Danjie Jiang

Elevated PLA2G7 Gene Promoter Methylation as a Gender-Specific Marker of Aging Increases the Risk of Coronary Heart Disease in Females

PLA2G7 gene product is a secreted enzyme whose activity is associated with coronary heart disease (CHD). The goal of our study is to investigate the contribution of PLA2G7 promoter DNA methylation to the risk of CHD. Using the bisulphite pyrosequencing technology, PLA2G7 methylation was measured among 36 CHD cases and 36 well-matched controls. Our results indicated that there was a significant association between PLA2G7 methylation and CHD (adjusted P = 0.025). Significant gender-specific correlation was observed between age and PLA2G7 methylation (males: adjusted r = −0.365, adjusted P = 0.037; females: adjusted r = 0.373, adjusted P = 0.035). A breakdown analysis by gender showed that PLA2G7 methylation was significantly associated with CHD in females (adjusted P = 0.003) but not in males. A further two-way ANOVA analysis showed there was a significant interaction between gender and status of CHD for PLA2G7 methylation (gender*CHD: P = 6.04E−7). Moreover, PLA2G7 methylation is associated with the levels of total cholesterols (TC, r = 0.462, P = 0.009), triglyceride (TG, r = 0.414, P = 0.02) and Apolipoprotein B (ApoB, r = 0.396, P = 0.028) in females but not in males (adjusted P>0.4). Receiver operating characteristic (ROC) curves showed that PLA2G7 methylation could predict the risk of CHD in females (area under curve (AUC) = 0.912, P = 2.40E−5). Our results suggest that PLA2G7 methylation changes with aging in a gender-specific pattern. The correlation between PLA2G7 methylation and CHD risk in females is independent of other parameters including age, smoking, diabetes and hypertension. PLA2G7 methylation might exert its effects on the risk of CHD by regulating the levels of TC, TG, and ApoB in females. The gender disparities in the PLA2G7 methylation may play a role in the molecular mechanisms underlying the pathophysiology of CHD.

The Diagnostic Value of DNA Methylation in Leukemia: A Systematic Review and Meta-Analysis

Background Accumulating evidence supports a role of DNA methylation in the pathogenesis of leukemia. The aim of our study was to evaluate the potential genes with aberrant DNA methylation in the prediction of leukemia risk by a comprehensive meta-analysis of the published data. Methods A series of meta-analyses were done among the eligible studies that were harvested after a careful filtration of the searching results from PubMed literature database. Mantel-Haenszel odds ratios and 95% confidence intervals were computed for each methylation event assuming the appropriate model. Results A total of 535 publications were initially retrieved from PubMed literature database. After a three-step filtration, we harvested 41 case-control articles that studied the role of gene methylation in the prediction of leukemia risk. Among the involving 30 genes, 20 genes were shown to be aberrantly methylated in the leukemia patients. A further subgroup meta-analysis by subtype of leukemia showed that CDKN2A, CDKN2B, ID4 genes were significantly hypermethylated in acute myeloid leukemia. Conclusions Our meta-analyses identified strong associations between a number of genes with aberrant DNA methylation and leukemia. Further studies should be required to confirm the results in the future.

Elevation of peripheral BDNF promoter methylation links to the risk of Alzheimer's disease.

Brain derived neurotrophic factor (BDNF) has been known to play an important role in various mental disorders or diseases such as Alzheimers disease (AD). The aim of our study was to assess whether BDNF promoter methylation in peripheral blood was able to predict the risk of AD. A total of 44 AD patients and 62 age- and gender-matched controls were recruited in the current case-control study. Using the bisulphite pyrosequencing technology, we evaluated four CpG sites in the promoter of the BDNF. Our results showed that BDNF methylation was significantly higher in AD cases than in the controls (CpG1: p = 10.021; CpG2: p = 0.002; CpG3: p = 0.007; CpG4: p = 0.005; average methylation: p = 0.004). In addition, BDNF promoter methylation was shown to be significantly correlated with the levels of alkaline phosphatase (ALP), glucose, Lp(a), ApoE and ApoA in males (ALP: r = −0.308, p = 0.042; glucose: r = −0.383, p = 0.010; Lp(a): r = 0.333, p = 0.027; ApoE: r = −0.345, p = 0.032;), ApoA levels in females (r = 0.362, p = 0.033), and C Reactive Protein (CRP) levels in both genders (males: r = −0.373, p = 0.016; females: r = −0.399, p = 0.021). Our work suggested that peripheral BDNF promoter methylation might be a diagnostic marker of AD risk, although its underlying function remains to be elaborated in the future.

GCK gene-body hypomethylation is associated with the risk of coronary heart disease.

Objectives. Glucokinase encoded by GCK is a key enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Variants of GCK gene were shown to be associated with type 2 diabetes (T2D) and coronary heart disease (CHD). The goal of this study was to investigate the contribution of GCK gene-body methylation to the risk of CHD. Design and Methods. 36 patients (18 males and 18 females) and 36 age- and sex-matched controls were collected for the current methylation research. DNA methylation level of the CpG island (CGI) region on the GCK gene-body was measured through the sodium bisulfite DNA conversion and pyrosequencing technology. Results. Our results indicated that CHD cases have a much lower methylation level (49.77 ± 6.43%) compared with controls (54.47 ± 7.65%, P = 0.018). In addition, GCK gene-body methylation was found to be positively associated with aging in controls (r = 0.443, P = 0.010). Conclusions. Our study indicated that the hypomethylation of GCK gene-body was significantly associated with the risk of CHD. Aging correlates with an elevation of GCK methylation in healthy controls.

An association study between genetic polymorphisms related to lipoprotein-associated phospholipase A2 and coronary heart disease

Previous genome-wide association studies (GWAS) have revealed seven single nucleotide polymorphisms (SNPs) that affect lipoprotein-associated phospholipase A2 (Lp-PLA2) activity or levels in American and European individuals. A total of 290 coronary heart disease (CHD) patients, 198 non-CHD patients and 331 unrelated healthy volunteers were recruited for the present case-control study of Han Chinese. Four SNPs (rs964184 of ZNF259, rs7528419 of CELSR2 and rs7756935 and rs1805017 of PLA2G7) were shown to be significantly associated with CHD. The rs964184-G allele of the ZNF259 gene was identified as a risk factor of CHD in females (odds ratio (OR) =1.49, 95% confidence interval (CI) =1.00–2.22, P=0.05). The rs7528419-G allele of the CELSR2 gene was protective against CHD in males (OR=0.48, 95% CI=0.25–0.93, P=0.04). The other two alleles (rs7756935-C and rs1805017-A) of the PLA2G7 gene acted as protective factors against CHD in females (rs7756935-C: OR=0.59, 95% CI=0.35–1.00, P=0.05; rs1805017-A: OR=0.51, 95% CI=0.28–0.93, P=0.03). Moreover, rs1805017 of the PLA2G7 gene was associated with the severity of CHD only in females (r2=0.02, P=0.04). We identified four Lp-PLA2-associated SNPs significantly associated with CHD in a Han Chinese population. Specifically, rs7528419 was protective factor against CHD in males, while the other two SNPs (rs7756935 and rs1805017 of the PLA2G7 gene) were protective factors against CHD in females and rs964184 of the ZNF259 gene was regarded as a risk factor for CHD in females.

Apolipoprotein A5 gene variants and the risk of coronary heart disease: A case-control study and meta-analysis

Previous studies have shown that apolipoprotein A5 (APOA5) gene variants are genetic determinants of the concentration of triglycerides, which are a known risk factor for coronary heart disease (CHD). Using the standardized coronary angiography method, 290 CHD patients and 198 non-CHD controls were recruited from Ningbo Lihuili Hospital. In addition, 331 unrelated healthy volunteers were recruited as healthy controls from Ningbo Ximen Community residents. Three variants of the APOA5 gene, S19W, -1131T>C and 553G>T, were analyzed for their association with CHD. Under a dominant inheritance model, -1131CT>C was shown to be a CHD risk factor (P=0.030; OR, 1.422; 95% CI, 1.036–1.952). The single nucleotide polymorphism, 553G>T, was found to correlate with the severity of CHD in males (P=0.032). Meta-analysis showed that -1131T>C was significantly associated with CHD (P<0.0001). By contrast, negative correlations with CHD were observed for S19W and 553G>T. In the present case-control study, APOA5 gene variants were not found to correlate with the risk of CHD in the populations studied; however, -1131CT>C was shown to be a CHD risk factor under a dominant inheritance model. Meta-analysis showed a significant contribution of -1131T>C to the risk of CHD, implying an ethnic difference in APOA5 gene variants.

Meta-analyses of HFE variants in coronary heart disease.

AIM HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. METHODS AND RESULTS We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. RESULTS Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P=0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values>0.05). In addition, the results of our case-control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. CONCLUSIONS Our meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese.

Meta-analysis of DNA methylation biomarkers in hepatocellular carcinoma

DNA methylation is an epigenetic mechanism in the pathogenesis of hepatocellular carcinoma (HCC). Here, we conducted a systematic meta-analysis to evaluate the contribution of DNA methylation to the risk of HCC. A total of 2109 publications were initially retrieved from PubMed, Web of Science, Cochrane Library, Embase, CNKI and Wanfang literature database. After a four-step filtration, we harvested 144 case-control articles in the meta-analysis. Our results revealed that 24 genes (carcinoma tissues vs adjacent tissues), 17 genes (carcinoma tissues vs normal tissues) and six genes (carcinoma serums vs normal serums) were significantly hypermethylated in HCC. Subgroup meta-analysis by geographical populations showed that six genes (carcinoma tissues vs adjacent tissues) and four genes (carcinoma tissues vs normal tissues) were significantly hypermethylated in HCC. Our meta-analysis identified the correlations between a number of aberrant methylated genes (p16, RASSF1A, GSTP1, p14, CDH1, APC, RUNX3, SOCS1, p15, MGMT, SFRP1, WIF1, PRDM2, DAPK1, RARβ, hMLH1, p73, DLC1, p53, SPINT2, OPCML and WT1) and HCC. Aberrant DNA methylation might become useful biomarkers for the prediction and diagnosis of HCC.

Association of CDKN2BAS Polymorphism rs4977574 with Coronary Heart Disease: A Case-Control Study and a Meta-Analysis

The goal of our study was to explore the significant association between a non-protein coding single nucleotide polymorphism (SNP) rs4977574 of CDKN2BAS gene and coronary heart disease (CHD). A total of 590 CHD cases and 482 non-CHD controls were involved in the present association study. A strong association of rs4977574 with CHD was observed in females (genotype: p = 0.002; allele: p = 0.002, odd ratio (OR) = 1.57, 95% confidential interval (CI) = 1.18–2.08). Moreover, rs4977574 was more likely to be a risk variant of CHD under the recessive model in females (χ2 = 10.29, p = 0.003, OR = 2.14, 95% CI = 1.31–2.77). A breakdown analysis by age had shown that there was an 87% increased risk of CHD for females younger than 65 years (genotype: χ2 = 14.64, degrees of freedom (df) = 2, p = 0.0002; allele: χ2 = 11.31, df = 1, p = 0.0008, OR = 1.87, 95% CI = 1.30–2.70). Similar observation was also found in males younger than 65 years (genotype: χ2 = 8.63, df = 2, p = 0.04; allele: χ2 = 7.55, df = 1, p = 0.006, OR = 1.45, 95% CI = 1.11–1.90). p values were adjusted by age, sex, smoking, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Meta-analysis of 23 studies among 36,452 cases and 39,781 controls showed a strong association between rs4977574 and the risk of CHD (p < 0.0001, OR = 1.27, 95% CI = 1.22–1.31).

Significant association between DRD3 gene body methylation and schizophrenia

The current study was the first one to reveal the contribution of DRD3 methylation to the risk of different (SCZ) subtypes. This study comprised a total of 30 paranoid (15 males and 15 females) and 29 undifferentiated (15 males and 14 females) SCZ patients and 26 age- and gender-matched controls. Our results showed a significant association of CpG2 with SCZ. A breakdown analysis by gender showed that CpG2 and CpG3 methylation were significantly higher in male patients than male controls, and that CpG5 methylation was significantly higher in female patients than female controls. A further breakdown analysis by both gender and SCZ subtype showed that CpG2 and CpG3 methylation were significantly higher in male paranoid SCZ and male undifferentiated SCZ than male controls. In contrast, CpG2 and CpG3 methylation were significantly lower in female undifferentiated SCZ than female controls. Additionally, CpG5 methylation was significantly higher in female paranoid SCZ than female controls. In conclusion, our findings supported that DRD3 gene body hypermethylation was significantly associated with the risk of SCZ. Future study is needed to clarify the mechanisms by which DRD3 gene body hypermethylation contributes to the risk of SCZ.