found here., (© 2020 S. Karger AG, Basel.)

Selenoproteins are involved in antioxidant defense, the redox signaling pathway and cell homeostasis. Primary studies have shown that single-nucleotide polymorphisms in the selenoprotein gene ( SEP15 ) are associated with cancer risk. However, conflicting outcomes warrant a meta-analysis to obtain more precise estimates. Literature search yielded 18 case-control studies from 12 articles. We calculated pooled odds ratios (OR) and 95% confidence intervals (CI) of two SEP15 polymorphisms (rs5845 and rs5859) using standard genetic models (homozygous, recessive, dominant and codominant). Subgroup analysis was based on statistical power (80% cutoff) and cancer type (breast/respiratory/genitourinary/colorectal). Heterogeneity of the outcomes necessitated examining their sources (outlier treatment). Multiple comparison outcomes were corrected with the False Discovery Rate ( P aF ). Our core findings lay in the post-outlier recessive subgroup outcomes, where risks in the powered study (≥ 80%) was increased (OR 1.26, 95% CI 1.02-1.57, P aF  = 0.047) while that in genitourinary cancer was protective (OR 0.29, 95% CI 0.20-0.43, P aF < 10 -4 ). The potency of outlier treatment in unmasking significant associations and generating homogeneity provides good evidence of SEP15 's role in cancer. In the clinical sense, selenium chemo-intervention may be of benefit among persons with particular SEP15 genotypes.AbbreviationsAnumber of unduplicated articles that contributed to instabilityAManalysis modelBnumber of robust comparisonsBCbreast cancerBLCbladder cancercDNAcomplementary deoxyribonucleic acidCIconfidence intervalCIDconfidence interval differenceCRCcolorectal cancerDdecreased riskEHeliminated heterogeneityFfixed-effectsFDRFalse Discovery RateGUCgenitourinary cancersGSgained significanceHBhospital-basedHWEHardy-Weinberg EquilibriumIincreased risk I 2 measure of heterogeneitykDakiloDaltonLAClaryngeal cancerLUClung cancermafminor allele frequency n number of studiesNnumber of comparisonsNMnot mentionedNOSNewcastle-Ottawa ScaleORodds ratio P a P value for association P aδ P value for association (pre-FDR) P aF P value for association FDR-corrected P b P value for heterogeneityPBpopulation-basedPCprostate cancerPRISMAPreferred Reporting Items for Systematic Reviews and Meta-AnalysesPROpre-outlierPSOpost-outlierRrandom-effects[R]referenceRCrespiratory cancersRNSretained non-significanceROSreactive oxygen speciesSEPselenoproteins SEP15 selenoprotein geneSNPsingle nucleotide polymorphismSWShapiro-Wilk testUSAUnited States of Americavvvariantwvheterozygouswwwild-type.

Background: Genetic involvement of Killer Immunoglobulin-like Receptor (KIR) polymorphisms and Human Immunodeficiency Virus (HIV)-exposed seronegative (HESN) compared to HIV-infected (HIVI) individuals has been reported. However, inconsistency of the outcomes reduces precision of the estimates. A meta-analysis was applied to obtain more precise estimates of association., Methods: A multi-database literature search yielded thirteen case-control studies. Risks were expressed as odds ratios (ORs) and 95% confidence intervals (CIs) with significance set at a two-tailed P-value of ≤ 0.05. We used two levels of analyses: (1) gene content that included 13 KIR polymorphisms (2DL1-3, 2DL5A, 2DL5B, 2DS1-3, 2DS4F, 2DS4D, 2DS5, 3DL1 and 3DS1); and (2) 3DL1/S1 genotypes. Subgroup analysis was ethnicity-based (Caucasians, Asians and Africans). Outlier treatment was applied to heterogeneous effects which dichotomized the outcomes into pre-outlier (PRO) and post-outlier (PSO). Multiple comparisons were addressed with the Bonferroni correction., Results: We generated 52 and 18 comparisons from gene content and genotype analyses, respectively. Of the 70 comparisons, 13 yielded significant outcomes, two (indicating reduced risk) of which survived the Bonferroni correction (Pc). These protective effects pointed to the Caucasian subgroup in 2DL3 (OR 0.19, 95% CI 0.09, 0.40, Pc < 10-3) and 3DS1S1 (OR 0.37, 95% CI 0.24, 0.56, Pc < 10-3). These two PSO outcomes yielded effects of increased magnitude and precision, as well as raised significance and deemed robust by sensitivity analysis. Of the two, the 2DL3 effect was improved with a test of interaction (Pc interaction < 10-4)., Conclusion: Multiple meta-analytical treatments presented strong evidence of the protective effect (up to 81%) of the KIR polymorphisms (2DL3 and 3DS1S1) among Caucasians. The Asian and African outcomes were inconclusive due to the low number of studies., Competing Interests: The authors have declared that no competing interests exist.

Objective: Non-syndromic cleft lip, with or without cleft palate (NSCL/P), is a common craniofacial birth defect, the risk of which is influenced from multiple genetic loci. Association study outcomes between single nucleotide polymorphisms (SNPs) near the muscle segment homeobox gene 1 (MSX1) and NSCL/P have been inconsistent. This compels a meta-analysis to obtain more precise estimates., Methods: From 15 publications, we examined 12 SNPs under six groups (SG), based on linkage disequilibrium. Pooled odds ratios and 95% confidence intervals were calculated under the standard genetic models. The pooled effects were subjected to subgroup, outlier, sensitivity, and funnel plot (publication bias) analyses., Results: Three of the six SGs showed significant associations. SG1 and SG4 effects indicated reduced risks. SG1 outcomes were attributed to outlier treatment, which the Asian outcomes validated. In contrast, increased risks were observed in SG3. All these significant outcomes were deemed robust by sensitivity analysis with no evidence of publication bias., Conclusions: Our study shows eight MSX1 SNPs associated with risk of NSCL/P. SG1 and SG4 carriers are protected (up to 23%), but SG3 carriers are 1.3-fold susceptible. Outlier treatment unmasked the significant associations in SG1. Non-heterogeneity and robustness helped elevate the level of evidence in our significant findings., (© 2019 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd. All rights reserved.)

Objective: The special status accorded to elite athletes stems from their uncommon genetic potential to excel in world-class power sports (PS). Genetic polymorphisms have been reported to influence elite PS status. Reports of associations between the α-actinin-3 gene (ACTN3) R577X polymorphism and PS have been inconsistent. In light of new published studies, we perform a meta-analysis to further explore the roles of this polymorphism in PS performance among elite athletes., Methods: Multi-database literature search yielded 44 studies from 38 articles. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used in estimating associations (significance threshold was set at Pa ≤ 0.05) using the allele-genotype model (R and X alleles, RX genotype). Outlier analysis was used to examine its impact on association and heterogeneity outcomes. Subgroup analysis was race (Western and Asian) and gender (male/female)-based. Interaction tests were applied to differential outcomes between the subgroups, P-values of which were Bonferroni corrected (Pinteraction BC). Tests for sensitivity and publication bias were performed., Results: Significant overall R allele effects (OR 1.21, 95% CI 1.07-1.37, Pa = 0.002) were confirmed in the Western subgroup (OR 1.11, 95% CI 1.01-1.22, Pa = 0.02) and with outlier treatment (ORs 1.12-1.20, 95% CIs 1.02-1.30, Pa < 10-5-0.01). This treatment resulted in acquired significance of the RX effect in Asian athletes (OR 1.91, 95% CI 1.25-2.92, Pa = 0.003). Gender analysis dichotomized the RX genotype and R allele effects as significantly higher in male (OR 1.14, 95% CI 1.02-1.28, Pa = 0.02) and female (OR 1.58, 95% CI 1.21-2.06, Pa = 0.0009) athletes, respectively, when compared with controls. Significant R female association was improved with a test of interaction (Pinteraction BC = 0.03). The overall, Asian and female outcomes were robust. The R allele results were more robust than the RX genotype outcomes. No evidence of publication bias was found., Conclusions: In this meta-analysis, we present clear associations between the R allele/RX genotype in the ACTN3 polymorphism and elite power athlete status. Significant effects of the R allele (overall analysis, Western and female subgroups) and RX genotype (Asians and males) were for the most part, results of outlier treatment. Interaction analysis improved the female outcome. These robust findings were free of publication bias., Competing Interests: The authors have declared that no competing interests exist.

Aim: The potential of biomarkers in detecting early cholangiocarcinoma (CCA) is facilitated by examining CCA-associated proteins from primary studies. One such protein is mucin 5AC (MUC5AC) but inconsistency of reported associations between its expression/serum levels and CCA prompts a meta-analysis to obtain more precise estimates., Methods: A literature search yielded 17 included articles where multiple data in some raised the number of studies to 22. We calculated pooled odds ratios (OR) and 95% confidence intervals from negative and positive readings of MUC5AC levels. Data were subgrouped by ethnicity, detection method, sample source, and cancer type., Results: Outcome in the overall analysis was non-significant but those in the subgroups were. Thus, significant associations (P < 0.001) indicating high MUC5AC levels were found in three subgroups: (i) Thai (OR 8.32) and (ii) serum (OR 4.52). Heterogeneity of these two outcomes (I 2  = 90-93%) was erased with outlier treatment (I 2  = 0%) which also modulated the pooled effects (OR 2.48-2.59). (iii) Immunoblot (OR 2.61) had low initial heterogeneity (I 2  = 2%). Robustness and significant tests for interaction (P interaction  = 0.01-0.02) improved MUC5AC associations with CCA in the Thai population., Conclusions: Our pooled effect findings target the biomarker potential of MUC5AC to the Thai population.

Background: Genetics plays a role in determining potential for athletic ability (AA) and sports performance (SP). In this study, AA involves comparing sedentary controls with competitive athletes in power and endurance activities as well as a mix between the two (SP). However, variable results from genetic association studies warrant a meta-analysis to obtain more precise estimates of the association between PPARGC1A Gly482Ser polymorphism and AA/SP., Methods: Multi-database literature search yielded 14 articles (16 studies) for inclusion. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate associations. Summary effects were modified based on statistical power. Subgroup analysis was based on SP (power, endurance and mixed) and race (Caucasians and Asians). Heterogeneity was assessed with the I2 metric and its sources examined with outlier analysis which dichotomized our findings into pre- (PRO) and post-outlier (PSO)., Results: Gly allele effects significantly favoring AA/SP (OR > 1.0, P < 0.05) form the core of our findings in: (i) homogeneous overall effect at the post-modified, PSO level (OR 1.13, 95% CI 1.03-1.25, P = 0.01, I2 = 0%); (ii) initially homogeneous power SP (ORs 1.22-1.25, 95% CI 1.05-1.44, P = 0.003-0.008, I2 = 0%) which precluded outlier treatment; (iii) PRO Caucasian outcomes (ORs 1.29-1.32, 95% CI 1.12-1.54, P = 0.0005) over that of Asians with a pooled null effect (OR 0.99, 95% CI 0.72-1.99, P = 0.53-0.92) and (iv) homogeneous all > 80% (ORs 1.19-1.38, 95% CI 1.05-1.66, P = 0.0007-0.007, I2 = 0%) on account of high statistical power (both study-specific and combined). In contrast, none of the Ser allele effects significantly favored AA/SP and no Ser-Gly genotype outcome favored AA/SP. The core significant outcomes were robust and showed no evidence of publication bias., Conclusion: Meta-analytical applications in this study generated evidence that show association between the Gly allele and AA/SP. These were observed in the overall, Caucasians and statistically powered comparisons which exhibited consistent significance, stability, robustness, precision and lack of bias. Our central findings rest on association of the Gly allele with endurance and power, differentially favoring the latter over the former., Competing Interests: The authors have declared that no competing interests exist.

Background: Managing nephropathy associated with diabetes mellitus warrant investigation of relevant biomarkers in predicting this condition. Adiponectin (ADP) may hold promise as a biomarker for diabetic nephropathy (DN). In this study, we examine associations of ADP with DN by meta-analyzing relevant literature. We also examined the predictive potential of ADP and estimate progression of DN., Methods: Multi-database literature searches and serial omissions of articles yielded 13 studies for inclusion in the meta-analysis. We compared ADP levels between controls/ normoalbuminuria and cases with micro- and macroalbuminuria (MI and MA, respectively) as well as MI versus MA using standardized mean differences (SMD). Associations of ADP with DN were indicated with the P-value considered significant at ≤ 0.05. Subgrouping was based on diabetes type (1 and 2). Predictive potential of ADP was explored with AUC (area under the curve) derived from Receiver Operating Characteristic curve analysis., Results and Conclusion: At high P-values of <10-5, overall and subgroup outcomes indicated ADP associations with DN (up to SMD = 1.89-2.26, respectively). However, heterogeneity of the initial SMD effects (up to I2 = 99%) warranted examination of their sources which with the Galbraith plot method, either eliminated or reduced their heterogeneity, signifying combinability of the studies. This feature along with consistency of significant associations, robust outcomes and significant AUC values provide good evidence of the associative and predictive roles of ADP in DN., Competing Interests: The authors have declared that no competing interests exist.

Background: Tendons and ligaments are common sites of musculoskeletal injuries especially during physical activity. The multifactorial etiology of tendon-ligament injury (TLI) includes both genetic and environmental factors. The genetic component could render influence on TLI risk to be either elevation or reduction., Objective: Inconsistency of reported associations of the collagen type V alpha 1 chain (COL5A1) polymorphisms, mainly rs12722 (BstUI) and rs13946 (DpnII), with TLI warrant a meta-analysis to determine more precise pooled associations., Methods: Multi-database literature search yielded eight articles (11 studies) for inclusion. Pooled odds ratios (ORs) and 95% confidence intervals were used to estimate associations. Heterogeneity of outcomes warranted examining their sources with outlier treatment., Results: All rs12722 effects indicated reduced risk (OR < 1.0). The significant outcomes (ORs 0.59-0.77, p = 0.0009-0.04) in the pre-outlier analysis were non-heterogeneous (p > 0.10). The non-significant and heterogeneous (ORs 0.63-0.98, p = 0.13-0.95; up to I 2  = 86%) pre-outlier rs12722 and rs13946 results became significant (ORs 0.32-0.78, p = 10 -5 -0.01) and heterogeneity eliminated (I 2  = 0%) with outlier treatment. Significant associations (ORs 0.26-0.65, p = 0.002-0.03) were also observed in other COL5A1 polymorphisms (rs71746744 and rs16399). Sensitivity analysis deemed all significant outcomes to be robust., Conclusions: In summary, COL5A1 polymorphisms reduce the risk of TLI among Caucasians. These findings are based on the evidence of significance, homogeneity, consistency, and robustness. Additional studies are warranted to draw more comprehensive conclusions.

Aims: Steroid hormones play a central role in modulating the growth of uterine leiomyoma, and several studies have suggested that polymorphisms in genes encoding these hormones and their receptors may be risk factors for developing the disease. Progesterone is a potent antagonist of estrogen-induced proliferation in the endometrium, and the PROGINS polymorphisms have been associated with leiomyoma, but the results are inconsistent. In this study, we aimed to investigate the possible associations between the PROGINS polymorphisms and uterine leiomyoma., Materials and Methods: MEDLINE using PubMed, Science Direct, and Google Scholar databases was searched using the terms "PROGINS," "progesterone receptor," "polymorphism," and "leiomyoma." We estimated risk with odds ratios [ORs] and 95% confidence intervals using standard genetic models (homozygous, recessive, dominant, and codominant)., Results: Six studies were included in this meta-analysis based on 837 cases and 1011 controls. Subjects in three studies were Asian (365 cases/391 controls), and five were non-Asian (472 cases/620 controls). Our findings showed no association between PROGINS and leiomyoma in the overall analysis (OR 0.91-1.07, p = 0.15-0.57) nor in either of the subgroups (Asian: OR 0.84-1.04, p = 0.68-0.98; or non-Asian: OR 0.77-1.34, p = 0.33-0.93), in all genetic models., Conclusion: The PROGINS polymorphisms cannot be considered a risk factor for developing uterine leiomyoma.

Background: Evidence of an adverse influence of soil transmitted helminth (STH) infections on cognitive function and educational loss is equivocal. Prior meta-analyses have focused on randomized controlled trials only and have not sufficiently explored the potential for disparate influence of STH infection by cognitive domain. We re-examine the hypothesis that STH infection is associated with cognitive deficit and educational loss using data from all primary epidemiologic studies published between 1992 and 2016., Methods: Medline, Biosis and Web of Science were searched for original studies published in the English language. Cognitive function was defined in four domains (learning, memory, reaction time and innate intelligence) and educational loss in two domains (attendance and scholastic achievement). Pooled effect across studies were calculated as standardized mean differences (SMD) to compare cognitive and educational measures for STH infected/non-dewormed children versus STH uninfected /dewormed children using Review Manager 5.3. Sub-group analyses were implemented by study design, risk of bias (ROB) and co-prevalence of Schistosoma species infection. Influential studies were excluded in sensitivity analysis to examine stability of pooled estimates., Findings: We included 36 studies of 12,920 children. STH infected/non-dewormed children had small to moderate deficits in three domains-learning, memory and intelligence (SMD: -0.44 to -0.27, P<0.01-0.03) compared to STH-uninfected/dewormed children. There were no differences by infection/treatment status for reaction time, school attendance and scholastic achievement (SMD: -0.26 to -0.16, P = 0.06-0.19). Heterogeneity of the pooled effects in all six domains was high (P<0.01; I2 = 66-99%). Application of outlier treatment reduced heterogeneity in learning domain (P = 0.12; I2 = 33%) and strengthened STH-related associations in all domains but intelligence (SMD: -0.20, P = 0.09). Results varied by study design and ROB. Among experimental intervention studies, there was no association between STH treatment and educational loss/performance in tests of memory, reaction time and innate intelligence (SMD: -0.27 to 0.17, P = 0.18-0.69). Infection-related deficits in learning persisted within design/ROB levels (SMD: -0.37 to -52, P<0.01) except for pre-vs post intervention design (n = 3 studies, SMD = -0.43, P = 0.47). Deficits in memory, reaction time and innate intelligence persisted within observational studies (SMD: -0.23 to -0.38, all P<0.01) and high ROB strata (SMD:-0.37 to -0.83, P = 0.07 to <0.01). Further, in Schistosoma infection co-prevalent settings, associations were generally stronger and statistically robust for STH-related deficits in learning, memory and reaction time tests(SMD:-0.36 to -0.55, P = 0.003-0.02). STH-related deficits in school attendance and scholastic achievement was noted in low (SMD:-0.57, P = 0.05) and high ROB strata respectively., Interpretation: We provide evidence of superior performance in five of six educational and cognitive domains assessed for STH uninfected/dewormed versus STH infected/not-dewormed school-aged children from helminth endemic regions. Cautious interpretation is warranted due to high ROB in some of the primary literature and high between study variability in most domains. Notwithstanding, this synthesis provides empirical support for a cognitive and educational benefit of deworming. The benefit of deworming will be enhanced by strategically employing, integrated interventions. Thus, multi-pronged inter-sectoral strategies that holistically address the environmental and structural roots of child cognitive impairment and educational loss in the developing world may be needed to fully realize the benefit of mass deworming programs.

Background: By means of meta-analysis of information from all relevant epidemiologic studies, we examined the hypothesis that Schistosoma infection in school-aged children (SAC) is associated with educational loss and cognitive deficits., Methodology/principal Findings: This review was prospectively registered in the PROSPERO database (CRD42016040052). Medline, Biosis, and Web of Science were searched for studies published before August 2016 that evaluated associations between Schistosoma infection and cognitive or educational outcomes. Cognitive function was defined in four domains-learning, memory, reaction time, and innate intelligence. Educational outcome measures were defined as attendance and scholastic achievement. Risk of bias (ROB) was evaluated using the Newcastle-Ottawa quality assessment scale. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated to compare cognitive and educational measures for Schistosoma infected /not dewormed vs. uninfected/dewormed children. Sensitivity analyses by study design, ROB, and sequential exclusion of individual studies were implemented. Thirty studies from 14 countries, including 38,992 SAC between 5-19 years old, were identified. Compared to uninfected children and children dewormed with praziquantel, the presence of Schistosoma infection and/or non-dewormed status was associated with deficits in school attendance (SMD = -0.36, 95%CI: -0.60, -0.12), scholastic achievement (SMD = -0.58, 95%CI: -0.96, -0.20), learning (SMD = -0.39, 95%CI: -0.70, -0.09) and memory (SMD = -0.28, 95%CI: -0.52, -0.04) tests. By contrast, Schistosoma-infected/non-dewormed and uninfected/dewormed children were similar with respect to performance in tests of reaction time (SMD = -0.06, 95%CI: -0.42, 0.30) and intelligence (SMD = -0.25, 95%CI: -0.57, 0.06). Schistosoma infection-associated deficits in educational measures were robust among observational studies, but not among interventional studies. The significance of infection-associated deficits in scholastic achievement was sensitive to ROB. Schistosoma infection-related deficits in learning and memory tests were invariant by ROB and study design., Conclusion/significance: Schistosoma infection/non-treatment was significantly associated with educational, learning, and memory deficits in SAC. Early treatment of children in Schistosoma-endemic regions could potentially mitigate these deficits., Trial Registration: ClinicalTrials.gov CRD42016040052.

Background: Anorectal malformation (ARM) is a common congenital anomaly with a wide clinical spectrum. Recently, many genetic and molecular studies have been conducted worldwide highlighting the contribution of genetic factors in its etiology. We summarize the current literature on such genetic factors., Materials and Methods: Literature search was done using different combinations of terms related to genetics in anorectal malformations. From 2012 to June 2017, articles published in the English literature and studies conducted on human population were included., Observations and Results: A paradigm shift was observed from the earlier studies concentrating on genetic aberrations in specific pathways to genome wide arrays exploring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in ARM patients. Rare CNVs (including 79 genes) and SNPs have been found to genetically contribute to ARM. Out of disrupted 79 genes one such putative gene is DKK4. Down regulation of CDX-1 gene has also been implicated in isolated ARM patients. In syndromic ARM de novo microdeletion at 17q12 and a few others have been identified., Conclusion: Major genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.

Background and Aim: Dengue virus entry into a host is associated with a cell surface protein, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin). A common CD209-336G/A (rs4804803) polymorphism in DC-SIGN may affect severity of dengue virus infection (DEN) and incidence of dengue fever (DF) or the more severe dengue hemorrhagic fever (DHF). However, the reported associations of these two outcomes and CD-209 have been inconsistent, which prompted a meta-analysis to obtain more precise estimates., Methods: A literature search yielded seven case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals using standard genetic models. Outlier treatment examined sources of potential heterogeneity. Subgroup analysis was performed for ethnicity and age., Results: All significant outcomes for association indicating reduced risk were pegged at P=0.007-0.05. In the homozygous and recessive models, these were observed in the overall analysis (OR 0.52-0.55), and subgroups of South/Central Americans (OR 0.30-0.32) and school-age children (OR 0.44) in the DHF analysis as well as the codominant model among Asians in DF (OR 0.59). These significant outcomes are strengthened by their non-heterogeneity (P>0.10) and robustness of the effects. Most pooled effects in DF and DEN were variable., Conclusions: The DC-SIGN -336G/A polymorphism significantly affects DHF and DF incidence with the effect more pronounced in certain analyzed patient subgroups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: An epigenetic approach to explaining endometrial carcinogenesis necessitates good understanding of Ras association domain family 1 isoform A (RASSF1A) promoter methylation data from primary studies., Aims: Differential magnitude of reported associations between RASSF1A promoter methylation and endometrial cancer (EC) prompted a meta-analysis to obtain more precise estimates., Methods: Literature search yielded eight included articles. We calculated pooled odds ratios (OR) and 95% confidence intervals and subgrouped the data by race. Sources of heterogeneity were investigated with outlier analysis., Results: The pooled ORs indicated increased risk, mostly significant. The overall effect (OR 11.46) was reflected in the European outcome (OR 15.07). However, both findings were heterogeneous (I 2 =57-70%) which when subjected to outlier treatment, erased heterogeneity (I 2 =0%) and retained significance (OR 9.85-12.66). Significance of these pre- and post-outlier outcomes were pegged at P≤0.0001. Only the Asian pre-outlier (OR 6.85) and heterogeneous (I 2 =82%) outcome was not significant (P=0.12) but when subjected to outlier treatment, erased heterogeneity (I 2 =0%) and generated significance (OR 23.74, P≤0.0001)., Conclusions: Consistent increased risk associations underpinned by significance and robustness render RASSF1A with good biomarker potential for EC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inconsistency of reported associations between the tumor necrosis factor-alpha-308 (TNFα-308) polymorphism (rs1800629) and dengue virus infection prompted a meta-analysis, to obtain more precise estimates. A literature search yielded 14 case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals in three groups according to severity, dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue (DEN) using standard genetic models. Pooled ORs were subjected to modifier treatment where re-analysis was confined to Hardy-Weinberg compliant (HWC) studies. Heterogeneity of outcomes warranted examining their sources with outlier treatment. In subgroup analysis, we compared Asian and South/Central American (SCA)/Brazilian effects. Overall pooled outcomes yielded no significant effects (OR 0.66-1.44, P=0.08-0.96). In the dominant-codominant model, pooled effects were heterogeneous (I 2 =47%-71%) which was lost/reduced (I 2 =0%-43%) when outlier treatment was applied. This also yielded significant associations (OR 0.68-0.77, P=0.02-0.05). Our results are best seen in the Asian subgroup, which in itself already yielded significant effects in DEN (OR 0.62-0.67, P=0.01-0.02). These reduced risk findings were significant from the tests of interaction (P=0.001-0.02) which highlights the protective effects of TNFα-308 among Asians. TNFα-308 effects on dengue are based on significance and non-heterogeneity of the post-outlier outcomes in the dominant and codominant models. Here, pooled effects may also be ethnic specific, where Asians are protected but not SCA. Both modified and Asian effects are up to 38% protective., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate PTPN22 C1858T polymorphism and the risk of endometriosis., Methods: A meta-analysis of 10 published case-control studies (from four articles), with a total sample of 971 cases and 1,181 controls, was performed. We estimated risk (odds ratio and 95% confidence intervals) of endometriosis associations with the C1858T polymorphism., Results: A significant increased risk in all genetic models of the variant T allele with endometriosis (odds ratio: 3.14-5.55; p<0.00001-0.002) was found. The analysis without the study whose controls deviated from the Hardy-Weinberg equilibrium exacerbated these effects in the homozygous and recessive models (odds ratio: 7.19-9.45; p<0.00001-0.0002). In the Italian subgroup, a significant risk association was found in the homozygous and recessive models (odds ratio: 8.72-11.12; p=0.002)., Conclusion: The associations observed between PTPN22 (C1858T) and the risk of endometriosis suggest this polymorphism might be a useful susceptibility marker for this disease., Objetivo: Avaliar o polimorfismo PTPN22 C1858T e o risco de endometriose., Métodos: Foi realizada uma metanálise de 10 estudos caso-controle publicados (a partir de quatro artigos), com uma amostra total de 971 casos e 1.181 controles. O risco da associação da endometriose com o polimorfismo C1858T foi estimado em razão de chance e intervalo de confiança de 95%., Resultados: Observou-se um aumento de risco significativo em todos os modelos genéticos com o alelo variante T e a endometriose (razão de chance: 3,14-5,55; p<0,00001-0,002). A análise sem incluir o estudo, em que os controles não estavam em equilíbrio de Hardy-Weinberg, mostrou aumento significativo nos modelos homozigotos e recessivos (razão de chance: 7,19-9,45; p<0,00001-0,0002). No subgrupo italiano, uma associação significativa foi encontrada considerando os modelos homozigoto e recessivo (razão de chance: 8,72-11,12; p=0,002)., Conclusão: As associações observadas entre PTPN22 (C1858T) e o risco de endometriose sugerem que este polimorfismo pode ser um marcador de suscetibilidade para a endometriose.

Background: Evidence supporting an association of intervertebral disc degeneration (DD) with polymorphisms of the vitamin D receptor (VDR) gene has been controversial. We performed a meta-analysis of these studies to determine if there was substantial evidence to support such an association between the VDR polymorphisms and DD., Methods: PubMed, Embase, and Science Direct databases were searched for studies that investigated associations of the FokI (rs2228570, rs10735810), and ApaI (rs7975253) polymorphisms of the VDR gene with DD. From the extracted genotype data from 14 publications, we estimated risk (odds ratio [OR] with 95% confidence intervals)., Results: Overall associations of FokI with DD were absent (OR 0.96-1.04, p = 0.73-0.95) with heterogeneity in the dominant and codominant models (p heteroegeneity <0.10, I 2  = 47-57%). Post-outlier pooled effects yielded dominant significance indicating reduced risk (OR 0.77, p = 0.01) with concomitant zero heterogeneity (I 2  = 0%). ApaI effects pointed to reduced risks, with overall dominant significance (OR 0.69, p = 0.04) and Asian subgroup nonsignificance (OR 0.75-0.93, p = 0.17-0.74). In FokI, Non-Hispanic Caucasians (OR 0.77, p = 0.01) and males (OR 0.36-0.66, p = 0.001-0.04) were protected but not Hispanic Caucasians (OR 1.39-1.85, p = 0.006-0.05) and females (OR 1.72, p = 0.05). Tests of interaction between the genders highlighted female susceptibility and male protection (p = 0.001-0.005). Zero heterogeneity (I 2  = 0%) is a key strength of these significant effects., Conclusion: This meta-analysis confirmed the protective role of the ApaI polymorphism, however, susceptibility and protective effects of the FokI polymorphism may be ethnic and gender specific.

Background/aims: Reported associations of reproductive outcomes (RO) and polycystic ovary syndrome (PCOS) with genotypes of the Ile49Ser and -482A>G polymorphisms in the Anti-Müllerian hormone (AMH) gene and its type II receptor (AMHRII), respectively, have conflicting results., Methods: PubMed, Google Scholar and Science Direct databases were searched for studies that investigated Ile49Ser and -482A>G in RO and PCOS. Using the metaanalytic approach, we estimated risk (odds ratio [OR] with 95% confidence intervals) using standard genetic models., Results: All calculated summary effects were non-significant. Overall associations of Ile49Ser and -482A>G with RO were absent (OR 0.95-0.99, P = 0.76-0.96) but implied increased risk in PCOS (OR 1.07-1.17, P = 0.49-0.55). Where heterogeneity of the pooled ORs were present, its sources were explored using the Galbraith plot. Detection and omission of the outlying studies in both polymorphisms not only erased heterogeneity of the recalculated pooled outcomes but also changed direction of association, where null effects turned to increased risk (Ile49Ser in RO) and increased risk became reduced risk (-482A>G in PCOS). Implications of the Ile49Ser and -482A>G, effects pointed to protection for Caucasians (OR 0.64-0.89, P = 0.36-0.73) in RO and increased risk in PCOS (OR 1.19-1.45, P = 0.28-0.65). Asian effects in RO and PCOS were variable (OR 0.97-1.24, P = 0.58-0.91)., Conclusions: In summary, we found no evidence of significant associations of Ile49Ser and -482A>G with RO and PCOS, although contrasting Ile49Ser effects were implied among Caucasians between RO (up to 0.36% reduced risk) and PCOS (up to 1.5-fold increased risk)., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Background: Reported associations of ACE polymorphisms with gastric cancer have been inconsistent, prompting a meta-analysis of 12 published case-control studies where we estimated risk (odds ratio [OR])., Methods: We searched MEDLINE through PubMed and EMBASE for suitable articles that had case-control design with gastric cancer as outcome. In this meta-analysis, our overall findings were subjected to modifier analyses (outlier and sensitivity treatments). We also performed subgroup analysis based on ethnicity (German and Japanese) and histological subtype (intestinal and diffuse)., Results: Significance of the protective effects among homozygote carriers of the II genotype (OR 0.54-0.63, P = 0.01-0.02) disappeared with outlier analysis (OR 0.81-0.88, P = 0.12-0.14). Among DD homozygotes, this treatment altered the direction of association from weak protection (OR 0.95-0.96, P = 0.79-0.82) to increased risk (OR 1.13-1.19, P = 0.14-0.16). No significant associations were observed among ID genotype carriers (OR 0.91-0.94, P = 0.69-0.72). Japanese pooled effects varied across the genotype comparisons (OR 0.93-1.06, P = 0.54-0.72). Sensitivity treatment demonstrated robustness of the II genotype, but not the other two, both in overall and subgroup analyses. Histological subtype analysis yielded protection from intestinal cancer across the comparisons (OR 0.38-0.71, P = 0.15-0.50) but variable results for the diffuse type (OR 0.59-1.32, P = 0.19-0.92)., Conclusion: In summary, carriers of the ACE II genotype appear to be protected from gastric cancer, regardless of ethnicity or tumor type.

Inconsistency in the reported associations between the A66G polymorphism in the methionine synthase reductase (MTRR) gene and colorectal cancer (CRC) prompted a meta-analysis, so that we could obtain a more precise estimate. Databases searches of the published literature yielded 20 case-control studies from 17 articles (8,371 cases and 12,574 controls). We calculated pooled odds ratios (ORs) and 95% confidence intervals in three genetic comparisons (A allele, G allele, and A/G genotype). We found no evidence of overall associations between MTRR A66G and CRC risk (OR 0.96-1.05, P = 0.12-0.44). This was materially unchanged when reanalyzed without the Hardy-Weinberg equilibrium (HWE)-deviating studies (OR 0.97-1.06, P = 0.11-0.65). In the A allele comparison, however, outlier treatment generated significant protection (OR 0.91, P = 0.01). Combined removal of the outliers and HWE-deviating studies reflected this summary effect (OR 0.90, P = 0.01) as did the pooled OR from high-quality studies (OR 0.90, P = 0.01). Only the Asian subgroup showed significant (both at P = 0.05) A allele (OR 1.13) and A/G genotype (OR 0.88) associations. In conclusion, post-outlier A allele effects were protective. Our study also suggests ethnic-specific associations with Asian susceptibility and protection in the A allele and A/G genotype comparisons, respectively. Folate status showed no association of this polymorphism with CRC.

Background: Reported associations of the G241R and K469E polymorphisms of the intercellular adhesion molecule-1 gene (ICAM-1) gene with endometriosis have differed in magnitude., Materials and Methods: In a meta-analysis of six published case-control studies (from five articles), we estimated risk [odds ratio (OR) 95 % confidence intervals (CI)] of associations with these polymorphisms using the Review Manager 5.3 software., Results: Based on 1213 cases and 1103 controls, overall analysis showed significant increased risk in the homozygous (OR 2.83, 95 % CI 0.99-8.10, p = 0.05), dominant (OR 1.86, 95 % CI 1.00-3.46, p = 0.05) and codominant (OR 2.15, 95 % CI 1.06-4.35, p = 0.03) models. Confined to the studies in Hardy-Weinberg Equilibrium erased the significance (OR 1.59-2.59, 95 % CI 0.81-8.22, p = 0.10-0.15). Asian effects were variable (OR 0.93-1.09, p = 0.50-0.57), but Caucasian effects were not (OR 4.09-13.60, p < 0.0001). Independent data for the late stages of endometriosis suggest protection of the ICAM-1 K469E polymorphism among the Asians (OR 0.91-0.95, p = 0.35-0.71). These effects were weak but non-heterogeneous (P heterogeneity = 0.17-0.57, I (2) = 0-40 %)., Conclusion: In summary, strengths of the overall effects were consistency, significance and robustness but limited by their high heterogeneity. These strengths and limitations were also observed in the Caucasian subgroup which when tested for interaction against the contrasting Asian effects, highlighted Caucasian susceptibility (p = 0.004-0.01). The findings are an interplay of strengths and limitations, which warrant awareness of their interpretation as susceptibility markers for this disorder.

Purpose: The +331G/A progesterone receptor (PgR) gene polymorphism may influence risk of endometrial cancer. However, data from published studies have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and endometrial cancer, we considered all available studies in a meta-analysis., Methods: We searched PubMed and EMBASE and identified eight studies representing data for 3,790 cases and 6,458 controls. We estimated risk [odds ratio (OR) and 95 % confidence interval] of these associations, which were non-significant in the entire body of results., Results: Overall effects indicated increased risks, slightly pronounced in the homozygous and recessive models (OR 1.16-1.17, p = 0.57-0.60). These effects were exacerbated when confined to studies in Hardy-Weinberg Equilibrium (OR 1.33-1.36, p = 0.33-0.35) and in the underpowered subgroup (OR 1.62-1.68, p = 0.27-0.30). The exception is the powered subgroup which showed reduced risk (OR 0.96-0.97, p = 0.92-0.93). None of the comparisons were heterogeneous, in fact, 10 of the 16 comparisons had zero heterogeneity (I (2) = 0 %)., Conclusion: In summary, the non-significant results suggest that the PgR +331G/A polymorphism might not be a conspicuous low-penetrant risk factor for developing endometrial cancer.

Background/aims: Reported associations of controlled ovarian hyperstimulation response (COH) with genotypes of the Ser680Asn (N680S) polymorphism in the follicle stimulating hormone receptor (FSHR) gene have conflicting results., Methods: PubMed and Embase databases were searched for studies that investigated the N680S polymorphism in the FSHR gene in COH. Parameters used to examine ovarian response were poor and hyper-responses to COH. Using the meta-analytic approach, we estimated ovarian response risk (odds ratio [OR] with 95% confidence intervals) according to genotype., Results: Our findings showed that SS genotype carriers were most likely to be poor responders (OR 1.61, p = 0.08) compared to the NN and NS genotypes which showed no associations (OR 0.93-0.95, p = 0.75-0.78). Heterogeneity of these pooled ORs warranted examining its sources. We detected outlying studies in each of the three N680S genotypes. Omitting these outliers erased the heterogeneity of the recalculated pooled outcomes. It also materially altered the SS effects where carriers became slightly unlikely to be poor responders (OR 0.90, p = 0.52). The S allele carrier effect was modulated for poor responders (OR 1.24, p = 0.39) in the Non-Hispanic Caucasian (NHC) subgroup. The likelihood of the S allele carriers (OR 1.47, p = 0.02) and the unlikelihood of the N allele carriers (OR 0.64, p = 0.007) were significant in our hyper-response findings. Confined to NHC retained significance of the S allele effects (OR 1.57, p = 0.01) but not among the N allele carriers (OR 0.68, p = 0.18)., Conclusions: In summary, this is a meta-analytical confirmation of the FSHR SS genotype role in COH response. Hyper-responder analysis strengths lie on the non-heterogeneity and robustness of its results. Non-robustness and heterogeneity of the poor-responder results compose its limitations. Thus, poor response findings probably require caution as to the interpretation as a susceptibility marker for ovarian response.

Background: Reported associations of progesterone receptor gene polymorphism (PROGINS) with endometriosis have been inconsistent., Aim of the Study: To evaluate the association between the PROGINS polymorphism and the risk of endometriosis., Methodology: A meta-analysis of 12 published case-control studies with a total sample size of 3,321 (1,323 cases/1,998 controls) was performed. We estimated the risk (odds ratio [OR] 95 % confidence intervals) of endometriosis association with the PROGINS polymorphism., Results: An association between the presence of the variant allele and risk of endometriosis was found, more in the homozygous and recessive models (OR 1.41-1.43, p = 0.15-0.17), and less in the dominant and co-dominant models (OR 1.22, p = 0.11-0.15). Reanalysis without the studies whose controls deviated from the Hardy-Weinberg Equilibrium did not materially alter the dominant and co-dominant effects (OR 1.19-1.22, p = 0.19-0.32), but exacerbated the homozygous and recessive effects (OR 1.59, p = 0.09). The subgroups based on geography showed increased risk associations, consistently significant in the European (OR 1.52-2.72, p = 0.0008-0.03) but not in the Brazilian studies, where ORs ranged from reduced (OR 0.70-0.74, p = 0.54-0.61) to increased (OR 1.11, p = 0.75) risks. Heterogeneity was confined in all comparisons to the dominant and co-dominant models (I (2) = 38-70 %), except in the European subgroup, which had zero heterogeneity (I (2) = 0 %) in all genetic models, as did all homozygous and recessive effects., Conclusion: This meta-analysis provides a comprehensive profile of the role of the PROGINS polymorphism in endometriosis by exploring the magnitude of the summary effects with modifier analysis. This magnitude is expressed with modulation or exacerbation of the summary effects, as defined by the parameters of the analysis. Thus, the results showed trend towards an increased risk of the variant PROGINS allele and susceptibility for the endometriosis.

Aim: Inconsistency of reported associations of the G/A polymorphism (rs2301756) in the PTPN11 gene and gastric atrophy prompted us to undertake a meta-analysis., Materials and Methods: We searched PubMed for published literature up to July 2013. Individual data from studies with case-control design were evaluated for the PTPN11 G/A polymorphism in Helicobacter pylori (-) (seronegative) and (+) (seropositive) subjects (four studies each, totaling 3,597 cases and 4,865 controls)., Results: Associations of PTPN11 polymorphism with gastric atrophy in H. pylori (-) and (+) subjects are more readily interpreted in the homozygous and recessive models given that the dominant codominant effects skirted null associations. Thus, homozygous and recessive effects indicated reduced risk [odds ratio (OR) 0.92-0.96, p = 0.51-0.74], which is significant among H. pylori (+) subjects (OR 0.66-0.68, p = 0.04-0.05). Confined to the Japanese, reduced risk effects were unaltered in both groups, less protective among seronegative subjects (OR 0.85-0.86, p = 0.71-0.73) than seropositive subjects with significance in the recessive model (OR 0.67, p = 0.05). Sensitivity analysis demonstrated robustness of the seropositive findings, but probably not the seronegative results where homozygous and recessive pooled ORs were altered from protection to increased risk., Conclusions: Evidence of overall and subgroup decreased risks, strong in seropositive subjects, demonstrates protective effects of the PTPN11 G/A polymorphism from gastric atrophy.

Background: Reported associations of capsaicin with gastric cancer development have been conflicting. Here, we examine 10 published articles that explore these associations using 2,452 cases and 3,996 controls., Methods: We used multiple search strategies in MEDLINE through PubMed to seek for suitable articles that had case-control design with gastric cancer as outcome., Results: The outcomes of our study shows protection (odds ratio [OR] 0.55, P = 0.003) and susceptibility (OR 1.94, P = 0.0004), both significant with low and medium-high intake of capsaicin, respectively, although under relatively heterogeneous conditions (P(heterogeneity) = <0.0001). Outlier analysis resulted in loss of overall heterogeneity (P = 0.14) without affecting the pooled ORs. Among the subgroups, low intake elicited protection in both Korean (OR 0.37) and Mexican (OR 0.63) populations while high intake rendered these subgroups susceptible (OR 2.96 and OR 1.57, respectively). These subgroup values were highly significant (P = 0.0001-0.01) obtained in heterogeneous conditions (P(heterogeneity) < 0.0001-0.04). The homogeneous (P(heterogeneity) = 0.27-0.37) H. pylori (OR 0.60 and 1.69) effects were highly significant (P < 0.001) in the low and medium-high intake analyses, respectively. Given outcomes from the tests of interaction, high capsaicin intake is significantly different from the protection that low consumption offers., Conclusions: This meta-analysis implies moderation in capsaicin consumption in order to derive its protective benefits.