Association of VEGF Genetic Polymorphisms with Recurrent Spontaneous Abortion Risk: A Systematic Review and Meta-Analysis

Background

Studies of the associations between the genetic polymorphisms of the vascular endothelial growth factor (VEGF) gene and recurrent spontaneous abortion (RSA) have revealed conflicting results. The present meta-analysis was performed to provide a more precise estimation of these relationships and to explore potential sources of heterogeneity that may have influenced the reported disparities.

Methods

An extensive literature search for relevant studies was conducted on PubMed, Embase, and The Cochrane Library through June 6, 2014. Crude odds ratio (OR) with 95% confidence intervals were calculated.

Results

10 case-control studies including 1,832 RSA patients and 2,271 healthy controls were identified. Meta-analysis indicated that rs1570360, rs3025039, rs2010963, and rs3025020 polymorphisms in the VEGF gene correlated with elevated RSA risk. The rs1570360 variant was statistically significantly relevant to RSA risk among non-Asian populations. Interestingly, the rs3025039 variant was statistically significantly relevant to RSA risk among Asian populations.

Conclusions

The current meta-analysis indicates that rs1570360, rs3025039, rs2010963, and rs3025020 polymorphisms increase RSA susceptibility. Moreover, rs1570360 and rs3025039 polymorphisms may play various roles in RSA susceptibility in various geographic groups.     

Association Studies of ERCC1 Polymorphisms with Lung Cancer Susceptibility: A Systematic Review and Meta-Analysis

Background

Excision repair cross-complimentary group 1 (ERCC1) is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial.

Objectives

An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following ERCC1 polymorphisms: rs11615 (T>C), rs3212986 (C>A), rs3212961 (A>C), rs3212948 (G>C), rs2298881 (C>A).

Methods

Several major databases (MEDLINE, EMBASE and Scopus) and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of associations.

Results

Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies (8,215 cases vs. 11,402 controls) suggested a significant association of ERCC1 rs11615 with increased risk for lung cancer (homozygous: CC versus TT, OR = 1.24, 95% CI: 1.04–1.48, P = 0.02). However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation (heterozygous: CG vs.GG, OR = 0.78, 95% CI: 0.67–0.90, P = 0.001; dominant: CG/CC vs.GG, OR = 0.79, 95% CI: 0.69–0.91, P = 0.001).

Conclusion

Overall, this meta-analysis suggests that ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully designed studies with large sample size involving different ethnicity, smoking status, and cancer types are needed to validate these findings.     

Four Genetic Polymorphisms of Lymphotoxin-Alpha Gene and Cancer Risk: A Systematic Review and Meta-Analysis

Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P < 0.0001, I² = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I² = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I² = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93-1.10, P = 0.771, I² = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01–1.20, P = 0.023, I² = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I² = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk.     

Myocilin Polymorphisms and Primary Open-Angle Glaucoma: A Systematic Review and Meta-Analysis

Background

Glaucoma is the leading cause of irreversible blindness in the world. Recent evidence indicates a role for genetic susceptibility to primary open-angle glaucoma (POAG). The relation between myocilin polymorphisms and POAG susceptibility has been studied in different populations.

Methods

A meta-analysis of 32 published genetic association case-control studies, which examined the relation between POAG and the R46X, R76K, Y347Y, T353I, and Q368X polymorphisms of the myocilin gene, was carried out.

Results

In meta-analysis, significant associations were observed between POAG risk and two myocilin polymorphisms with summarized odds ratio of 4.68 (95%CI, 2.02–10.85) for Q368X and 2.17 (95% CI, 1.32–3.57) for T353I. Both Q368X and T353I were significantly associated with high-tension glaucoma, with summarized odds ratio of 4.26 (1.69, 10.73) and 2.26 (1.37–3.72). In Westerners, significant association was observed for Q368X mutation (odds ratio, 5.17; 95% CI, 2.16–12.40). However, in Asians it was for T353I (odds ratio, 2.17; 95% CI, 1.32–3.57).

Conclusions

There is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I.     

A Systematic Review and Meta-Analysis of the Association between Serotonergic Gene Polymorphisms and Obstructive Sleep Apnea Syndrome

Background

5-Hydroxytryptamine receptor (5-HTR) and 5-hydroxytryptamine transporter (5-HTT) gene polymorphisms have been reported to be associated with susceptibility to obstructive sleep apnea syndrome (OSAS). The associations, derived from sporadic, inconsistent, small-sample-size studies, need to be evaluated further in a meta-analysis.

Methods

Relevant studies were identified by searching PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Eligible data were extracted from each included study. Odds ratios (ORs) were calculated using a fixed-effects or a random-effects model. The ORs and 95% confidence interval (CI) were used to assess the strength of the association between serotonergic gene polymorphisms and OSAS in the dominant and recessive models, as well as alleles. The Q statistic was used to evaluate homogeneity and Begg’s test was used to assess publication bias.

Results

Eight studies were finally included in the meta-analysis of the association between 5-HTR2A gene variants (including 102T/C and 1438G/A), 5-HTT gene polymorphisms (including 5-HTT gene-linked promoter region (5-HTTLRP), and serotonin transporter intron 2 variable number tandem repeat (STin2VNTR) and OSAS risk. The G allele of 5-HTR2A 1438G/A, long 5-HTTLPR, and 10-tandem-repeats STin2VNTR were shown to increase OSAS susceptibility, with ORs of 2.33 (A vs. G, 95% CI 1.48–3.66), 1.24 (L vs. S, 95% CI: 1.04–1.49), and 2.87 (10 vs. 12, 95% CI: 1.38–5.97), respectively. These significant differences were determined in both dominant and recessive models. Of the 5-HTR2A 1438G/A gene polymorphism, the AA genotype increased the OSAS risk, with an OR of 4.21 (95% CI: 2.83–6.25) in a recessive model in male OSAS patients, but no significant association was found in females.

Conclusions

Our meta-analysis demonstrated that polymorphisms in the 5-HTR2A 1438G/A and 5-HTT genes contributed to susceptibility to OSAS. The A allele of the 1438G/A gene polymorphism is predominantly distributed in males and increased the OSAS risk significantly.     

NOD2 Polymorphisms and Pulmonary Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis

The association between NOD2 and tuberculosis (TB) risk has been reported widely, but the results of previous studies remained controversial and ambiguous. To assess the association between NOD2 polymorphisms and TB risk, a meta-analysis was performed. A literature search was conducted by using the PubMed, Ovid, ISI Web of Knowledge, Elsevier ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI). We identified the data from all articles estimating the association between NOD2 polymorphisms and TB risk. In total, 2,215 cases and 1,491 controls in 7 case-control studies were included. In meta-analysis, we found significant association between the Arg702Trp polymorphism and TB risk (OR = 0.43, 95% CI = 0.20-0.90, P = 0.02). However, no significant association was found between the Arg587Arg (OR = 1.31, 95% CI = 0.83-2.07, P = 0.25) and Gly908Arg (OR = 0.78, 95% CI = 0.21-2.87, P = 0.71) polymorphisms and TB risk. The present meta-analysis suggested that NOD2 Arg702Trp polymorphism was likely to be a protective factor for TB. However, the Arg587Arg and Gly908Arg polymorphisms might not be the genetic risk factors for TB susceptibility.     

The Association of 5-HT2A, 5-HTT,and LEPR Polymorphisms with Obstructive Sleep Apnea Syndrome: A Systematic Review and Meta-Analysis

Objective

A consensus has not been reached regarding the association of several different gene polymorphisms and susceptibility to obstructive sleep apnea syndrome (OSAS). We performed a meta-analysis to better evaluate the associations between 5-HT2A, 5-HTT, and LEPR polymorphisms, and OSAS.

Method

5-HT2A, 5-HTT, and LEPR polymorphisms and OSAS were identified in PubMed and EMBASE. The pooled odd rates (ORs) with 95%CIs were estimated using a fixed-effect or random-effect models. The associations between these polymorphisms and OSAS risk were assessed using dominant, recessive and additive models.

Results

Twelve publications were included in this study. The -1438 “A” allele of 5-HT2A was identified as a candidate genetic risk factor for OSAS (OR: 2.33, 95%CI 1.49–3.66). Individuals carrying the -1438 “G” allele had a nearly 70% reduced risk of OSAS when compared with AA homozygotes (OR: 0.30, 95%CI 0.23–0.40). There was no significant association between 5-HT2A 102C/T and OSAS risk, using any model. The “S” allele of 5-HTTLPR conferred protection against OSAS (OR: 0.80, 95%CI 0.67–0.95), while the “10” allele of 5-HTTVNTR contributed to the risk of OSAS (OR: 2.08, 95%CI: 1.58–2.73). The “GG” genotype of LEPR was associated with a reduced risk of OSAS (OR: 0.39, 95%CI 0.17–0.88).

Conclusion

The meta-analysis demonstrated that 5-HTR-1438 “A” and 5-HTTVNTR “10” alleles were significantly associated with OSAS. The “S” allele of 5-HTTLPR and the “GG” genotype of LEPR conferred protection against OSAS. Further studies, such as Genome-Wide Association study (GWAS), should be conducted in a large cohort of OSAS patients to confirm our findings.     

Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms with Coronary Artery Disease: An Updated Meta-Analysis and Systematic Review

Several association studies of endothelial nitric oxide synthase (NOS3) gene polymorphisms with respect to coronary artery disease (CAD) have been published in the past two decades. However, their association with the disease, especially among different ethnic subgroups, still remains controversial. This prompted us to conduct a systematic review and an updated structured meta-analysis, which is the largest so far (89 articles, 132 separate studies, and a sample size of 69,235), examining association of three polymorphic forms of the NOS3 gene (i.e. Glu298Asp, T786-C and 27bp VNTR b/a) with CAD. In a subgroup analysis, we tested their association separately among published studies originating predominantly from European, Middle Eastern, Asian, Asian-Indian and African ancestries. The pooled analysis confirmed the association of all the three selected SNP with CAD in three different genetic models transcending all ancestries worldwide. The Glu298Asp polymorphism showed strongest association (OR range = 1.28–1.52, and P<0.00001 for all comparisons), followed by T786-C (OR range = 1.34–1.42, and P<0.00001 for all comparisons) and 4b/a, (OR range = 1.19–1.41, and P≤0.002 for all comparisons) in our pooled analysis. Subgroup analysis revealed that Glu298Asp (OR range = 1.54–1.87, and P<0.004 for all comparisons) and 4b/a (OR range = 1.71–3.02, and P<0.00001 for all comparisons) have highest degree of association amongst the Middle Easterners. On the other hand, T786-C and its minor allele seem to carry a highest risk for CAD among subjects of Asian ancestry (OR range = 1.61–1.90, and P≤0.01 for all comparisons).     

Association between Polymorphisms in XRCC1 Gene and Treatment Outcomes of Patients with Advanced Gastric Cancer: A Systematic Review and Meta-Analysis

Background

Many reports have shown inconsistent results on the relationship between single nucleotide polymorphisms (SNPs) of X-ray repair cross complementing protein (XRCC1) gene and platinum-based chemotherapeutic efficacy. This meta-analysis aimed to summarize published data about the association between two SNPs of XRCC1 (Arg194Trp and Arg399Gln) and treatment outcomes of patients with advanced gastric cancer.

Methodology/Principal Findings

We retrieved the relevant articles from MEDLINE, Web of Knowledge, and the China National Knowledge Infrastructure (CNKI) databases. Studies were selected according to specific inclusion and exclusion criteria. Study quality was assessed according to the guidelines outlined by Hayden, et al. and PRISMA guidelines. We estimated the odds ratio (OR) for response rate versus no response after platinum-based chemotherapy. Progression-free survival (PFS) and overall survival (OS) were evaluated by pooled Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs). We found that none of the XRCC1 Arg194Trp and Arg399Gln polymorphisms was significantly associated with tumor response. Stratified analysis by ethnicity or sensitivity analysis also showed that XRCC1 SNPs were not related with chemotherapy response. Patients with minor variant A allele were likely to have poorer 2-year survival rate than those with G/G genotype. However, in the group of 5-year follow up, there was no significant association between the A allele and OS yet.

Conclusions/Significance

There is no evidence to support the use of XRCC1 Arg194Trp and Arg399Gln polymorphisms as prognostic predictors of TR and PFS in gastric patients treated with platinum-based chemotherapy. The relationship between minor variant A allele and OS requires further verification.     

Association between Dental Caries and Down Syndrome: A Systematic Review and Meta-Analysis

Scientific evidence of susceptibility to dental caries in the population with Down Syndrome (DS) is limited and conflicting, making it difficult to establish firm conclusions. The aim of this systematic review and meta-analysis was to obtain scientific evidence of the possible association between dental caries and individuals with DS, compared to individuals without DS (control). An electronic search of five databases was performed, with no language or publication date restrictions. The studies were selected by two independent reviewers (Kappa = 0.83). The systematic review included 13 studies, while eight studies were included in the meta-analysis. The studies are presumably all at risk of bias given their observational character. Two of these evaluated the presence or absence of caries in permanent and deciduous teeth, and six evaluated the mean DMFT index in permanent teeth. Combined odds ratios (OR), standard difference, standard error and a 95% confidence interval (CI) were obtained. The vast majority of the studies found that individuals from control groups had more carious lesions or caries experience than those with DS. The results were statistically significant in seven studies (p<0.05). Meta-analysis of two studies revealed that individuals with DS had a lower dental caries than those in the control group (OR = 0.36; 95% CI = 0.22–0.57). In six studies, individuals with DS had a significantly lower mean DMFT index than individuals from the control group (Sd = -0.18; SE = 0.09; 95% CI = -0.35–-0.02). The quality of the studies varied and in general had a high risk of bias. Scientific evidence suggests that individuals with DS have fewer dental caries than individuals without DS.     

The Association between VEGFR Gene Polymorphisms and Stroke: A Meta-Analysis

Several published articles investigated the relationship between VEGF receptor gene polymorphisms and stroke, but they failed to reach the same conclusion. This meta-analysis was performed to identify the relationships between VEGF receptor gene and the risk of stroke. The PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang Chinese database, and VIP Chinese database were systemically searched. Data was extracted by two independent reviewers. The pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. 5 case-control studies with a total of 2904 patients with stroke and 2824 control subjects were included, including 2904 cases and 2824 controls for -604T>C, 2733 cases and 2663 controls for +1192C>T, and 2733 cases and 2663 controls for +1719A>T. Under the dominant and recessive models, respectively, the overall ORs and 95% CIs of -604 C were 0.749, 0.493–1.138 (P = 0.176) and 0.819, 0.544–1.234 (P = 0.340); the overall ORs and 95% CIs of +1192 T were 1.148, 0.876–1.504 (P = 0.318) and 1.611, 1.004–2.586 (P = 0.048); the overall ORs and 95% CIs of +1719 T were 1.227, 0.932–1.615 (P = 0.146) and 1.139, 1.015–1.279 (P = 0.027). Our finding indicates that +1192C>T and +1719A>T may be associated with the risk of stroke, but not -604T>C.     

Polymorphisms of microRNA Sequences or Binding Sites and Lung Cancer: A Meta-Analysis and Systematic Review

Objective

Functional single nucleotide polymorphisms (SNPs) of microRNA (miRNA) sequences or binding sites (miRNA-SNPs) are associated with lung cancer risk and survival. The objective of this study was to systematically review genetic association studies about miRNA-SNPs in lung cancer.

Methods

Eligible genetic association studies were retrieved from databases of PubMed, EMBASE, China National Knowledge Infrastructure and SinoMed. Two investigators selected related studies and assessed methodological quality independently. Quantitative data synthesis was conducted for common SNPs of miRNA (miRNA-196a2 rs11614913, miRNA146a rs2910164, miRNA149 rs2292832, miRNA-605 rs2043556 and miRNA499 rs3746444). GRADE profiler was used to grade the quality of evidence for each miRNA-SNP.

Results

15 eligible studies and 27 miRNA-SNPs were retrieved and 10 miRNA-SNPs were reported with a significant association with susceptibility to or survival of lung cancer. Methodological quality of eligible studies was adequate with an average score of 8.5. miRNA-196a2 rs11614913 polymorphism was associated with increased lung cancer risk (homozygote comparison, OR = 1.299, 95% CI: 1.096–1.540; dominant model, OR = 1.217, 95% CI: 1.041–1.421) and decreased survival. And according to GRADE profiler, quality of evidence was moderate for MYCL1 rs3134615, while quality of the other significant associations was low.

Conclusions

Based on this first systematic review about miRNA-SNPs in lung cancer, quality of evidence was low for most genetic association studies. Polymorphisms of miRNA-196a2 rs11614913 and MYCL1 rs3134615 could be potential biomarkers of lung cancer.     

Association of OPA1 Polymorphisms with NTG and HTG: A Meta-Analysis

Background

Genetic polymorphisms of the Optic atrophy 1 gene have been implicated in altering the risk of primary open angle glaucoma (POAG), especially the susceptibility to normal tension glaucoma (NTG), but the results remain controversial.

Methods

Multiple electronic databases (up to January 20, 2012) were searched independently by two investigators. A meta-analysis was performed on the association between Optic atrophy 1 polymorphisms (rs 166850 and rs 10451941) and normal tension glaucoma (NTG)/high tension glaucoma (HTG). Summary odds ratios (ORs) and 95% confidence intervals (CI) were estimated.

Results

Seven studies of 713 cases and 964 controls for NTG and five studies of 1200 cases and 971 controls for HTG on IVS8+4C>T (rs 166850) and IVS8+32T>C (rs10451941) were identified. There were significant associations between the OPA1 rs10451941polymorphism and NTG susceptibility for all genetic models(C vs. T OR = 1.26, 95% CI 1.09–1.47, p = 0.002; CC vs. TT: OR = 1.52, 95% CI 1.04–2.20, p = 0.029; CC vs. CT+TT: OR = 1.64, 95% CI 1.16–2.33, p = 0.005; CC+CT vs. TT: OR = 1.21, 95% CI 1.02–1.44, p = 0.032). However, no evidence of associations was detected between the OPA1 IVS8+32C>T polymorphism and POAG susceptibility to HTG. Similarly, clear associations between the rs 166850 variant and NTG were observed in allelic and dominant models (T vs. C OR = 1.52, 95% CI 1.16–1.99, p = 0.002; TT+TC vs. CC OR = 1.50, 95% CI 1.13–2.01, p = 0.006) but not to HTG. In subgroup analyses by ethnicity, we detected an association between both OPA1 polymorphisms and risk for NTG in Caucasians but not in Asians. By contrast, no significant findings were noted between OPA1 variants for HTG, either in Caucasians or in Asians.

Conclusions

Both the IVS8+4C>T and IVS8+32T>C variants may affect individual susceptibility to NTG. Moreover, stratified analyses for NTG detecting the effects of both OPA1 polymorphisms seemed to vary with ethnicity. Further investigations are needed to validate the association.     

Association of VEGF Gene Polymorphisms with Diabetic Retinopathy: A Meta-Analysis

Background

Studies on the association of vascular endothelial growth factor (VEGF) gene -460T/C and -2578C/A polymorphisms with diabetic retinopathy (DR) have reported conflicting results. The aim of the present study was to assess the association by using meta-analysis.

Methods

A systematic search of electronic databases (PubMed, EMBASE, Elsevier Science Direct, ISI Web of Science, CBM, CNKI and VIP) was carried out until Sept 18, 2013. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.

Results

Eleven studies (-460T/C: 6 studies including 932 cases and 722 controls; -2578C/A: 6 studies including 1,071 cases and 1,137 controls) were involved in this meta-analysis. Significant association was found for -460T/C polymorphism (C versus T: OR=1.48, 95%CI=1.07–2.05, P=0.02; TC+CC versus TT: OR=1.78, 95%CI=1.02–3.12, P=0.04; CC versus TT+TC: OR=1.76, 95%CI=1.10–2.81, P=0.02), but not for -2578C/A polymorphism (P>0.05). Similar results were found in the subgroup analysis.

Conclusions

This meta-analysis demonstrates that DR is associated with VEGF gene -460T/C polymorphism, but not -2578C/A polymorphism. Further case-control studies based on larger sample size are still needed, especially for -2578C/A polymorphism.     

Serological Association of Chlamydia pneumoniae Infection with Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis

Background

We investigated the serological association of Chlamydia pneumoniae infection with age-related macular degeneration (AMD).

Methods

A systematic review and meta-analysis was performed. PubMed, Embase, Web of Science and the Association of Research in Vision and Ophthalmology abstracts were searched to identify studies investigating the serological association of Chlamydia pneumoniae infection with age-related macular degeneration. The quality of original studies was assessed using the Newcastle-Ottawa scale. Heterogeneity was explored with meta-regression. The odds ratios (ORs) and standardized mean differences (SMD) of Chlamydia pneumoniae infection between AMD patients and controls were pooled.

Results

In total, 9 studies met the inclusion criteria using the Newcastle-Ottawa scale scores ranging from 4 to 9. There was heterogeneity among studies due to a difference in the study designs and measurement of exposure to Chlamydia pneumoniae infection. The overall OR of Chlamydia pneumoniae infection with AMD was 1.11 (95% confidence interval: 0.78–1.57, P = 0.56). The overall SMD of antibody titer between AMD and control was 0.43 (95% confidence interval: −0.12 to 0.99, P = 0.13).

Conclusions

Evidence from the current published literature suggested no statistically significant association between Chlamydia pneumoniae infection and AMD.     

Association of Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms with Cancer: A Meta-Analysis

Background

Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and cancer risk report conflicting results. To derive a more precise estimation of the relationship between MTHFD1 polymorphisms and cancer risk, the present meta-analysis was carried out.

Methodology/Principal Findings

A comprehensive search was conducted to determine all the eligible studies about MTHFD1 polymorphisms and cancer risk. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between the MTHFD1 polymorphisms and cancer risk. We investigated by meta-analysis the effects of 2 polymorphisms in MTHFD1: G1958A (17 studies, 12348 cases, 44132 controls) and G401A (20 studies, 8446 cases, 14020 controls). The overall results indicated no major influence of these 2 polymorphisms on cancer risk. For G1958A, a decreased cancer risk was found in acute lymphoblastic leukemia (ALL)/Asians (the dominant: OR = 0.74, 95% CI = 0.58–0.94, P = 0.01; allelic: OR = 0.80, 95% CI = 0.65–0.99, P = 0.04) and other cancers (recessive: OR = 0.80, 95% CI = 0.66–0.96, P = 0.02). For G401A, the data showed that MTHFD1 G401A polymorphism was associated with a decreased colon cancer risk under dominant model (OR = 0.89, 95% CI = 0.80–0.99, P = 0.04).

Conclusions

The results suggest that MTHFD1 G1958A polymorphism might be associated with a decreased risk of ALL and other cancers. Meanwhile, the MTHFD1 G401A might play a protective role in the development of colon cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

Association of Four Genetic Polymorphisms of AGER and Its Circulating Forms with Coronary Artery Disease: A Meta-Analysis

Background

Considerable efforts have been devoted to evaluating the association of the receptor for advanced glycation end-products (gene AGER and protein: RAGE) genetic variants to coronary artery disease (CAD); the results, however, are often irreproducible. To generate more information, we sought to explore four common polymorphisms of AGER and its circulating forms associated with the risk of CAD via a meta-analysis.

Methodology/Principal Findings

Articles were identified by searching PubMed, EMBASE, Wanfang and CNKI databases before March 2013. Qualified articles had case-control designs and investigated AGER four polymorphisms (T-429C, T-374A, Gly82Ser, G1704A) or circulating soluble RAGE (sRAGE) or endogenous secretory RAGE (esRAGE) levels associated with CAD. Twenty-seven articles involving 39 independent groups fulfilled the predefined criteria. Overall, no significance was observed for all examined polymorphisms under allelic and dominant models. When restricting groups to CAD patients with diabetes mellitus or renal disease, deviations of risk estimates from the unity were stronger than overall estimates for all polymorphisms except for G1704A due to limited available studies. For example, under dominant model, having -429C allele increased the odds of developing CAD in diabetic patients by 1.22-fold (95% confidence interval (95% CI) 0.99–1.51; P = 0.06; I ² = 6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; P = 0.111; I ² = 18.0%). Circulating sRAGE levels were non-significantly lower in CAD patients than in controls, whereas this reduction was totally and significantly reversed in CAD patients with diabetes mellitus (weighted mean difference: 185.71 pg/ml; 95% CI: 106.82 to 264.61 pg/ml). Circulating esRAGE levels were remarkably lower in CAD patients, as well as in subgroups with or without diabetes mellitus and without renal disease.

Conclusions

Our findings demonstrated that association of AGER genetic polymorphisms with CAD was potentiated in patients with diabetes mellitus or renal disease. Practically, circulating esRAGE might be a powerful negative predictor for the development of CAD.     

Association of IL10 Polymorphisms and Leprosy: A Meta-Analysis

Leprosy is a chronic infectious disease that depends on the interplay of several factors. Single nucleotide polymorphisms (SNPs) in host immune related genes have been consistently suggested as participants in susceptibility towards disease. Interleukin-10 (IL-10) is a crucial immunomodulatory cytokine in mycobacterial pathogenesis and especially the -819C>T SNP (rs1800871) has been tested in several case-control studies indicating association with leprosy risk, although a recent consensus estimate is still missing. In this study, we evaluated the association of the -819C>T SNP and leprosy in two new Brazilian family-based populations. Then, we performed meta-analysis for this polymorphism summarizing published studies including these Brazilian family-based groups. Finally, we also retrieved published studies for other distal and proximal IL10 polymorphisms: -3575 T>A (rs1800890), -2849 G>A (rs6703630), -2763 C>A (rs6693899), -1082 G>A (rs1800896) and -592 C>A (rs1800872). Results from meta-analysis supported a significant susceptibility association for the -819T allele, with pooled Odds Ratio of 1.22 (CI = 1.11–1.34) and P-value = 3x10^–5 confirming previous data. This result remained unaltered after inclusion of the Brazilian family-based groups (OR = 1.2, CI = 1.10–1.31, P-value = 2x10^–5). Also, meta-analysis confirmed association of -592 A allele and leprosy outcome (OR = 1.24, CI = 1.03–1.50, P-value = 0.02). In support of this, linkage disequilibrium analysis in 1000 genomes AFR, EUR, ASN and AMR populations pointed to r² = 1.0 between the -592C>A and -819C>T SNPs. We found no evidence of association for the other IL10 polymorphisms analyzed for leprosy outcome. Our results reinforce the role of the -819C>T as a tag SNP (rs1800871) and its association with leprosy susceptibility.     

TGF-beta1 Gene Polymorphism in Association with Diabetic Retinopathy Susceptibility: A Systematic Review and Meta-Analysis

Background

Transforming growth factor-beta (TGF-β1) gene has been regarded as an important mechanism in angiogenesis, endothelial cell proliferation, adhesion,and the deposition of extracellular matrix. The TGF-β1 gene may be involved in the development of diabetic retinopathy (DR) through disrupting angiogenesis. However, studies investigating the relationship between −509C/T and +869T/C(L10P) polymorphisms and DR yielded contradictory and inconclusive outcomes. In order to realize these ambiguous findings, a meta-analysis was performed to assess the association between the TGF-β1 gene polymorphisms and susceptibility to DR.

Methodology/Principal Findings

We conducted a search of all English reports on studies for the association between the TGF-β1 gene polymorphisms and susceptibility to DR using Medline, the Cochrane Library, EMbase, Web of Science, Google (scholar), and all Chinese reports were identified manually and on-line using CBMDisc, Chongqing VIP database, and CNKI database. The strict selection criteria and exclusion criteria were determined, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. The fixed or random effect model was selected based on the heterogeneity test among studies. Publication bias was estimated using Begg''s funnel plots and Egger''s regression test.

Results

A total of three studies were included in the meta-analysis and all included studies analyzed patients with type 2 diabetes. For +869T/C(L10P) polymorphism, significant association was observed in an allele model (L versus P: OR = 1.34, 95%CI = 1.03–1.73) and the recessive model (LL versus LP+PP: OR = 1.70, 95%CI = 1.13–2.56). As regards −509C/T polymorphism, no obvious associations were found for all genetic models.

Conclusions

This meta-analysis suggested that the +869T/C(L10P) polymorphism in TGFβ1 gene would be a potential protect factor for DR. However, the −509C/T polymorphism is not associated with DR.     

X-Ray Repair Cross-Complementing Group 1 (XRCC1) Genetic Polymorphisms and Cervical Cancer Risk: A HuGE Systematic Review and Meta-Analysis

Background

Previous studies investigating the association between X-ray repair cross-complementation group 1(XRCC1) polymorphisms and cervical cancer (CC) risk has provided inconsistent results. The aim of our study was to assess the association between the XRCC1 gene Arg399Gln, Arg194Trp, Arg280His polymorphisms and risk of CC.

Methods

Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before March 2011.Summary odds ratios (ORs) and 95% confidence intervals (CIs) for XRCC1 polymorphisms and CC were calculated in a fixed-effects model or a random-effects model when appropriate.

Results

Ultimately, 9, 5 and 2 studies were found to be eligible for meta-analyses of Arg399Gln, Arg194Trp and Arg280His, respectively. Our analysis suggested that the variant genotypes of Arg194Trp were associated with a significantly increased CC risk (Trp/Trp vs Arg/Arg, OR = 2.21, 95% CI = 1.60–3.06; Arg/Trp vs Arg/Arg, OR = 1.23, 95% CI = 1.02–1.49; dominant model, OR = 1.36, 95% CI = 1.14–1.63; recessive model, OR = 2.06, 95% CI = 1.51–2.82). For Arg280His polymorphism, no obvious associations were found for all genetic models. For Arg399Gln polymorphism, also no obvious associations were found for all genetic models. In the subgroup analyses by ethnicity/country, a significantly increased risk was observed among Asian, especially among Chinese. To get more precise evidences, adjusted ORs (95%CI) by potential confounders (such as age, ethnicity or smoking, etc) were also calculated for XRCC1 Arg399Gln and Arg194Trp, however, the estimated pooled adjusted OR still did not change at all.

Conclusion

This meta-analysis suggests that Arg194Trp polymorphism may be associated with CC risk, Arg399Gln polymorphism might be a low-penetrent risk factor for CC only in Asians, and there may be no association between Arg280His polymorphism and CC risk.