Vascular endothelial growth factor enhances tendon-bone healing by activating Yes-associated protein for angiogenesis induction and rotator cuff reconstruction in rats

Local angiogenesis following rotator cuff reconstruction is crucial for tendon-bone healing. The current research on the mechanism underlying angiogenesis that promotes tendon-bone healing is scarce. This study investigates the mechanism underlying vascular endothelial growth factor (VEGF)-Hippo signaling pathway's involvement in tendon-bone healing following rotator cuff reconstruction. Verteporfin, the inhibitor of the Yes-associated protein (YAP), was used to mechanically test and analyze two groups of tensile-failure loads following rotator cuff reconstruction and to detect collagen and angiogenesis-related marker expressions in the tendon. The interaction mechanism of the VEGF-Hippo signaling pathway was assessed using human umbilical vein endothelial cells (HUVECs). The diameter of the supraspinatus tendon reduced following verteporfin treatment. Mechanical tests revealed that verteporfin significantly reduces the tensile-failure load of the supraspinatus tendon. Verteporfin significantly reduces collagen 1 (Col 1), Col 3, Angiopoietin 2, CD31, Von Willebrand factor, CTGF, and CYR61 expressions. In HUVECs, VEGF activates VEGF receptors and inhibits LATS and YAP phosphorylation. YAP is then transferred to the nucleus to further activate downstream pathways. Therefore, verteporfin can inhibit VEGF-induced YAP pathway activation by inhibiting YAP activity. Angiogenesis in tendon-bone healing following rotator cuff reconstruction requires VEGF-Hippo signaling pathway synergy.     

Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case–control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA + AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR = 1.20, 95%CI: 1.03–1.40, P = 0.021; MI: RR = 1.32, 95%CI: 1.11–1.57, P = 0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR = 0.92, 95%CI: 0.73–1.15, P = 0.445; MI: RR = 0.93, 95%CI: 0.84–1.03, P = 0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI.     

Association between -251A>T polymorphism in the interleukin-8 gene and oral cancer risk: A meta-analysis

Background

Emerging evidence showed that the most common functional polymorphism (-251A>T, rs4073) in the promoter region of the interleukin-8 (IL-8) gene is involved in the regulation of the activities of interleukin-8, thus increasing an individual's susceptibility to oral cancer; but individually published results are inconclusive. The aim of this meta-analysis was to investigate the associations between IL-8 -251A>T polymorphism and oral cancer risk.

Methods

The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to October 1st, 2012 that addressed IL-8 -251A>T polymorphism and oral cancer risk. Statistical analyses were performed using STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Six case–control studies were included with a total of 1324 oral cancer cases and 1879 healthy controls. When all available studies were pooled into the meta-analysis, the results showed that the AA and AT genotypes of IL-8 -251A>T polymorphism were associated with increased risk of oral cancer (OR = 1.23, 95% CI: 1.03–1.46, P = 0.025; OR = 1.25, 95% CI: 1.07–1.47, P = 0.006; respectively). In the subgroup analysis by ethnicity, significant associations were observed between the AA and AT genotypes of IL-8 -251A>T polymorphism and increased risk of oral cancer among Caucasian populations (OR = 1.40, 95% CI: 1.14–1.72, P = 0.001; OR = 1.29, 95% CI: 1.06–1.57, P = 0.011; respectively). However, no statistically significant associations were found between IL-8 -251A>T polymorphism and oral cancer risk among Asian populations.

Conclusions

Results from the current meta-analysis indicate that the AA and AT genotypes of IL-8 -251A>T polymorphism might increase the risk of oral cancer, especially among Caucasian populations.     

Angiotensin-converting enzyme insertion/deletion polymorphism and risk of myocardial infarction in an updated meta-analysis based on 34 993 participants

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism and risk of myocardial infarction (MI) has been extensively studied. However, the results were in controversy. This study aimed to explore the association between ACE I/D polymorphism and risk of MI by using a meta-analysis. We retrieved the following databases to indentify eligible studies: Medline, Embase, ISI, VIP, CBM and Wan Fang database. The latest update was 10th May, 2012. Odds ratio and 95% confidence interval (95% CI) were used to present the strength of the association. A total of 40 case–control studies with 34 993 participants were included. Overall, D allele of ACE I/D polymorphism was significantly associated with an increased risk of MI in genetic comparison models (OR (95% CI): 1.41 (1.22–1.64) for DD vs. II; 1.11 (1.01–1.21) for ID vs. II; 1.23 (1.10–1.37) for D carriers vs. II; 1.28 (1.15–1.43) for DD vs. I carriers and 1.06 (1.02–1.10) for D carriers vs. I carriers). Subgroup analyses, according to ethnicities and countries of participants also indicated that D allele was significantly associated with an increased risk of MI in Asians (especially for Chinese) and Caucasians (especially for English, French, Germans and Italians) (OR (95% CI) of DD vs. ID + II: 2.11 (1.65–2.70) for Asians and 1.15 (1.05–1.27) for Caucasians). In conclusion, this meta-analysis indicated that D allele of ACE I/D polymorphism was a possible risk factor for MI incidence for both Asians and Caucasians.     

Lack of association between EGF + 61A>G polymorphism and melanoma susceptibility in Caucasians: A HuGE review and meta-analysis

Emerging evidence showed that the common polymorphism (+ 61A>G, rs4444903) in the promoter region of epidermal growth factor (EGF) gene might be associated with melanoma susceptibility in humans. But individually published results are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of the association between EGF + 61A>G polymorphism and melanoma risk. The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to July 1st, 2012. Seven case–control studies were included with a total of 2367 melanoma cases and 4184 healthy controls. Meta-analysis results showed that there was no significant relationship between EGF + 61A>G polymorphism and the risk of melanoma (G vs A: odds ratio [OR] = 1.08, 95% confidence interval [CI]: 0.91–1.28, P = 0.386; GG + AG vs AA: OR = 1.05, 95%CI: 0.88–1.26, P = 0.580; GG vs AA + AG: OR = 1.10, 95%CI: 0.81–1.49, P = 0.552; GG vs AA: OR = 1.06, 95%CI: 0.80–1.41, P = 0.700; GG vs AG: OR = 1.12, 95%CI: 0.81–1.56, P = 0.494). Further subgroup analyses based on source of controls, country, detection samples, genotype methods, and Breslow thickness of tumor, we also found no significant association between EGF + 61A>G polymorphism and melanoma risk. In conclusion, this meta-analysis indicates that EGF + 61A>G polymorphism might not be a primary determinant in melanoma development and progression; EGF gene might be expected to interact with other genes in different signaling pathways to initiate and promote the carcinogenic process.     

Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease

The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta-analysis by combining all available case–control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel–Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR = 1.212 for T allele, 95% CI = 1.097–1.340, p-value = 0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR = 1.187 for T allele, 95% CI = 1.058–1.332, p-value = 0.004) and Asian samples (allelic model, pooled OR = 1.293 for T allele, 95% CI = 1.058–1.580, p-value = 0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value = 0.0149) and CHB (Chinese, p-value = 0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD.     

An association between − 866G/A polymorphism in the promoter of UCP2 and obesity: A meta-analysis

− 866G/A polymorphism in the promoter of UCP2 gene has been reported to be associated with obesity, but the results remain inconclusive. To assess the relation of UCP2 − 866G/A polymorphism and obesity susceptibility, a meta-analysis was performed. PubMed, ISI, Wanfang database, VIP and CBM were searched to identify relevant studies up to July 31, 2012. Odds ratios (OR) and 95% confidence interval (95% CI) were pooled using fixed or random effect models. Subgroup analysis was performed by ethnicity (categorized as Asian and European). Heterogeneity and publication bias evaluation were performed to validate the credibility. Meta-regression and the ‘leave one out’ sensitive analysis were used to explore the potential sources of between-study heterogeneity. 14 studies were included in this meta-analysis. After exclusion of articles that deviated from the HWE in controls, and were the key contributors to between-study heterogeneity, the meta-analysis showed a significant association of the A allele with reduced risk of obesity in overall analysis and in European in the dominant, codominant and additional models. In Asian, no significant association was found between the − 866G/A in UCP2 gene and obesity susceptibility. The meta-analysis suggested that UCP2 − 866G/A polymorphism was associated with obesity. The A allele may be an important protective factor for obesity in European, but not in Asian. Further studies are needed to elucidate the relationship.     

Association of the macrophage migration inhibitory factor gene − 173G/C polymorphism with inflammatory bowel disease: A meta-analysis of 4296 subjects

A variety of epidemiologic studies have focused on the association between macrophage migration inhibitory factor (MIF) gene − 173G/C polymorphism and inflammatory bowel disease (IBD). However, results in different studies have been inconsistent. In order to derive a more precise estimation of the associations, we performed this meta-analysis and systematic searches of electronic databases PubMed and Web of Science (up to April 30, 2013). Based on our search criteria, a total of seven eligible studies concerning the MIF − 173G/C polymorphism and IBD risk were included in the final meta-analysis, comprising 2162 IBD cases and 2134 controls. Significant association was found between MIF − 173G/C polymorphism and the risk of IBD when all studies were pooled into the meta-analysis (for C allele vs. G allele: OR = 1.25, 95% CI = 1.12–1.41, p = 0.000; for C/C vs. G/G: OR = 1.71, 95% CI = 1.23–2.39, p = 0.002; for C/C + G/C vs. G/G: OR = 1.24, 95% CI = 1.09–1.42, p = 0.002; for C/C vs. G/C + G/G: OR = 1.67, 95% CI = 1.20–2.33, p = 0.002). Heterogeneity and publication bias did not exist in the overall comparisons. The present meta-analysis suggests an association between the MIF − 173G/C polymorphism and IBD risk. However, due to few studies and the selection bias existed in some studies, the results should be interpreted with caution.     

Association between the polymorphisms of glutathione S-transferase genes and rheumatoid arthritis: A meta-analysis

The glutathione S-transferases (GSTs) are a family of phase II xenobiotic metabolizing enzymes known to be involved in the detoxification and elimination of reactive oxygen species (ROS), thus defending tissues against oxidative stress. Recently, several studies have examined the potential contributions of GSTM1 and GSTT1 gene polymorphisms toward susceptibility to rheumatoid arthritis (RA), but these studies have produced diverse results. To verify the association between GSTM1 and GSTT1 gene polymorphisms and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before April 2012. A meta-analysis on the association between the GSTM1 polymorphism and RA was performed for 4636 patients with RA and 3916 controls from 8 published studies. In addition, a total of 5 studies involving 3174 RA patients and 2958 controls were considered in the meta-analysis of the association between the GSTT1 polymorphism and RA. No significant association was found between the GSTM1 null genotype and RA susceptibility in all subjects; however, a significant increased risk was found in East Asians. The GSTT1 null genotype was not associated with susceptibility to RA in any study subject. No apparent effect of smoking was found in stratified analysis. The results of our meta-analysis indicated that the GSTM1 null genotype is significantly associated with RA in East Asians alone, indicating that GSTM1 is another non-human leukocyte antigen (non-HLA) susceptibility gene for RA in East Asian populations.     

Genetic associations with coronary heart disease: Meta-analyses of 12 candidate genetic variants

Aims

The aim of this study was to evaluate the combined contribution of 12 genetic variants to the risk of coronary heart disease (CHD).

Methods

Through a comprehensive literature search for genetic variants involved in the CHD association study, we harvested a total of 10 genes (12 variants) for the current meta-analyses. These genes consisted of GPX1 (rs1050450), PPARD (rs2016520), ALOX15 (rs34210653), SELPLG (rs2228315), FCGR2A (rs1801274), CCL5 (rs2107538), CYP1A1 (rs4646903), TP53 (rs1042522), CX37 (rs1764391), and PECAM1 (rs668, rs12953, and rs1131012).

Results

A total of 45 studies among 23,314 cases and 28,430 controls were retrieved for the meta-analyses of 12 genetic variants. The results showed a significant association between the GPX1 rs1050450 polymorphism and CHD (odd ratio (OR) = 1.61, 95% confidence interval (CI) = 1.25–2.07, P = 0.0002). Other meta-analyses of the rest 11 variants suggested a lack of association with the risk of CHD.

Conclusion

Our results confirmed that GPX1 rs1050450 was associated with susceptibility to CHD in Chinese and Indian populations.