The barrier-protective effect of ß-eudesmol against type 2-inflammatory cytokine-induced tight junction disassembly in airway epithelial cells.

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 ß-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.

Inhibitory effect of Zingiber cassumunar Roxb. (Phlai) on nasal cytokine productions and eosinophilic recruitment in patients with allergic rhinitis.

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.

Tumor necrosis factor-α (TNF-α) -308G >a promoter polymorphism (rs1800629) promotes Asians in susceptibility to Plasmodium falciparum severe malaria: A meta-analysis.

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.

Immunogenicity and Safety of the Third Booster Dose with mRNA-1273 COVID-19 Vaccine after Receiving Two Doses of Inactivated or Viral Vector COVID-19 Vaccine.

The changes in the severe acute respiratory syndrome coronavirus 2 and the tapering of immunity after vaccination have propelled the need for a booster dose vaccine. We aim to evaluate B and T cell immunogenicity and reactogenicity of mRNA-1273 COVID-19 vaccine (100 µg) as a third booster dose after receiving either two doses of inactivated COVID-19 vaccine (CoronaVac) or two doses of viral vector vaccine (AZD1222) in adults not previously infected with COVID-19. The anti-receptor-binding-domain IgG (anti-RBD IgG), surrogate virus neutralization test (sVNT) against the Delta variant, and Interferon-Gamma (IFN-γ) level were measured at baseline, day (D)14 and D90 after vaccination. In D14 and D90, the geometric means of sVNT were significantly increased to 99.4% and 94.5% inhibition in CoronaVac, respectively, whereas AZD1222 showed inhibition of 99.1% and 93%, respectively. Anti-RBD IgG levels were 61,249 to 9235 AU/mL in CoronaVac and 38,777 to 5877 AU/mL in AZD1222 after D14 and D90 vaccination. Increasing median frequencies of S1-specific T cell response by IFN-γ concentration were also elevated in D14 and were not significantly different between CoronaVac (107.8-2035.4 mIU/mL) and AZD1222 (282.5-2001.2 mIU/mL). This study provides evidence for the high immunogenicity of the mRNA-1273 booster after two doses of CoronaVac or AZD1222 in the Thai population.

Associations of CB1 cannabinoid receptor (CNR1) gene polymorphisms with risk for alcohol dependence: Evidence from meta-analyses of genetic and genome-wide association studies.

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.

ß-eudesmol but not atractylodin exerts an inhibitory effect on CFTR-mediated chloride transport in human intestinal epithelial cells.

Oriental herbal medicine with the two bioactive constituents, ß-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 (ISC) and apical Cl- current (ICl-) 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 (IC50 of ~1.05 µM) reduced cAMP-mediated, CFTRinh-172 inhibitable Cl- secretion as determined by transepithelial ISC across a monolayer of T84 cells. Potency of CFTR-mediated ICl- 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 ICl-. 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.

Influence of Lysyl oxidase Polymorphisms in Cancer Risk: An Updated Meta-analysis.

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 [pa] < 0.00001), homogeneity (I2 = 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 (pa < 0.05), indicating increased risk, (OR >1.00) found in all cancer groups except breast (pa = 0.10-0.91). Of the 13, three met all criteria (core) for strength of evidence (pa < 0.00001, CIDs 0.49-0.56 and I2 = 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.

Correction: Association of PPARGC1A Gly482Ser (rs8192678) polymorphism with potential for athletic ability and sports performance: A meta-analysis.

[This corrects the article DOI: 10.1371/journal.pone.0200967.].

Ethnic and age-specific acute lung injury/acute respiratory distress syndrome risk associated with angiotensin-converting enzyme insertion/deletion polymorphisms, implications for COVID-19: A meta-analysis.

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 (Pa = 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.

Influence of polymorphisms in the vascular endothelial growth factor gene on allograft rejection after kidney transplantation: a meta-analysis.

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.

An Updated Meta-Analysis of Controlling Myopia with Auricular Acupoint Stimulation.

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.

Influence of Polymorphisms in the Interleukin-18 Gene on Allergic Rhinitis: A Meta-Analysis.

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.

Association of the selenoprotein 15-kDa (SEP15) polymorphisms with cancer risk: a meta-analysis.

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 (PaF). 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, PaF = 0.047) while that in genitourinary cancer was protective (OR 0.29, 95% CI 0.20-0.43, PaF < 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 riskI2measure of heterogeneitykDakiloDaltonLAClaryngeal cancerLUClung cancermafminor allele frequencynnumber of studiesNnumber of comparisonsNMnot mentionedNOSNewcastle-Ottawa ScaleORodds ratioPaP value for associationPaδP value for association (pre-FDR)PaFP value for association FDR-correctedPbP value for heterogeneityPBpopulation-basedPCprostate cancerPRISMAPreferred Reporting Items for Systematic Reviews and Meta-AnalysesPROpre-outlierPSOpost-outlierRrandom-effects[R]referenceRCrespiratory cancersRNSretained non-significanceROSreactive oxygen speciesSEPselenoproteinsSEP15selenoprotein geneSNPsingle nucleotide polymorphismSWShapiro-Wilk testUSAUnited States of Americavvvariantwvheterozygouswwwild-type.

Effects of the killer immunoglobulin-like receptor (KIR) polymorphisms on HIV acquisition: A meta-analysis.

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.

Association of the ACTN3 R577X (rs1815739) polymorphism with elite power sports: A meta-analysis.

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.

MSX1 gene polymorphisms and non-syndromic cleft lip with or without palate (NSCL/P): A meta-analysis.

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.

Association of PPARGC1A Gly428Ser (rs8192678) polymorphism with potential for athletic ability and sports performance: A meta-analysis.

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.

Association of COL5A1 gene polymorphisms and risk of tendon-ligament injuries among Caucasians: a meta-analysis.

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 I2 = 86%) pre-outlier rs12722 and rs13946 results became significant (ORs 0.32-0.78, p = 10-5-0.01) and heterogeneity eliminated (I2 = 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.

Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK.

Marked increases in fructose consumption have been tightly linked to metabolic diseases. One-third of ingested fructose is metabolized in the small intestine, but the underlying mechanisms regulating expression of fructose-metabolizing enzymes are not known. We used genetic mouse models to test the hypothesis that fructose absorption via glucose transporter protein, member 5 (GLUT5), metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein in brain 11a (Rab11a)-dependent endosomes are required for the regulation of intestinal fructolytic and gluconeogenic enzymes. Fructose feeding increased the intestinal mRNA and protein expression of these enzymes in the small intestine of adult wild-type (WT) mice compared with those gavage fed with lysine or glucose. Fructose did not increase expression of these enzymes in the GLUT5 knockout (KO) mice. Blocking intracellular fructose metabolism by KHK ablation also prevented fructose-induced upregulation. Glycolytic hexokinase I expression was similar between WT and GLUT5- or KHK-KO mice and did not vary with feeding solution. Gavage feeding with the fructose-specific metabolite glyceraldehyde did not increase enzyme expression, suggesting that signaling occurs before the hydrolysis of fructose to three-carbon compounds. Impeding GLUT5 trafficking to the apical membrane using intestinal epithelial cell-specific Rab11a-KO mice impaired fructose-induced upregulation. KHK expression was uniformly distributed along the villus but was localized mainly in the basal region of the cytosol of enterocytes. The feedforward upregulation of fructolytic and gluconeogenic enzymes specifically requires GLUT5 and KHK and may proactively enhance the intestine's ability to process anticipated increases in dietary fructose concentrations.

Chronic high fructose intake reduces serum 1,25 (OH)2D3 levels in calcium-sufficient rodents.

Excessive fructose consumption inhibits adaptive increases in intestinal Ca2+ transport in lactating and weanling rats with increased Ca2+ requirements by preventing the increase in serum levels of 1,25(OH)2D3. Here we tested the hypothesis that chronic fructose intake decreases 1,25(OH)2D3 levels independent of increases in Ca2+ requirements. Adult mice fed for five wk a high glucose-low Ca2+ diet displayed expected compensatory increases in intestinal and renal Ca2+ transporter expression and activity, in renal CYP27B1 (coding for 1α-hydroxylase) expression as well as in serum 1,25(OH)2D3 levels, compared with mice fed isocaloric glucose- or fructose-normal Ca2+ diets. Replacing glucose with fructose prevented these increases in Ca2+ transporter, CYP27B1, and 1,25(OH)2D3 levels induced by a low Ca2+ diet. In adult mice fed for three mo a normal Ca2+ diet, renal expression of CYP27B1 and of CYP24A1 (24-hydroxylase) decreased and increased, respectively, when the carbohydrate source was fructose instead of glucose or starch. Intestinal and renal Ca2+ transporter activity and expression did not vary with dietary carbohydrate. To determine the time course of fructose effects, a high fructose or glucose diet with normal Ca2+ levels was fed to adult rats for three mo. Serum levels of 1,25(OH)2D3 decreased and of FGF23 increased significantly over time. Renal expression of CYP27B1 and serum levels of 1,25(OH)2D3 still decreased in fructose- compared to those in glucose-fed rats after three mo. Serum parathyroid hormone, Ca2+ and phosphate levels were normal and independent of dietary sugar as well as time of feeding. Thus, chronically high fructose intakes can decrease serum levels of 1,25(OH)2D3 in adult rodents experiencing no Ca2+ stress and fed sufficient levels of dietary Ca2+. This finding is highly significant because fructose constitutes a substantial portion of the average diet of Americans already deficient in vitamin D.