Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis

Background

A number of studies have reported an association of angiotensin-converting enzyme (ACE) gene polymorphism with primary intracerebral hemorrhage (PICH), however the reports have demonstrated inconclusive results. To clarify this conflict, we updated the previously performed meta-analysis by Peck et al., which revealed negative results, by investigating the ACE polymorphism and its correlation to PICH.

Methods

PubMed and Embase databases (through Dec 2012) were searched for English articles on the relationship of the I/D polymorphism in ACE with PICH in humans. Summary odds ratios (ORs) were estimated and potential sources of heterogeneity and bias were explored.

Results

A total of 805 PICH cases and 1641 control cases obtained from 8 case-control studies were included. The results suggest that in dominant genetic models, the ACE I/D polymorphic variant was associated with a 58% increase in susceptibility risk of PICH (OR = 1.58; 95% CI = 1.07–2.35 for DD vs. DI+II). However, in the subgroup analysis based on race, a significant increased risk was found in Asian DD homozygote carriers (OR = 1.76 and 95% CI = 1.16–2.66 for DD vs. DI+II), but not in Caucasian DD homozygote carriers (OR = 1.18, 95% CI = 0.36–3.88, P = 0.784 for DD vs. DI+II). The heterogeneity between studies was remarkable, and its major sources of heterogeneity were due to the year in which the study was published. No potential publication bias was observed in dominant genetic models.

Conclusions

These data demonstrated evidence of a positive association between ACE I/D polymorphism with PICH, and suggested that the ACE gene is a PICH susceptible gene in Asian populations.     

STK39 Polymorphism Is Associated with Essential Hypertension: A Systematic Review and Meta-Analysis

Background

A recent genome-wide association study identified STK39as a candidate gene for blood pressure (BP) in Europeans. Subsequently, several studies have attempted to replicate the association across different ethnic populations. However, the results have been inconsistent.

Objective and Methods

We performed a meta-analysis to elucidate the association between the STK39 rs3754777 polymorphism (or proxy) and hypertension. Published literature from PubMed and Embase databases were retrieved and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.

Results

Using appropriate inclusion/exclusion criteria, we identified 10 studies that included 21, 863 hypertensive cases and 24, 480 controls from different ethnicities. The meta-analysis showed a significant association of STK39 rs3754777 variant with hypertension (OR = 1.10, 95%CI = 1.06–1.15, p = 7.95×10⁻⁶). Further subgroup analysis by ethnicity suggested that the association was significant in Europeans (OR = 1.08, 95% CI = 1.03–1.14, p = 0.002) and in East Asians (OR = 1.16, 95%CI = 1.07–1.25, p = 4.34×10⁻⁴), but not in Africans (OR = 1.01, 95%CI 0.80–1.27, p = 0.932). We further confirmed the positive association by sensitivity analysis. No publication bias was detected (Begg’s test, p = 0.721; Egger’s test, p = 0.744).

Conclusions

The present meta-analysis confirms the significant association of STK39 polymorphism with susceptibility to hypertension in Europeans and East Asians. Future studies should include gene–gene and gene–environment interactions to investigate the identified association.     

Association between MLH1 -93G>A Polymorphism and Risk of Colorectal Cancer

Background

The -93G>A (rs1800734) polymorphism located in the promoter of mismatch repair gene, MLH1, has been identified as a low-penetrance variant for cancer risk. Many published studies have evaluated the association between the MLH1 -93G>A polymorphism and colorectal cancer (CRC) risk. However, the results remain conflicting rather than conclusive.

Objective

The aim of this study was to assess the association between the MLH1 -93G>A polymorphism and the risk of CRC.

Methods

To derive a more precise estimation of the association, a meta-analysis of six studies (17,791 cases and 13,782 controls) was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. Four of these published studies were performed on subjects of known microsatellite instability (MSI) status. An additional analysis including 742 cases and 10,895 controls was used to assess the association between the MLH1 -93G>A polymorphism and the risk of MSI-CRC.

Results

The overall results indicated that the variant genotypes were associated with a significantly increased risk of CRC (AG versus GG: OR = 1.06, 95% CI = 1.01–1.11; AA/AG versus GG: OR = 1.06, 95% CI = 1.01–1.11). This increased risk was also found during stratified analysis of MSI status (AA versus GG: OR = 2.52, 95% CI = 1.94–3.28; AG versus GG: OR = 1.29, 95% CI = 1.10–1.52; AA/AG versus GG: OR = 1.45, 95% CI = 1.24–1.68; AA versus AG/GG: OR = 2.29, 95% CI = 1.78–2.96). Egger’s test did not show any evidence of publication bias.

Conclusion

Our results suggest that the MLH1 -93G>A polymorphism may contribute to individual susceptibility to CRC and act as a risk factor for MSI-CRC.     

Predictors of Seizure Outcomes in Children with Tuberous Sclerosis Complex and Intractable Epilepsy Undergoing Resective Epilepsy Surgery: An Individual Participant Data Meta-Analysis

Objective

To perform a systematic review and individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Tuberous Sclerosis Complex undergoing resective epilepsy surgery.

Data Sources

Electronic databases (MEDLINE, EMBASE, CINAHL and Web of Science), archives of major epilepsy and neurosurgery meetings, and bibliographies of relevant articles, with no language or date restrictions.

Study Selection

We included case-control or cohort studies of consecutive participants undergoing resective epilepsy surgery that reported seizure outcomes. We performed title and abstract and full text screening independently and in duplicate. We resolved disagreements through discussion.

Data Extraction

One author performed data extraction which was verified by a second author using predefined data fields including study quality assessment using a risk of bias instrument we developed. We recorded all preoperative factors that may plausibly predict seizure outcomes.

Data Synthesis

To identify predictors of a good seizure outcome (i.e. Engel Class I or II) we used logistic regression adjusting for length of follow-up for each preoperative variable.

Results

Of 9863 citations, 20 articles reporting on 181 participants were eligible. Good seizure outcomes were observed in 126 (69%) participants (Engel Class I: 102(56%); Engel class II: 24(13%)). In univariable analyses, absence of generalized seizure semiology (OR = 3.1, 95%CI = 1.2–8.2, p = 0.022), no or mild developmental delay (OR = 7.3, 95%CI = 2.1–24.7, p = 0.001), unifocal ictal scalp electroencephalographic (EEG) abnormality (OR = 3.2, 95%CI = 1.4–7.6, p = 0.008) and EEG/Magnetic resonance imaging concordance (OR = 4.9, 95%CI = 1.8–13.5, p = 0.002) were associated with a good postoperative seizure outcome.

Conclusions

Small retrospective cohort studies are inherently prone to bias, some of which are overcome using individual participant data. The best available evidence suggests four preoperative factors predictive of good seizure outcomes following resective epilepsy surgery. Large long-term prospective multicenter observational studies are required to further evaluate the risk factors identified in this review.     

Sulfotransferase SULT1A1 Arg213His Polymorphism with Cancer Risk: A Meta-Analysis of 53 Case-Control Studies

Background

The SULT1A1 Arg213His (rs9282861) polymorphism is reported to be associated with many kinds of cancer risk. However, the findings are conflicting. For better understanding this SNP site and cancer risk, we summarized available data and performed this meta-analysis.

Methods

Data were collected from the following electronic databases: PubMed, Web of Knowledge and CNKI. The association was assessed by odd ratio (OR) and the corresponding 95% confidence interval (95% CI).

Results

A total of 53 studies including 16733 cancer patients and 23334 controls based on the search criteria were analyzed. Overall, we found SULT1A1 Arg213His polymorphism can increase cancer risk under heterozygous (OR = 1.09, 95% CI = 1.01–1.18, P = 0.040), dominant (OR = 1.10, 95% CI = 1.01–1.19, P = 0.021) and allelic (OR = 1.08, 95% CI = 1.02–1.16, P = 0.015) models. In subgroup analyses, significant associations were observed in upper aero digestive tract (UADT) cancer (heterozygous model: OR = 1.62, 95% CI = 1.11–2.35, P = 0.012; dominant model: OR = 1.63, 95% CI = 1.13–2.35, P = 0.009; allelic model: OR = 1.52, 95% CI = 1.10–2.11, P = 0.012) and Indians (recessive model: OR = 1.93, 95% CI = 1.22–3.07, P = 0.005) subgroups. Hospital based study also showed marginally significant association. In the breast cancer subgroup, ethnicity and publication year revealed by meta-regression analysis and one study found by sensitivity analysis were the main sources of heterogeneity. The association between SULT1A1 Arg213His and breast cancer risk was not significant. No publication bias was detected.

Conclusions

The present meta-analysis suggests that SULT1A1 Arg213His polymorphism plays an important role in carcinogenesis, which may be a genetic factor affecting individual susceptibility to UADT cancer. SULT1A1 Arg213His didn''t show any association with breast cancer, but the possible risk in Asian population needs further investigation.     

Fish Intake and Ovarian Cancer Risk: A Meta-Analysis of 15 Case-Control and Cohort Studies

Background

Previous epidemiological studies have shown that fish consumption may modify the risk of ovarian cancer. However, these studies yielded controversial results. The present meta-analysis was undertaken to evaluate the relationship between fish intake and ovarian cancer risk.

Methods

A literature search was carried out using Pubmed, Embase, and Cochrane Library Central database for all relevant studies up to August 2013. We pooled the relative risks (RR) from individual studies using fixed-effect or random-effect model, and carried out heterogeneity and publication bias analyses.

Results

A total of 15 (ten case–control, and five cohort) studies were included in the present meta-analysis, representing data for 889,033 female subjects and 6,087 ovarian cancer cases. We found that total fish intake was not significantly associated with the risk of ovarian cancer among cohort studies (RR = 1.04 95% CI [0.89, 1.22]) as well as case–control studies (RR = 0.90, 95% CI [0.73,1.12]). There was no evidence of publication bias as suggested by Begg''s test (P = 0.55) and Egger''s test(P = 0.29).

Conclusions

The present meta-analysis showed that total fish consumption was not significantly associated with the risk of ovarian cancer. Further analysis on different fish species and food preparation methods should be conducted in future studies.     

Endothelial NO Synthase Gene Polymorphisms and Risk of Ischemic Stroke in Asian Population: A Meta-Analysis

Background

The association between polymorphism 4b/a, T-786C and G894T in endothelial NO synthase gene (eNOS) and ischemic stroke (IS) remains controversial in Asian. A meta-analysis was performed to better clarify the association between eNOS gene and IS risk.

Methods

Based on the search of PubMed, Web of Science (ISI), CNKI (National Knowledge Infrastructure), Wan Fang Med Online and CBM (Chinese Biology Medical Literature Database) databases, all eligible case-control or cohort studies were identified. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from fixed and random effect models were calculated. Heterogeneity among studies was evaluated using the I². Meta-regression was used to explore the potential sources of between-study heterogeneity. Begg''s test was used to estimate publication bias.

Results

Our study included 27 articles, contained 28 independent case–control studies, involved a total of 3,742 cases and 3,691 controls about 4b/a, 1,800 cases and 1,751 controls about T-786C and 2,747 cases and 2,872 controls about G894T. A significant association of 4a allele with increased risk of IS was found in dominant (FEM: OR = 1.498, 95% CI = 1.329–1.689), recessive (FEM: OR = 2.132, 95% CI = 1.383–3.286) and codominant (REM: OR = 1.456, 95% CI = 1.235–1.716) models. For T-786C and G894T, there were significant associations with dominant and codominant genetic models, but not with recessive genetic model.

Conclusions

The meta-analysis indicated that eNOS gene 4b/a, T-786C, G894T polymorphism might be associated with IS.     

Association of Three Common Single Nucleotide Polymorphisms of ATP Binding Cassette G8 Gene with Gallstone Disease: A Meta-Analysis

Background

In this study, we evaluated the association between these polymorphisms and gallstone disease using meta-analysis and compared the hepatic ABCG5/G8 mRNA expression and biliary lipids composition in patients with different genotypes of T400K and Y54C.

Methods

Data were analyzed using the Stata/SE 11.0 software and a random- effects model was applied irrespective of between-study heterogeneity. Hepatic mRNA expression of ABCG5/G8 genes in 182 patients with gallstone disease and 35 gallstone-free patients who underwent cholecystectomy were determined using real-time PCR. Genotypes of Y54C and T400K in the ABCG8 gene were determined by allelic discrimination using either genomic DNA or hepatic cDNA as template by Taqman assays. Biliary compostion in gallbladder bile was assayed in these patients as well.

Results

Ten papers including 13 cohorts were included for the final analysis. In the genotype model, the overall association between genotype with gallstone was significant for D19H (OR = 2.43, 95%CI: 2.23–2.64, P<0.001), and for Y54C (OR = 1.36, 95%CI: 1.01–1.83, P = 0.044), or T400K (OR = 1.17, 95%CI: 0.96–1.43. P = 0.110). In allele model, minor alleles of D19H polymorphism (allele D: OR = 2.25, 95%CI: 2.10–2.42, P<0.001) and of T400K polymorphism (allele K: OR = 1.18, 95%CI: 1.06–1.31, P<0.001) were related with an increased risk of gallstone disease. However, minor allele of Y54C polymorphism (allele Y, OR = 1.08, 95%CI: 0.96–1.21, P = 0.146) was not related with gallstone disease. I ² statistics indicated no significant between-study heterogeneity for all genetic models for any of the three polymorphisms. Funnel plot and Egger’s test suggested the absence of publication bias as well. However, no association of T400K and Y54C polymorphism with hepatic ABCG8/G5 mRNA expression or biliary lipids composition was found.

Conclusions

Our study showed strong association of D19H polymorphism with gallstone disease. T400K and Y54C polymorphism, though to a less extent, may also relate with gallstone disease.     

Use of Neuraminidase Inhibitors for Rapid Containment of Influenza: A Systematic Review and Meta-Analysis of Individual and Household Transmission Studies

Objectives

To assess the effectiveness of neuraminidase inhibitors for use in rapid containment of influenza.

Method

We conducted a systematic review and meta-analysis in accordance with the PRISMA statement. Healthcare databases and sources of grey literature were searched up to 2012 and records screened against protocol eligibility criteria. Data extraction and risk of bias assessments were performed using a piloted form. Results were synthesised narratively and we undertook meta-analyses to calculate pooled estimates of effect, statistical heterogeneity and assessed publication bias.

Findings

Nine randomised controlled trials (RCTs) and eight observational studies met the inclusion criteria. Neuraminidase inhibitors provided 67 to 89% protection for individuals following prophylaxis. Meta-analysis of individual protection showed a significantly lower pooled odds of laboratory confirmed seasonal or influenza A(H1N1)pdm09 infection following oseltamivir usage compared to placebo or no therapy (n = 8 studies; odds ratio (OR) = 0.11; 95% confidence interval (CI) = 0.06 to 0.20; p<0.001; I² = 58.7%). This result was comparable to the pooled odds ratio for individual protection with zanamivir (OR = 0.23; 95% CI 0.16 to 0.35). Similar point estimates were obtained with widely overlapping 95% CIs for household protection with oseltamivir or zanamivir. We found no studies of neuraminidase inhibitors to prevent population-wide community transmission of influenza.

Conclusion

Oseltamivir and zanamivir are effective for prophylaxis of individuals and households irrespective of treatment of the index case. There are no data which directly support an effect on wider community transmission.

Protocol Registry

PROSPERO registration number: CRD42013003880     

Serum Vitamin D,Vitamin D Binding Protein,and Risk of Colorectal Cancer

Background

We previously reported a positive association between serum 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to vitamin D binding protein (DBP), the primary 25(OH)D transport protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk.

Methods

In a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1∶1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free, unbound circulating 25(OH)D.

Results

Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend  = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D:DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend  = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend  = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend  = 0.87), although the interaction was not statistically significant (p for interaction  = 0.24).

Conclusion

Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non-smokers.     

Genetic Polymorphism in PDE4D Gene and Risk of Ischemic Stroke in Chinese Population: A Meta-Analysis

Background

Stroke is the second most common cause of death and major cause of disability worldwide. The SNP 83 in PDE4D gene has been suggested as a risk factor in ischemic stroke, but direct evidence from genetic association studies remains inconclusive even in Chinese population.

Methods

Meta-analysis of case-control studies on the relationship between SNP 83 in PDE4D gene and susceptibility to ischemic stroke in Chinese population published domestically and abroad from January 2003 to September 2012.

Results

9 case-control studies were selected. Meta-analysis results showed that the significant association between SNP 83 and ischemic stroke was found under the dominant model (OR = 1.34, 95% CI: 1.20–1.49) and recessive model (OR = 1.45, 95% CI: 1.19–1.76) in Chinese population. In subgroup meta-analysis, SNP 83 and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the dominant model (OR = 1.69, 95% CI: 1.41–2.01) and recessive model (OR = 1.47, 95% CI: 1.04–2.06).

Conclusions

The results suggest that SNP 83 in PDE4D gene is significantly associated with susceptibility to ischemic stroke in Chinese population.     

Vitamin A Intake and Risk of Melanoma: A Meta-Analysis

Background

Mounting evidence from experimental and animal studies suggests that vitamin A may have a protective effect on melanoma, but the findings on the association of vitamin A intake with risk of melanoma have been inconsistently reported in epidemiologic studies. We attempted to elucidate the association by performing a meta-analysis.

Methods

Eligible studies were identified by searching PubMed and EMBASE databases, as well as by reviewing the references of retrieved publications. Summary odds ratios (OR) with corresponding 95% confidence interval (CI) were computed with a random-effects model. Study-specific ORs and 95% CIs for the highest vs. lowest categories of vitamin A intake were pooled.

Results

A total of 8 case-control studies and 2 prospective studies comprising 3,328 melanoma cases and 233,295 non-case subjects were included. The summary OR for the highest compared with the lowest intake of total vitamin A, retinol and beta-carotene was 0.86 (95% CI = 0.59–1.25), 0.80 (95% CI = 0.69–0.92) and 0.87 (95%CI = 0.62–1.20), respectively. Significant heterogeneity was observed among studies on vitamin A and beta-carotene intake, but not among studies on retinol intake. Subgroup and sensitivity analyses confirmed these findings. There was no indication of publication bias.

Conclusion

Findings from this meta-analysis suggest that intake of retinol, rather than of total vitamin A or beta-carotene, is significantly associated with reduced risk of melanoma.     

The ?842G/C Polymorphisms of PIN1 Contributes to Cancer Risk: A Meta-Analysis of 10 Case-Control Studies

Background

Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN1) plays an important role in cancer development. The relationship between PIN1 −842G/C (rs2233678) polymorphism and cancer risk was inconclusive according to published literature.

Methodology/Principal Findings

A literature search, up to February 2013, was carried out using PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database. A total of 10 case-control studies including 4619 cases and 4661 controls contributed to the quantitative analysis. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, individuals with the variant CG (OR = 0.728, 95% CI: 0.585,0.906; P_{heterogeneity}<0.01) and CG/CC (OR = 0.731, 95% CI: 0.602,0.888; P_{heterogeneity}<0.01) genotypes were associated with a significantly reduced cancer risk compared with those with wild GG genotype. Sub-group analysis revealed that the variant CG (OR = 0.635, 95% CI: 0.548,0.735; P_{heterogeneity} = 0.240) and CG/CC (OR = 0.645, 95% CI: 0.559,0.744, Pheterogeneity = 0.258) genotypes still showed an reduced risk of cancer in Asians; while no significant association was observed in Caucasians (CG vs.GG: OR = 0.926, 95% CI: 0.572,1.499, P_{heterogeneity}<0.01; CG/CC vs. GG: OR = 0.892, 95% CI: 0.589,1.353; P_{heterogeneity}<0.01). Furthermore, sensitivity analysis confirmed the stability of results. Begg''s funnel plot and Egger''s test did not reveal any publication bias.

Conclusions

This meta-analysis suggests that the PIN1 −842G/C polymorphism is associated with a significantly reduced risk of cancer, especially in Asian populations.     

Hematopoietically-Expressed Homeobox Gene Three Widely-Evaluated Polymorphisms and Risk for Diabetes: A Meta-Analysis

Background

The hematopoietically-expressed homeobox (HHEX) gene is identified as a promising candidate for type 2 diabetes by genome-wide association studies, triggering plenty of subsequent replications; however, the results are conflicting. We therefore conducted a meta-analysis of three widely-evaluated polymorphisms in HHEX gene and diabetes risk.

Methodology/Principal Findings

A random-effects model was adopted irrespective of heterogeneity. Data and study quality were assessed in duplicate. There were 49 studies (cases/controls: 57931/74658) for rs1111875, 18 studies (18227/30366) for rs5015480 and 26 studies (25725/30579) for rs7923837, respectively. Overall analyses indicated that rs1111875-C allele (odds ratio [OR] = 1.16; 95% confidence interval [CI]: 1.13–1.2; P<0.0005), rs5015480-C allele (OR = 1.16; 95% CI: 1.06–1.26; P = 0.001) and rs7923837-G allele (OR = 1.18; 95% CI: 1.12–1.24; P<0.0005) conferred significantly increased risk for type 2 diabetes, yet accompanying moderate to strong evidence of heterogeneity. Despite vast divergence in allele distributions, subgroup analyses by ethnicity showed comparable risk estimates between Asians and Caucasians for three examined polymorphisms. Moreover, results of studies with hospital-based controls deviated greatly from that of all qualified studies, especially for rs7923837-G allele carrying a doubled risk (OR = 1.37 versus 1.18). Furthermore, when only large studies (≥500 case-patients) were considered, risk effects were identical to the overall estimates for three examined polymorphisms. The Begg''s funnel plot and Egger''s test indicated low probability of publication bias.

Conclusions

Our results provide clarification to the significant association of rs1111875, rs5015480 and rs7923837 in HHEX gene with type 2 diabetes.     

MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies

Background

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent.

Methods and Findings

Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (P _{heterogeneity} = 0.000) and publication bias (P _egger = 0.039), but it turned into null after the trim-and-fill method was implemented (OR = 1.12, 95% CI = 0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (P _{heterogeneity} = 0.150, OR = 1.16, 95% CI = 1.05–1.29) and publication bias (P _egger = 0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size.

Conclusions

Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs.     

The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis

Background

The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke.

Methods

Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models.

Findings

A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03–1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05–1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71–1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34–2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14–2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34–2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74–1.33; p = 0.950). Egger''s regression test suggested a low probability of publication bias for all analyses (p>0.05).

Conclusions

The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.     

Association of SMAD7 rs12953717 Polymorphism with Cancer: A Meta-Analysis

Background

Accumulating evidence has suggested that Mothers against decapentaplegic homolog 7 (SMAD7) rs12953717 polymorphism might be related to cancer risk. However, epidemiologic findings have been inconsistent. We therefore performed a meta-analysis to clarify the association between the SMAD7 rs12953717 polymorphism and cancer risk.

Methods

A comprehensive search was conducted to identify all eligible studies of SMAD7 rs12953717 polymorphism and cancer risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. Heterogeneity, publication bias, and sensitivity analysis were also explored.

Results

A total of 14 case-control studies, including 16928 cases and 14781 controls, were included in the present meta-analysis. The overall results showed that the variant genotypes were associated with a significantly increased risk of all cancer types (homozygote comparison, OR = 1.23, 95%CI = 1.10–1.38, P<0.01; heterozygote comparison, OR = 1.12, 95%CI = 1.02–1.22, P = 0.02; recessive model, OR = 1.17, 95%CI = 1.07–1.29, P<0.01; dominant model, OR = 1.15, 95%CI = 1.06–1.25, P<0.01; allelic model, OR = 1.12, 95%CI = 1.06–1.18, P<0.01). Further sensitivity analysis confirmed the significant association. In the subgroup analysis by ethnicity, SMAD7 rs12953717 polymorphism was significantly associated with cancer risk in both Caucasians and Asians. In the subgroup analysis by cancer types, SMAD7 rs12953717 polymorphism was significantly associated with colorectal cancer.

Conclusions

Our investigations demonstrate that rs12953717 polymorphism is associated with the susceptibility of cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

Single Nucleotide Polymorphisms of PIN1 Promoter Region and Cancer Risk: Evidence from a Meta-Analysis

Background

Peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) is involved in the process of tumorigenesis. The two single nucleotide polymorphisms (−677T>C, −842G>C) in the PIN1 promoter region have been suspected of being associated with cancer risk for years, but the conclusion is still inconclusive.

Methods

Eligible case-control studies were retrieved by searching databases and references of related reviews and studies. Genotype distribution data, adjusted odds ratios (ORs) and 95% confidence (CIs) intervals were extracted to calculate pooled ORs.

Results

A total of 4619 cancer cases and 4661 controls were included in this meta-analysis. Overall, the PIN1 −667T>C polymorphism was not associated with cancer risk, while the −842C allele was significantly associated with reduced cancer risk (CC+GC vs. GG, OR = 0.725, 95% CI: 0.607–0.865; P_{heterogeneity} = 0.012 and GC vs. GG: OR = 0.721, 95% CI: 0.591–0.880; P_{heterogeneity} = 0.003). Results from genotype distribution data were in agreement with those calculated with adjusted ORs and 95% CIs. No publication bias was detected.

Conclusions

Results of this meta-analysis suggest that the PIN1 −842G>C polymorphism is associated with decreased cancer risk, but that the −667T>C polymorphism is not.     

The rs2233678 Polymorphism in PIN1 Promoter Region Reduced Cancer Risk: A Meta-Analysis

Background

Published evidence suggests that the rs2233678 (−842 G>C) polymorphism in the PIN1 (peptidyl-prolyl cis/trans somerase NIMA-interacting 1) promoter region may be associated with cancer risk; however, the conclusion is still inconclusive.

Methods

We conducted a meta-analysis to determine whether −842 G>C polymorphism was associated with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Genotype distribution data and adjusted ORs were collected to calculate the pooled ORs. Meta-regression was conducted to detect the source of heterogeneity. Publication bias was evaluated by Egger’s test and Begg’s test.

Results

A total of 11 eligible studies, including 9280 participants, were identified and analyzed. Overall, we found that carriers of the −842 C allele were associated with significantly decreased cancer risk (C vs. G, OR = 0.750, 95% CI: 0.639–0.880, P_{heterogeneity} = 0.014, estimated by genotype distribution data; CC+GC vs. GG, OR = 0.668, 95% CI: 0.594–0.751, P_{heterogeneity} = 0.638, estimated by adjusted ORs). No evidence of publication bias was observed. Meta-regression revealed that ethnicities (p = 0.021) and sample size (p = 0.02) but not sources of control (p = 0.069) were the source of heterogeneity.

Conclusion

These results suggest that the PIN1 rs2233678 (−842 G>C) polymorphism significantly reduces cancer risk.     

Relationship between Rad51 G135C and G172T Variants and the Susceptibility to Cancer: A Meta-Analysis Involving 54 Case-Control Studies

Background

The associations between Rad51 gene polymorphisms (G135C and G172T) and risk of cancer have been investigated, but the results were inconclusive. To get a comprehensive evaluation of the association above, we performed a meta-analysis of published studies.

Methods

A computerized search of PubMed, Embase and Web of Knowledge databases for all relevant studies was performed and the data were analyzed in a meta-analysis. The overall odds ratio (OR) with the 95% confidence interval (95% CI) was calculated to assess the strength of the association between Rad51 polymorphisms and cancer risk. Data were analyzed using fixed- or random-effects model when appropriate. Sensitivity analysis and publication bias test were also estimated.

Results

Overall, a total of 54 case-control studies were included in the current meta-analysis, among which 42 studies with 19,142 cases and 20,363 controls for RAD51 G135C polymorphism and 12 studies with 6,646 cases and 6,783 controls for G172T polymorphism. For G135C polymorphism, the pooled results indicated that significantly increased risk was found in overall cancers (homozygote model: OR = 1.776, 95% CI = 1.288–2.449; allelic genetic model: OR = 1.169, 95% CI = 1.016–1.345; recessive model: OR = 1.946, 95% CI = 1.336–2.835), especially in breast cancer (homozygote model: OR = 1.498, 95% CI = 1.026–2.189; recessive model: OR = 1.732, 95% CI  =  1.170–2.562). For G172T polymorphism, a decreased cancer risk was observed in head and neck cancer (homozygote model: OR  =  0.621, 95% CI  =  0.460–0.837; allelic genetic model: OR  =  0.824, 95% CI  =  0.716–0.948; recessive model: OR  =  0.639, 95% CI = 0.488–0.837).

Conclusions

Our results suggested that the Rad51 G135C polymorphism is a candidate for susceptibility to overall cancers, especially to breast cancer, and that the Rad51 G172T might play a protective role in the development of head and neck cancer.