Xiaobo Li

The Relationship between XRCC1 and XRCC3 Gene Polymorphisms and Lung Cancer Risk in Northeastern Chinese

Background The prevalence of lung cancer in China will be the worlds highest if allowed to proceed uncurbed. To unravel its genetic underpinnings, we sought to investigate the association of three well-characterized nonsynonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC3 (Thr241Met) genes with lung cancer risk in northeastern Chinese. Methodology/Principal Findings This study was hospital-based in design, encompassing 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR (ligase detection reactions) method. Data were analyzed by R language and multifactor dimensionality reduction (MDR) software. Single-locus analysis identified significance in genotype distributions of polymorphism Arg194Trp (Pu200a=u200a0.002) and Arg399Gln (Pu200a=u200a0.017), and in allele distributions of Thr241Met (Pu200a=u200a0.005). Carriers of 399Gln/Gln genotype conferred a 147% increased risk relative to the non-carriers (odds ratio (OR): 2.47; 95% confidence interval (95% CI): 1.48–4.13; P<0.001). For Thr241Met, significance persisted under allelic (ORu200a=u200a1.63; 95% CI: 1.14–2.33; Pu200a=u200a0.005), additive (ORu200a=u200a1.64; 95% CI: 1.16–2.32; Pu200a=u200a0.005) and dominant (ORu200a=u200a1.67; 95% CI: 1.17–2.38; Pu200a=u200a0.004) models. However, common allele combinations were comparable in frequency between patients and controls. In interaction analysis, the overall best MDR model included Arg399Gln and Thr241Met polymorphisms, with a maximal testing accuracy of 63.18% and a maximal cross-validation consistency of 10 out of 10 (Pu200a=u200a0.0175). Conclusions Our study significantly demonstrated an independent and synergistic contribution of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms to lung cancer susceptibility in northeastern Chinese.

Apocynin attenuates oxidative stress and cardiac fibrosis in angiotensin II-induced cardiac diastolic dysfunction in mice

Aim:To investigate whether apocynin, a NADPH oxidase inhibitor, produced cardioproteictive effects in Ang II-induced hypertensive mice, and to elucidate the underlying mechanisms.Methods:C57BL/6 mice were subcutaneously infused Ang II for 4 weeks to mimic cardiac remodeling and fibrosis. Concomitantly the mice were administered apocynin (100 mg·kg−1·d−1) or/and the aldosterone receptor blocker eplerenone (200 mg·kg−1·d−1) via gavage for 4 weeks. Systolic blood pressure (SBP) and heart rate were measured, and transthoracic echocardiography was performed. For in vitro study, cardiac fibroblasts were treated with Ang II (10−7 mol/L) in the presence of apocynin (10−5 mol/L) or/and eplerenone (10−5 mol/L). Immunohistochemistry and Western blotting were used to quantify the expression levels of NADPH oxidase and osteopontin (OPN) proteins in the cells.Results:Both apocynin and eplerenone significantly decreased SBP, and markedly improved diastolic dysfunction in Ang II-induced hypertensive mice, accompanied with ameliorated oxidative stress and cardiac fibrosis. In the Ang II-treated cardiac fibroblasts, the expression levels of NOX4 and OPN proteins were markedly upregulated. Both Apocynin and eplerenone significantly suppressed the increased expression levels of NOX4 and OPN proteins in the Ang II-treated cells. In all the experiments, apocynin and eplerenone produced comparable effects. Co-administration of the two agents did not produce synergic effects.Conclusion:Apocynin produces cardioproteictive effects comparable to those of eplerenone. The beneficial effects of apocynin on myocardial oxidative stress and cardiac fibrosis might be mediated partly through a pathway involving NADPH oxidase and OPN.

The Association of Four Common Polymorphisms from Four Candidate Genes (COX-1, COX-2, ITGA2B, ITGA2) with Aspirin Insensitivity: A Meta-Analysis

Objective Evidence is mounting suggesting that a strong genetic component underlies aspirin insensitivity. To generate more information, we aimed to evaluate the association of four common polymorphisms (rs3842787, rs20417, rs201184269, rs1126643) from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity via a meta-analysis. Methods and Results In total, there were 4 (353/595), 6 (344/698), 10 (588/878) and 7 (209/676) articles (patients/controls) qualified for rs3842787, rs20417, rs20118426 and rs1126643, respectively. The data were extracted in duplicate and analyzed by STATA software (Version 11.2). The risk estimate was expressed as odds ratio (OR) and 95% confidence interval (95% CI). Analyses of the full data set indicated significant associations of rs20417 (OR; 95% CI; P: 1.86; 1.44–2.41; <0.0005) and rs1126643 (2.37; 1.44–3.89; 0.001) with aspirin insensitivity under allelic model. In subgroup analyses, the risk estimate for rs1126643 was greatly potentiated among patients with aspirin semi-resistance relative to those with aspirin resistance, especially under dominant model (aspirin semi-resistance: 5.44; 1.42–20.83; 0.013 versus aspirin resistance: 1.96; 1.07–3.6; 0.03). Further grouping articles by ethnicity observed a stronger prediction of all, but rs20417, examined polymorphisms for aspirin insensitivity in Chinese than in Caucasians. Finally, meta-regression analyses observed that the differences in percentage of coronary artery disease (Pu200a=u200a0.034) and averaged platelet numbers (Pu200a=u200a0.012) between two groups explained a large part of heterogeneity for rs20417 and rs1126643, respectively. Conclusion Our findings provide strong evidence that COX-2 and ITGA2 genetic defects might increase the risk of having aspirin insensitivity, especially for aspirin semi-resistance and in Chinese populations.

The relationship between five widely-evaluated variants in CDKN2A/B and CDKAL1 genes and the risk of type 2 diabetes: a meta-analysis.

The genes encoding two cyclin-dependent kinases-inhibitor-2A/B (CDKN2A/B) and 5 regulatory subunit-associated protein-like 1 (CDKAL1) have been investigated extensively in associations with type 2 diabetes; the results, however, are often irreproducible. We therefore sought to evaluate these associations by performing a meta-analysis on five widely-evaluated variants from the two genes. There were 38 studies (patients/controls: 51,940/52,234) for rs10811661, 16 studies (20,029/24,419) for rs564398 in CDKN2A/B gene, and 27 studies (28,383/47,635) for rs7756992, 26 studies (28,816/31,713) for rs7754840, 21 studies (29,260/38,400) for rs10946398 in CDKAL1 gene. Overall risk estimates for type 2 diabetes conferred by rs10811661-T, rs564398-A, rs7754840-C, rs7756992-G, and rs10946398-C alleles were 1.17 (95% CI: 1.10-1.23; P<0.0005; I(2)=83.9%), 1.1 (95% CI: 1.0-1.21; P=0.051; I(2)=88.3%), 1.24 (95% CI: 1.18-1.3; P<0.0005; I(2)=74.3%), 1.2 (95% CI: 1.11-1.3; P<0.0005; I(2)=92.0%), and 1.19 (95% CI: 1.1-1.29; P<0.0005; I(2)=90.8%), respectively. There was evident publication bias for rs564398 and rs7754840. Subgroup analyses by ethnicity showed remarkable divergences in risk estimate for rs564398 between Asians (odds ratio [OR]=1.01; 95% CI: 0.86-1.19; P=0.868) and Caucasians (OR=1.19; 95% CI: 1.03-1.35; P=0.012) (P<0.05). For all variants examined, the results of studies in retrospective design or with population-based controls were comparative with that of overall studies. In meta-regression analyses, age was found to exert a significant influence on the association between rs10811661 and type 2 diabetes (P=0.003), as well as between rs7754840 and gender (P=0.034). Taken together, our findings provide evidence for a significant contribution of CDKN2A/B gene rs10811661 and CDKAL1 gene rs7756992 and rs10946398 to type 2 diabetes.

Impact of Mineralocorticoid Receptor Antagonists on Changes in Cardiac Structure and Function of Left Ventricular Dysfunction

Background—A comprehensive evaluation of the benefits of mineralocorticoid receptor antagonists on cardiac remodeling is lacking. We aimed to evaluate the impact of mineralocorticoid receptor antagonists on changes in cardiac structure and function of left ventricular dysfunction. Methods and Results—Articles were identified by online searches in PubMed, EMBASE, Cochrane, and ClinicalTrials.gov databases before June 2012, by hand searches of reviews and relevant journals, and by contact with the authors. Qualified articles were restricted to randomized controlled trials. There were, respectively, 12, 4, and 3 qualified trials that randomized 572, 647, and 407 patients to spironolactone, canrenoate, and eplerenone, and 531, 655, and 395 patients to placebo or active treatment, respectively. Overall, under mineralocorticoid receptor antagonist treatment there was improvement in left ventricular ejection fraction (weighted mean difference, 2.97; 95% confidence interval [95% CI], 2.26–3.67; P<0.0005), left ventricular end-systolic and end-diastolic volume index (weighted mean difference, −5.64; 95% CI, −7.94 to −3.34; P<0.0005 and weighted mean difference, −7.46; 95% CI, −11.63 to −3.3; P<0.0005), serum amino-terminal peptide of procollagen type-III (weighted mean difference, −1.12; 95% CI, −1.49 to −0.74; P<0.0005), B-type natriuretic peptide (weighted mean difference, −67.06; 95% CI, −91.24 to −42.88; P<0.0005), peak velocities of early mitral inflow (E; weighted mean difference, −9.57; 95% CI, −12.98 to −6.17; P<0.0005), and E wave deceleration time (weighted mean difference, 7.08; 95% CI, 4.07–10.09; P<0.0005). There was low probability of heterogeneity and publication bias. Conclusions—Our findings demonstrate that mineralocorticoid receptor antagonist treatment may exert beneficial effects on the reversal of cardiac remodeling and improvement of left ventricular function.

Impact of Mineralocorticoid Receptor Antagonists on Changes in Cardiac Structure and Function of Left Ventricular Dysfunction A Meta-analysis of Randomized Controlled Trials

Background—A comprehensive evaluation of the benefits of mineralocorticoid receptor antagonists on cardiac remodeling is lacking. We aimed to evaluate the impact of mineralocorticoid receptor antagonists on changes in cardiac structure and function of left ventricular dysfunction. Methods and Results—Articles were identified by online searches in PubMed, EMBASE, Cochrane, and ClinicalTrials.gov databases before June 2012, by hand searches of reviews and relevant journals, and by contact with the authors. Qualified articles were restricted to randomized controlled trials. There were, respectively, 12, 4, and 3 qualified trials that randomized 572, 647, and 407 patients to spironolactone, canrenoate, and eplerenone, and 531, 655, and 395 patients to placebo or active treatment, respectively. Overall, under mineralocorticoid receptor antagonist treatment there was improvement in left ventricular ejection fraction (weighted mean difference, 2.97; 95% confidence interval [95% CI], 2.26–3.67; P<0.0005), left ventricular end-systolic and end-diastolic volume index (weighted mean difference, −5.64; 95% CI, −7.94 to −3.34; P<0.0005 and weighted mean difference, −7.46; 95% CI, −11.63 to −3.3; P<0.0005), serum amino-terminal peptide of procollagen type-III (weighted mean difference, −1.12; 95% CI, −1.49 to −0.74; P<0.0005), B-type natriuretic peptide (weighted mean difference, −67.06; 95% CI, −91.24 to −42.88; P<0.0005), peak velocities of early mitral inflow (E; weighted mean difference, −9.57; 95% CI, −12.98 to −6.17; P<0.0005), and E wave deceleration time (weighted mean difference, 7.08; 95% CI, 4.07–10.09; P<0.0005). There was low probability of heterogeneity and publication bias. Conclusions—Our findings demonstrate that mineralocorticoid receptor antagonist treatment may exert beneficial effects on the reversal of cardiac remodeling and improvement of left ventricular function.

Synergistic Association of PTGS2 and CYP2E1 Genetic Polymorphisms with Lung Cancer Risk in Northeastern Chinese

Background Lung cancer is the most common cause of cancer-related deaths worldwide. The aim of this study was to investigate the association of five extensively-studied polymorphisms in PTGS2 (rs689466, rs5275, rs20417) and CYP2E1 (rs2031920, rs6413432) genes with lung cancer risk in a large northeastern Chinese population. Methodology/Principal Findings This is a hospital-based case-control study involving 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR method. Data were analyzed using Haplo.stats and MDR programs. There were significant differences between patients and controls in allele/genotype distributions of rs5275 (Pu200a=u200a0.002/0.003) and rs6413432 (Pu200a=u200a0.037/0.044), as well as in genotype distributions of rs689466 (Pu200a=u200a0.02). The risk for lung cancer associated with the rs5275-C mutant allele was decreased by 60% (95% CI [confidence interval]: 0.21–0.74; Pu200a=u200a0.004) under the recessive model. Carriers of rs689466-G mutant allele had a 28% (95% CI: 0.57–0.92; Pu200a=u200a0.008) reduced risk of developing lung cancer relative to the AA genotype carriers. In haplotype analysis, haplotype G-C-C-T (in order of rs689466, rs5275, rs2031920 and rs6413432) decreased the odds of lung cancer by 28% (95% CI: 0.51–0.93; Pu200a=u200a0.019) after adjusting for confounding factors, whereas haplotype A-T-T-T had 1.49-fold (95% CI: 1.21–1.79; Pu200a=u200a0.012) increased risk for lung cancer. Using MDR method, the overall best model including rs5275, rs689466 and rs6413432 polymorphisms was identified with a maximal testing accuracy of 66.1% and a maximal cross-validation consistency of 10 out of 10 (Pu200a=u200a0.003). Conclusions/Significance Our findings demonstrated a potentially synergistic association of PTGS2 and CYP2E1 polymorphisms with the underlying cause of lung cancer in northeastern Chinese.

Angiotensin-converting enzyme gene deletion allele increases the risk of left ventricular hypertrophy: evidence from a meta-analysis

Large panels of studies have examined the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and risk for left ventricular hypertrophy (LVH), yet with inconclusive results. We therefore sought to evaluate this association via a comprehensive meta-analysis. A random-effects model was applied irrespective of between-study heterogeneity. Data and study quality were independently assessed by two investigators. Total 52 studies encompassing 3,663 case-patients and 8,953 controls were meta-analyzed. Overall results indicated that carriers homozygous for DD genotype conferred 1.59 times (95xa0% confidence interval [95xa0% CI]: 1.31–1.92; Pxa0<xa00.0005) more likely to develop LVH compared with those with II genotype, accompanying moderate evidence of heterogeneity (I2xa0=xa049.0xa0%). In subgroup analyses by ethnicity, DD homozygotes had a 90xa0% (95xa0% CI: 1.42–2.53; Pxa0<xa00.0005) increased risk in East Asians, but merely a 33xa0% (95xa0% CI: 1.03–1.73; Pxa0=xa00.032) increased risk in Caucasians. Moreover, differences in source of controls, cutoff for the definition of hypertension, and diagnostic method of LVH were also regarded as potential sources of heterogeneity. Further, the risk estimate associated with D allele was more pronounced in studies involving males (odds ratio [OR]xa0=xa01.47; 95xa0% CI: 1.2–1.8; Pxa0<xa00.0005) and untreated subjects (ORxa0=xa01.39; 95xa0% CI: 1.2–1.62; Pxa0<xa00.0005). The magnitude of publication bias was greatly improved in homozygous subgroups. Taken together, our results demonstrated significant association of ACE gene I/D polymorphism with LVH risk, especially in East Asians, and this association was more pronounced in studies involving males and untreated subjects.

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; Pu200a=u200a0.06; I 2u200a=u200a6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; Pu200a=u200a0.111; I 2u200a=u200a18.0%). 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.

Lack of Association between NADPH Quinone Oxidoreductase 1 (NQO1) Gene C609T Polymorphism and Lung Cancer: A Case-Control Study and a Meta-Analysis

Background The association between NAD(P)H:quinone oxidoreductase 1 (NQO1) gene C609T polymorphism (rs1800566) and lung cancer has been widely evaluated, and a definitive answer so far is lacking. We first conducted a case-control study to assess this association in northeastern Han Chinese, and then performed a meta-analysis to further address this issue. Methodology/Principal Findings This case-control study involved 684 patients clinically diagnosed as lung cancer and 602 age-matched cancer-free controls from Harbin city, Heilongjiang province, China. Genotyping was conducted using the PCR-LDR (ligase detection reactions) method. Meta-analysis was managed by STATA software. Data and study quality were assessed in duplicate. Our case-control association study indicated no significant difference in the genotype and allele distributions of C609T polymorphism between lung cancer patients and controls, consistent with the results of the further meta-analysis involving 7286 patients and 9167 controls under both allelic (odds ratio (OR)u200a=u200a0.99; 95% confidence interval (CI): 0.92–1.06; Pu200a=u200a0.692) and dominant (ORu200a=u200a0.98; 95% CI: 0.89–1.08; Pu200a=u200a0.637) models. However, there was moderate evidence of between-study heterogeneity and low probability of publication bias. Further subgroup analyses by ethnicity, source of controls and sample size detected no positive associations in this meta-analysis. Conclusions Our study in northeastern Han Chinese, along with the meta-analysis, failed to confirm the association of NQO1 gene C609T polymorphism with lung cancer risk, even across different ethnic populations.