Zhiyu Zeng

Kidney Stones and Cardiovascular Risk: A Meta-analysis of Cohort Studies

BACKGROUND Recent epidemiologic evidence suggests an association between kidney stones and incident cardiovascular disease after adjusting for other cardiovascular risk factors, but results are inconsistent. STUDY DESIGN Meta-analysis of cohort studies. SETTING & POPULATION Patients with kidney stones. SELECTION CRITERIA FOR STUDIES Cohort studies with data for kidney stones and cardiovascular morbidity identified in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings through February 27, 2014. PREDICTOR Kidney stones as determined by physician diagnosis, clinical coding, or self-reported scales. OUTCOMES Cardiovascular disease, coronary heart disease (CHD), and stroke. RESULTS 6 cohort studies that contained 49,597 patients with kidney stones and 3,558,053 controls, with 133,589 cardiovascular events, were included. Pooled results suggested that kidney stones were associated with an increased adjusted risk estimate for CHD (HR, 1.19; 95% CI, 1.05-1.35; P=0.05; n=6 cohorts) and stroke (HR, 1.40; 95% CI, 1.20-1.64; P<0.001; n=3 cohorts). In particular, kidney stones conferred HRs of 1.29 (95% CI, 1.10-1.52; n=6 cohorts) and 1.31 (95% CI, 1.05-1.65; n=4 cohorts) for myocardial infarction and coronary revascularization, respectively. Moreover, the pooled female cohorts showed a statistically significant association (HR, 1.49; 95% CI, 1.21-1.82; n=4 cohorts), whereas the male cohorts showed no association (HR, 1.15; 95% CI, 0.89-1.50; n=2 cohorts). LIMITATIONS Results may be limited by substantial heterogeneity, likelihood of residual confounding, and paucity of studies that separately evaluated for effect modification by sex. CONCLUSIONS Kidney stones were associated with increased cardiovascular risk, including the risk for incident CHD or stroke. There is some suggestion that the risk may be higher in women than men. Further prospective studies are needed to determine whether the association is sex specific.

DNA Repair Gene XRCC1 Polymorphisms, Smoking, and Bladder Cancer Risk: A Meta-Analysis

Background and Objective The X-ray repair cross-complementing group 1 (XRCC1) protein plays a crucial role in base excision repair (BER) pathway by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, a comprehensive meta-analysis of all available studies was performed in this study. Methods PubMed, EMBASE, and Chinese Biomedical Literature database (CBM) databases have been systematically searched to identify all relevant studies for the period up to February 2013. Data were abstracted independently by two reviewers and Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed mainly by ethnicity and smoking status. Results A total of 26 case-control studies, including 24 studies for R399Q polymorphism, 15 studies for R194W polymorphism, and 7 studies for R280H polymorphism met the inclusion criteria and were selected. With respect to R399Q polymorphism, significantly decreased bladder cancer risk was found among smokers (AA vs. GG: OR=0.693, 95%CI= 0.515-0.932, P=0.015 and recessive model AA vs. GA+GG: OR=0.680, 95%CI= 0.515-0.898, P=0.007, respectively). With respect to R194W and R280H polymorphism, significantly increased bladder cancer risk were observed among Asians (TT+CT vs. CC:OR = 1.327, 95% CI 1.086-1.622, P=0.006 for R194W, and AA+GA vs. GG: OR=2.094, 95% CI 1.211–3.621, P=0.008 for R280H, respectively). Conclusions This meta-analysis suggests that the XRCC1 R399Q polymorphism may play a protective role against bladder cancer among smokers. However, the XRCC1 R194W and R280H polymorphisms were both associated with increased bladder cancer risk among Asians. Further studies with larger sample sizes are needed to validate our finds.

CYP2D6 phenotypes and Parkinson's disease risk: A meta-analysis

BACKGROUND CYP2D6 polymorphisms have been reported to be associated with Parkinsons disease (PD) susceptibility, but the results of these previous studies were inconsistent. OBJECTIVES To explore whether PD patients with CYP2D6 gene variation have different risk to PD to those with normal function of CYP2D6. METHODS Systematic review with meta-analysis of case-controlled studies on the association between CYP2D6 and PD risk was conducted. Studies published up to August 1, 2013 were identified by searching electronic databases PubMed and Embase. Odds ratios (ORs) together with their corresponding 95% confidence intervals (CIs) were used to estimated the association between CYP2D6 polymorphisms and PD risk in different phenotype models. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed. RESULTS A total of 3521 PD Patients and 4476 controls from 29 case-control studies were identified. Overall, a borderline significant influence of the CYP2D6 polymorphisms on PD risk was observed (OR: 1.07, 95%CI: 0.99-1.16, p=0.106). Significant association was found when comparisons were performed in different phenotypes in PM versus EM (OR=1.33, 95% CI=1.01-1.74, p=0.044) and PM versus IM+EM (OR=1.32, 95% CI=1.11-1.56, p=0.002). In subgroup analysis stratified by country, significant association was demonstrated in British but not in other white subjects. No significant association was detected in subgroup analysis according to the age of onset and the source of patients. CONCLUSION The present meta-analysis demonstrated that the poor metabolizer phenotype of CYP2D6 confers a significant genetic susceptibility to PD in Caucasians, especially in British white subjects.

Association between the ACE I/D polymorphism and risk of ischemic stroke: An updated meta-analysis of 47,026 subjects from 105 case–control studies

BACKGROUND The association between the angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism and risk of ischemic stroke (IS) remains controversial and ambiguous. To clarify this association, a large meta-analysis was performed. METHODS Electronic databases in both English and Chinese were used to identify relevant studies (updated in February 2014). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the strength of the association. RESULTS One hundred and fifty eligible studies, including 18,258 IS cases and 28,768 controls, were identified. Meta-analysis of these studies pointed to a significant association between the ACE I/D polymorphism and IS risk: (D vs. I: OR=1.354, 95% CI=1.272-1.440, P<0.001; DD vs. II: OR=1.755, 95% CI=1.561-1.973, P<0.001; ID vs. II: OR=1.178, 95% CI=1.098-1.263, P<0.001; DD vs. ID/II OR=1.535, 95% CI=1.399-1.684, P<0.001; DD/ID vs. II: OR=1.353, 95% CI=1.251-1.463, P<0.001). Subgroup analysis revealed a significantly elevated risk among Asians, but with borderline statistical significance among Caucasians. CONCLUSION This meta-analysis indicated that the ACE I/D polymorphism may be a genetic susceptibility factor for IS, especially among Asians, but with borderline statistical significance for Caucasians. Further investigations are needed to validate our conclusions.

CYP2D6*4 Allele Polymorphism Increases the Risk of Parkinson’s Disease: Evidence from Meta-Analysis

Background Many epidemiological studies have been conducted to explore the association between a single CYP2D6 gene polymorphism and Parkinson’s disease (PD) susceptibility. However, the results remain controversial. Objectives To clarify the effects of a single CYP2D6 gene polymorphism on the risk of PD, a meta-analysis of all available studies relating to CYP2D6*4 polymorphism and the risk of PD was conducted. Methods A comprehensive literature search of PubMed, EMBASE, and the China National Knowledge Infrastructure (CNKI) up to September 1, 2013 was conducted. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Meta-regression, Galbraith plots, subgroup analysis, sensitivity analysis, and publication bias analysis were also performed. Results Twenty-two separate comparisons consisting of 2,629 patients and 3,601 controls were included in our meta-analysis. The pooled analyses showed a significant association between CYP2D6*4G/A polymorphism and PD risk in all of the comparisons (A vs. G allele: OR = 1.28, 95% CI = 1.14–1.43, P = 0.001; AA vs. GG: OR = 1.43, 95% CI = 1.06–1.93, P = 0.018; AG vs. GG: OR = 1.22, 95% CI = 1.06–1.40, P = 0.006; AG+AA vs. GG: OR = 1.26, 95% CI = 1.10–1.44, P = 0.001; AA vs. AG+GG: OR = 1.37, 95% CI = 1.02–1.83, P = 0.036). In subgroup analysis stratified by ethnicity, significant associations were also demonstrated in Caucasians but not in Asians. No significant association was found in subgroup analysis stratified by age of onset or disease form. Conclusions We concluded that the CYP2D6*4G/A polymorphism denotes an increased genetic susceptibility to PD in the overall population, especially in Caucasians. Further large and well-designed studies are needed to confirm this association.

Meta-analysis of the association between CR1 polymorphisms and risk of late-onset Alzheimer's disease.

CR1 polymorphisms have been reported to be associated with late-onset Alzheimers disease (LOAD) susceptibility. The findings of these studies, however, have been inconsistent. Therefore, we performed a meta-analysis to assess the association between CR1 variants and LOAD susceptibility. We retrieved all relevant studies of the associations between CR1 polymorphisms and the susceptibility to LOAD for the period up to March 30, 2014. The strength of the association between CR1 polymorphisms and LOAD risk was estimated by odds ratios (ORs) and their 95% confidence intervals (CIs). A total of 6 articles were eventually identified with 2752 LOAD cases and 2313 controls for the rs6656401 polymorphism, and 4 studies containing 2547 LOAD cases and 2338 controls were included for the rs3818361 polymorphism. Overall, the pooled data showed that the CR1 rs6656401 polymorphism was significantly associated with LOAD risk in the overall population (A vs. G: OR=1.32, 95%CI=1.17-1.50, P=0.000; AG+AA vs. GG: OR=1.39, 95%CI=1.20-1.61, P=0.000). With respect to the CR1 rs3818361 polymorphism, a statistically significant increased LOAD risk was observed in the overall population (T vs. C: OR=1.24, 95% CI=1.13-1.37, P=0.000; TT+TC vs. CC: OR=1.30, 95% CI=1.15-1.46, P=0.000; TT vs. TC+CC: OR=1.35, 95% CI=1.06-1.71, P=0.014). This meta-analysis demonstrated significant associations of both the CR1 rs6656401 and CR1 rs3818361 polymorphisms with LOAD susceptibility.

The MTHFR C677T polymorphism contributes to increased risk of Alzheimer’s Disease: Evidence based on 40 case-control studies

The association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and Alzheimers Disease (AD) risk has been widely reported with inconsistent results. We performed an updated meta-analysis of all available studies to clarify this situation. We conducted a comprehensive literature search in PubMed Alzgene, Embase, and Chinese Biomedical Literature database (CBM) for the period up to June 2014. Finally, a total of 40 case-control studies with 4503 AD cases and 5767 controls were included. Overall, significant increased AD risk was found, when all studies were pooled into the meta-analysis. In subgroup analyses stratified by ethnicity, age of onset, and APOE ϵ4 status, significant increased AD risk was found in Asians, late-onset AD, and APOE ϵ4 carriers, but not in Caucasians, early-onset AD, and non-APOE ϵ4 carriers. The present meta-analysis suggested that the MTHFR is a candidate gene for AD susceptibility. The MTHFR C677T polymorphism may be a risk factor for AD in Asians, APOE ϵ4 carriers, and late-onset AD. Further, investigations taking the potential gene-gene and gene-environmental interactions into consideration for the MTHFR C677T polymorphism should be conducted.

Quantitative assessment of CYP2D6 polymorphisms and risk of Alzheimer's disease: a meta-analysis.

BACKGROUND CYP2D6 gene encoding CYP2D6 enzyme belonging to the cytochrome P450 system has aroused long attention being a candidate gene for Alzheimers disease (AD), but the results remain inconsistent and underpowered. OBJECTIVES To investigate the contradictory results, the effect of single CYP2D6 polymorphism- CYP2D6*4, together with CYP2D6 phenotypes on the risk of AD, was evaluated using a meta-analysis. METHODS Electronic database search of PubMed, Embase and Cochrane Library was conducted up to Apr 17, 2014. Odds ratio (OR) along with the 95% confidence interval (CI) was calculated. Subgroup analysis was performed to examine the impact of CYP2D6 variants on different ethnic. Meta-regression was performed to explore possible source of heterogeneity. RESULTS A total of 11 studies involving 643AD cases and 1375 controls were included for CYP2D6*4 polymorphism, and 4 studies consisted of 411AD cases and 603 controls were included for CYP2D6 phenotypes. With respect to CYP2D6*4 polymorphism, significantly increased risk of AD was found in allelic contrast model of A vs. G (OR=1.29, 95%CI=1.03-1.62, P=0.026), co-dominant genetic model AA vs. GG (OR=1.91, 95%CI=1.04-3.51, P=0.038); and recessive genetic model AA vs. AG+GG (OR=1.88, 95%CI=1.03-3.46, P=0.041) in the overall populations. Similar results were also indicated in subgroup analysis in Caucasians. As for CYP2D6 phenotypes, no significant association with AD was revealed. CONCLUSIONS Our data support that the CYP2D6*4 polymorphism but not CYP2D6 phenotypes might be associated with increased AD risk, particularly in Caucasian populations.

Myeloperoxidase Polymorphism, Menopausal Status, and Breast Cancer Risk: An Update Meta-Analysis

Myeloperoxidase (MPO) is a metabolic/oxidative lysosomal enzyme secreted by reactive neutrophils at the sites of inflamed organs and tissues during phagocytosis. MPO has been either directly or indirectly linked to neoplasia, which is a well-established risk factor for many types of cancer. A large number of studies have reported the role of MPO G-463A polymorphism regarding breast-cancer risk. However, the published findings are inconsistent. Therefore, we conducted a meta-analysis to determine more precise estimations for the relationship. Eligible studies were identified by searching several electronic databases for relevant reports published before June 2012. According to the inclusion criteria and exclusion criteria, a total of five eligible studies were included in the pooled analyses. When the five eligible studies concerning MPO G-463A polymorphism were pooled into this meta-analysis, there was no evidence found for a significant association between MPO G-463A polymorphism and breast-cancer risk in any genetic model. We also categorized by ethnicity (Caucasian or Asian) for subgroup analysis; according to this subgroup analysis, we found no significant association between MPO G-463A polymorphism and breast-cancer risk in any genetic model. However, in the stratified analysis for the premenopausal group, women carrying the AA genotype were found to have a significantly reduced risk (OR = 0.56, 95% CI 0.34–0.94, p = 0.027). Under the recessive model, there was a significant association between MPO G-463A polymorphism and breast-cancer risk (OR = 0.57, 95% CI 0.34–0.93, p = 0.025). We conclude that MPO-G463A polymorphism might not be a good predictor of breast-cancer risk, though menopausal status modified women’s risk of developing breast cancer.

Association of the NQO1 C609T polymorphism with Alzheimer's disease in Chinese populations: a meta-analysis

Several molecular genetics studies have investigated the association of NQO1 C609T polymorphism with Alzheimers disease (AD) susceptibility in Chinese populations; however, the findings are inconclusive. To investigate the association, we performed the present meta-analysis of 5 case-control studies (including 735 AD cases and 828 controls). We searched literature from PubMed, Embase, HuGNet and CNKI databases for eligible articles that evaluated the association between NQO1 C609T polymorphism and AD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association. Overall, C609T polymorphism was significantly associated with an increased AD risk (homozygote: OR = 1.87, 95% CI = 1.39–2.51, P = 0.000; heterozygote: OR = 1.93, 95% CI = 1.22–3.06, P = 0.019; dominant: OR = 1.97, 95% CI = 1.25–3.12, P = 0.004). When stratified by source of control, significant results were observed in subjects of population-based (PB), whereas no increased risk was observed among the hospital-based (HB). When stratified by APOEϵ4 carrier status, no effect of the NQO1 C609T polymorphism was seen in subjects of APOEϵ4 carriers and APOEϵ4 non-carriers. In conclusion, our results showed that NQO1 C609T polymorphism increases the risk of AD in Chinese populations. Larger studies with different ethnic populations are required to validate our findings.