Genetic association of interleukin-10 promoter polymorphisms and susceptibility to diffuse large B-cell lymphoma: A meta-analysis

Published data on the association between interleukin-10 (IL-10) gene polymorphisms and diffuse large B-cell lymphoma (DLBCL) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed, focusing on four major IL-10 gene variants in the promoter region: –3575T/A, –1082A/G, –819C/T and –592C/A. We applied the false discovery rate (FDR) method to adjust for multiple testing. A significant association between IL-10 –3575T/A polymorphism and the risk of DLBCL was observed in the pooled 10 case–control studies (A vs. T: OR = 1.16, 95% CI = 1.08–1.25, P < 0.0001; AA + TA vs. TT: OR = 1.20, 95% CI = 1.08–1.33, P = 0.0009; AA vs. TA + TT: OR = 1.25, 95% CI = 1.09–1.44, P = 0.001). The results indicated that carriers of –1082G allele (–1082GG/GA genotypes) had a nearly 30% increased risk of DLBCL, as compared with carriers of –1082AA genotype (GG + GA vs. AA: OR = 1.30, 95% CI = 1.08–1.57, P = 0.005). When P-values were not adjusted for multiple testing, the risk was significantly decreased among people with –592AA genotype (AA vs. AC + CC: OR = 0.63, 95% CI = 0.43–0.94, P = 0.02), while carriers with –819TT genotype also modestly weakened the DLBCL susceptibility at a marginal level of significance (TT vs. CT + CC: OR = 0.59, 95% CI = 0.35–0.99, P = 0.05). However, these associations were not significant after correction for multiple testing. This meta-analysis suggests that IL-10 –3575A allele confers a greater risk to DLBCL susceptibility, while –1082A/G polymorphism also has significant association with DLBCL risk. These results may help to further clarify the malignancy-risk gene signature of DLBCL, and thus have prognostic and predictive value especially for early-stage DLBCL.     

Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population

Atherosclerosis, manifesting itself as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic progressive inflammatory disease which is driven by responses of both innate and adaptive immunity. Toll-like receptors (TLRs) and Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) are important effectors of the innate immune system, and polymorphisms within genes encoding them may increase risk of occurrence of various pathologies including cardiovascular disorders. Thus, we carried out a genetic association study on the sample of 702 consecutive Caucasian (Russian) patients with coronary artery disease (CAD) and 300 age-, sex-, and ethnicity-matched healthy controls. We revealed that the C/C genotype of the TLR1 rs5743551 polymorphism was significantly associated with a reduced risk of CAD according to the recessive model (OR = 0.41, 95% CI = 0.20–0.84, P = 0.017, adjusted by age and gender). Concerning TREM-1 gene polymorphisms, we found that A/A genotype of the rs2234237 polymorphism, the G/G genotype of the rs6910730 polymorphism, the C/C genotype of the rs9471535 polymorphism, and the T/T genotype of the rs4711668 polymorphism were significantly associated with elevated CAD risk according to the recessive model (OR = 5.52, 95% CI = 1.17–25.98, P = 0.011; OR = 4.28, 95% CI = 1.09–16.81, P = 0.021; OR = 5.55, 95% CI = 1.18–26.09, P = 0.011, and OR = 1.66, 95% CI = 1.10–2.52, P = 0.014, respectively, adjusted by age and gender). Conversely, the G allele of the rs1817537 polymorphism, the T allele of the rs2234246 polymorphism, and the T allele of the rs3804277 polymorphism significantly correlated with similarly decreased risk of CAD according to the dominant model (OR = 0.57, 95% CI = 0.40–0.81, P = 0.0013; OR = 0.59, 95% CI = 0.42–0.84, P = 0.003, and OR = 0.58, 95% CI = 0.41–0.81, P = 0.0014, respectively, adjusted by age and gender). We conclude that certain TLR and TREM-1 gene polymorphisms may be associated with CAD in Russian population; however, their significance as predictive and pathogenic markers of CAD should be interpreted with caution in other populations.     

Vascular endothelial growth factor polymorphisms and risk of Alzheimer's disease: A meta-analysis

There were conflicting results about whether promoter polymorphisms (− 2578C/A, − 1154G/A) of vascular endothelial growth factor (VEGF) gene is a risk factor of Alzheimer's disease (AD). To determine the relationship between them, a meta-analysis is needed urgently. We searched all the reports about VEGF promoter polymorphisms (− 2578C/A, − 1154G/A) and AD risk from PubMed, Web of Science, Cochrane Collaboration and Google Scholar database for the period up to 1 August, 2012. A total of 7 studies were included in this meta-analysis. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated applying fixed or random effects models. There was no significant association between VEGF − 2578C/A polymorphisms and AD risk in all gene models (OR = 1.08, 95% CI = 0.94–1.23 for A vs. C; OR = 1.19, 95% CI = 0.89–1.59 for AA vs. CC; OR = 1.15, 95% CI = 0.91–1.45 for AA vs. CC + CA; OR = 1.11, 95% CI = 0.98–1.25 for AA + CA vs. CC). Similar results were provided in subgroup analysis by ethnicity. For the VEGF − 1154G/A polymorphisms, lack of an association was also found (A vs. G: OR = 0.89, 95% CI = 0.79–1.01; AA vs. GG: OR = 0.82, 95% CI = 0.62–1.08; AA vs. GA + GG: OR = 0.89, 95% CI = 0.68–1.16; AA + AG vs. GG: OR = 0.85, 95% CI = 0.72–1.00). Conclusively, the result of this meta-analysis suggested that VEGF promoter polymorphisms (− 2578C/A, − 1154G/A) might not contribute to the susceptibility of AD.     

Matrix metalloproteinase-1 gene polymorphisms and periodontitis susceptibility: A meta-analysis based on 11 case-control studies

Matrix metalloproteinase-1 has been implicated in periodontal disease, but the association between the most-studied Matrix metalloproteinase-1 1G-to-2G polymorphism and the risk of periodontal disease were reported with inconclusive results. Therefore, the aim of this study was to investigate the association between the Matrix metalloproteinase-1 1G-to-2G polymorphism and periodontal disease. Electronic databases search yielded 11 studies with 1447 patients and 1710 control subjects evaluated the association of the polymorphisms of Matrix metalloproteinase-1 1G-to-2G and periodontitis risk were brought into this study. The association was evaluated by odds ratio (OR) and its 95% confidence interval (CI). The overall results showed that the variant genotypes were associated with a significantly increased risk of periodontitis (OR = 1.45, 95% CI = 1.02–1.26 for 2G/2G vs 1G/1G, and OR = 2.27, 95% CI = 1.22–4.23 for 2G/2G vs 1G/2G + 1G/1G). In the stratified analyses, there was a significantly increased risk for the studies of periodontitis (OR = 1.59, 95% CI = 1.15–2.21 for 2G/2G vs 1G/1G; OR = 3.48, 95% CI = 1.39–8.71 for 2G/2G vs 1G/2G + 1G/1G), which remained for the studies of Asian populations. And there was a significantly increased risk of severe periodontitis (OR = 2.15, 95% CI = 1.35–3.43 for 2G/2G vs 1G/1G; OR = 2.86, 95% CI = 1.31–2.64 for 2G/2G vs 1G/2G + 1G/1G; OR = 1.6, 95% CI = 1.12–2.39 for 1G/2G + 2G/2G vs 1G/1G; OR = 1.61, 95% CI = 1.28–2.03 for 2G allele vs 1G allele). The current study demonstrated that the Matrix metalloproteinase-1-1607 1G-to-2G polymorphism was associated with susceptibility to periodontitis, apparently, severe periodontitis.     

Association between apolipoprotein E gene polymorphism and the risk of multiple sclerosis: A meta-analysis of 6977 subjects

Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and multiple sclerosis (MS) risk. However, the results remain conflicting. Therefore, in order to derive a more precise association of ApoE gene polymorphism with MS risk, we performed this meta-analysis. Systematic searches of electronic databases PubMed, Embase and Web of Science, as well as hand searching of the references of identified articles were performed. Twenty studies were identified, covering a total of 4080 MS cases and 2897 controls. The results showed evidence for significant association between ApoE ε2 mutation and MS risk (for ε2/ε4 versus ε3/ε3: OR = 1.74, 95% CI = 1.12–2.71, p = 0.01; for ε2 allele versus ε3 allele: OR = 1.16, 95% CI = 1.01–1.35, p = 0.04). In the subgroup analysis by ethnicity, the similar results were obtained among Europeans (for ε2/ε4 versus ε3/ε3: OR = 1.81, 95% CI = 1.14–2.87, p = 0.01; for ε2 allele versus ε3 allele: OR = 1.19, 95% CI = 1.02–1.38, p = 0.03). After excluding the outlier studies by observing Galbraith plot, marginal association was found between ApoE ε3/ε4 genotype and the protective factor for MS (for ε3/ε4 versus ε3/ε3: OR = 0.86, 95% CI = 0.75–0.99, p = 0.04). In summary, the present meta-analysis provides evidence that ApoE ε2 mutation is associated with MS risk. In addition, ApoE ε3/ε4 genotype appears to be a protective factor for MS.     

Hsa-miR-499 polymorphism (rs3746444) and cancer risk: A meta-analysis of 17 case–control studies

Introduction

MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-499 rs3746444 polymorphism and cancer risk, which showed inconclusive results.

Methodology/main results

We conducted a meta-analysis of 17 studies that included 7842 cancer cases and 8989 case-free controls and assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, hsa-miR-499 rs3746444 polymorphism was associated with higher cancer risk in heterozygote model (AG vs AA, OR = 1.15, 95%CI = 1.01–1.30, P_{heterogeneity} < 0.001), dominant genetic model (GG/AG vs AA, OR = 1.18, 95% CI = 1.04–1.33, P_{heterogeneity} < 0.001) and allele contrast (G vs A, OR = 1.09, 95% CI = 1.01–1.18, P_{heterogeneity} = 0.021). In the stratified analyses, we observed that the GG/AG genotype might modulate breast cancer risk (OR = 1.13, 95% CI = 1.01–1.26, P_{heterogeneity} = 0.111) comparing with the AA genotype. Moreover, a significantly increased risk was found among Asian populations in heterozygote model (AG vs AA, OR = 1.23, 95% CI = 1.06–1.43, P_{heterogeneity} < 0.001), homozygote model (GG vs AA, OR = 1.22, 95% CI = 1.02–1.46, P_{heterogeneity} = 0.319), dominant model (GG/AG vs AA, OR = 1.25, 95% CI = 1.06–1.39, P_{heterogeneity} < 0.001) and allele contrast (G vs A, OR = 1.14, 95% CI = 1.04–1.25, P_{heterogeneity} = 0.021).

Conclusions

These findings supported that hsa-miR-499 rs3746444 polymorphism contributes to the susceptibility of cancers.     

Association between ADAM33 S2 and ST+4 polymorphisms and susceptibility to asthma: A meta-analysis

Objective

The aim of this study was to determine whether ADAM33 (a disintegrin and metalloproteinase domain 33) polymorphisms confer susceptibility to asthma in different populations.

Methods

We performed a meta-analysis on the association between the ADAM33 S2, ST+4, F+1, S1, and V4 polymorphisms and asthma.

Results

Thirteen studies in ten reports, which included 4942 patients and 7933 controls, were available for the meta-analysis. Meta-analysis stratified by ethnicity indicated an association between the ADAM33 S2 2 allele and asthma in Europeans (OR = 0.912, 95% CI = 0.851–0.977, p = 0.009). Meta-analysis revealed an association between asthma and the ADAM33 ST+4 2 allele (OR = 0.783, 95% CI = 0.762–0.999, p = 0.048). Stratification by ethnicity indicated an association between the ADAM33 ST+4 polymorphism and asthma in Asians. Stratification by age indicated an association between the ADAM33 ST+4 2 allele and asthma in adults (OR = 0.863, 95% CI = 0.782–0.964, p = 0.008). However, no association was found between asthma and the ADAM33 F+1, S1, and V4 polymorphisms.

Conclusions

This meta-analysis demonstrates that the ADAM33 S2 polymorphism confers susceptibility to asthma in Europeans and the ADAM33 ST+4 polymorphism is associated with asthma in Asians and adults.     

Association between MTHFR C677T polymorphism and primary open-angle glaucoma: A meta-analysis

Epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and primary open-angle glaucoma (POAG) risk. However, the results remain conflicting. The aim of this study was to investigate the association between MTHFRC677T polymorphism and POAG risk. All genetic association studies on MTHFR C677T polymorphism and POAG were systematically searched by the electronic databases PubMed, Embase and Web of Science. Study selection, data abstraction and study quality evaluation were conducted in duplicate independently. The strength of association between MTHFR C677T polymorphism and POAG was measured by odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 10 studies including 1224 cases and 1105 controls were included in our final meta-analysis. There was no evidence of significant association of the overall population (for allelic model: OR = 1.17, 95% CI = 0.94–1.46; for additive model: OR = 1.15, 95% CI = 0.85–1.57; for dominant model: OR = 1.19, 95% CI = 0.92–1.55 and for recessive model: OR = 1.11, 95% CI = 0.83–1.49). Significant associations were found between MTHFR C677T polymorphisms and POAG in allelic model (OR = 1.39, 95% CI = 1.05–1.83) and additive model (OR = 1.88, 95% CI = 1.04–3.43) for population-based (PB) subgroup. This meta-analysis suggested that there were significant associations between MTHFR C677T polymorphism and POAG in allelic model and additive model for PB subgroup which indicated that the T allele or TT genotype might increase the risk of POAG, whereas no evidence of significant association was shown of the overall studied population. However, this conclusion should be interpreted cautiously. More large sample-size and multi-ethnicity studies with well-defined POAG patients and well-study design are needed in the future study.     

The effect of chemokine receptor gene polymorphisms (CCR2V64I,CCR5-59029G>A and CCR5Δ32) on renal allograft survival in Pakistani transplant patients

Background

Gene polymorphisms of the chemokine receptors CCR2 and CCR5 (CCR2V64I, CCR5-59029G>A and CCR5Δ32) have been shown to be associated with renal allograft rejection. The aim of this study was to investigate the association of these polymorphisms with allograft rejection among Pakistani transplant patients.

Method

A total of 606 renal transplant patients and an equal number of their donors were included in this study. DNA samples were used to amplify polymorphic regions of CCR2V64I, CCR5-59029G>A and CCR5Δ32 by polymerase chain reaction using sequence specific primers. The amplified products of CCRV64I and CCR5-59029G>A were digested with restriction enzymes (BsaB1 and Bsp12861) respectively. The CCR5Δ32 genotypes were determined by sizing the PCR amplicons. The association of these polymorphisms with the biopsy proven rejection and other clinical parameters was evaluated using the statistical software SPSS v.17.

Results

In this study, the G/G genotype of CCR2V64I was associated with a high frequency of allograft rejection (p = 0.009; OR = 2.14; 95% CI = 1.2–3.7). Rejection episode(s) in the GA + AA genotypes were found to be significantly lower as compared to the GG genotype (p = 0.009; OR = 0.4; 95% CI = 0.2–0.8). The Kaplan–Meier curve also indicated a reduced overall allograft survival for patients with the G/G genotype of CCR2V64I (59.2 ± 1.4 weeks, log p = 0.008). There was a significant association with rejection by female donors possessing the CCR2 GG genotype (p = 0.02; OR = 2.6; CI = 1.1–6.3) and male donors with the CCR5-59029 GG genotype (p = 0.004; OR = 1.7; CI = 1.03–3.01).

Conclusion

This study shows an association of the CCR2V64I (G/G) genotype with renal allograft rejection. However, no such association was found for the CCR5 gene polymorphisms. Therapeutic interventions such as blocking the CCR2 receptor (especially G polymorphism) may yield better survival of renal allograft in this patient group. Further, chemokine receptors may be added to the spectrum of the immunogenetic factors that are known to be associated with renal allograft rejection.     

The effect of XPD/ERCC2 Lys751Gln polymorphism on acute leukemia risk: A systematic review and meta-analysis

Aims

Epidemiological studies have assessed the association between xeroderma pigmentosum group D (XPD) Lys751Gln and acute leukemia risk with conflicting results. We performed this meta-analysis to derive a more precise estimation of the relationship. Pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the strength of the association.

Results

Ten published case–control studies including a total of 1494 cases and 2259 controls were identified. Overall, significant risk effects of Lys751Gln genotype was found under the dominant model (OR = 1.16; 95% CI = 1.01–1.34; P = 0.032). When stratified by clinical types, the variant genotype was associated with the acute myeloid leukemia (AML) risk under the heterozygote comparison (OR = 1.20; 95% CI = 1.00–1.43; P = 0.048), the homozygote comparison (OR = 1.35; 95% CI = 1.05–1.74; P = 0.019) and the dominant model (OR = 1.23; 95% CI = 1.04–1.45; P = 0.015), respectively. Furthermore, significantly increased risks were also pronounced in Caucasian AML patients (the homozygote comparison: OR = 1.38; 95% CI = 1.07–1.78; P = 0.013; the dominant model: OR = 1.23; 95% CI = 1.03–1.46; P = 0.020; and the recessive model: OR = 1.26; 95% CI = 1.00–1.60; P = 0.050). No evident heterogeneities were observed for the overall data under all genetic models. In addition, no statistical evidence for publication bias was found using the method of Begg's and Egger's tests.

Conclusion

This meta-analysis suggested that XPD Lys751Gln polymorphism might be a risk factor for AML and Caucasian acute leukemia patients.