Qinwen Wang

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: pu200a=u200a10.021; CpG2: pu200a=u200a0.002; CpG3: pu200a=u200a0.007; CpG4: pu200a=u200a0.005; average methylation: pu200a=u200a0.004). 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: ru200a=u200a−0.308, pu200a=u200a0.042; glucose: ru200a=u200a−0.383, pu200a=u200a0.010; Lp(a): ru200a=u200a0.333, pu200a=u200a0.027; ApoE: ru200a=u200a−0.345, pu200a=u200a0.032;), ApoA levels in females (ru200a=u200a0.362, pu200a=u200a0.033), and C Reactive Protein (CRP) levels in both genders (males: ru200a=u200a−0.373, pu200a=u200a0.016; females: ru200a=u200a−0.399, pu200a=u200a0.021). 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.

Meta-Analyses of 8 Polymorphisms Associated with the Risk of the Alzheimer’s Disease

Aims The aim of this study was to evaluate the combined contribution of 8 polymorphisms to the risk of Alzheimers disease (AD). Methods Through a comprehensive literature search for genetic variants involved in the AD association study, we harvested a total of 6 genes (8 polymorphisms) for the current meta-analyses. These genes consisted of A2M (5bp I/D and V1000I), ABCA2 (rs908832), CHAT (1882G >A, 2384G >A), COMT (Val158Met), HTR6 (267C >T) and LPL (Ser447Ter). Results A total of 33 studies among 9,453 cases and 10,833 controls were retrieved for the meta-analyses of 8 genetic variants. It was showed that A2M V1000I (odd ratio (OR)u200a=u200a1.26, 95% confidence interval (CI)u200a=u200a1.07–1.49, Pu200a=u200a0.007), rs908832 allele of ABCA2 (ORu200a=u200a1.55, 95% CIu200a=u200a1.12–2.16, Pu200a=u200a0.009), 2384G >A of CHAT (ORu200a=u200a1.22, 95% CIu200a=u200a1.00–1.49, Pu200a=u200a0.05) and Ser447Ter of LPL in the Northern-American population (ORu200a=u200a0.56, 95% CIu200a=u200a0.35–0.91, Pu200a=u200a0.02) were significantly associated with the risk of AD. No association was found between the rest of the 5 polymorphisms and the risk of AD. Conclusion Our results showed that A2M V1000I polymorphism in German, Korean, Chinese, Spanish, Italian and Polish populations, rs90883 of ABCA2 gene in French, American, Swiss, Greek and Japanese populations, 2384G >A of CHAT gene in British and Korean populations and LPL Ser447Ter in the Northern-American population were associated with the risk of AD.

Elevated CpG island methylation of GCK gene predicts the risk of type 2 diabetes in Chinese males.

BACKGROUNDnThe GCK gene encodes hexokinase 4, which catalyzes the first step in most glucose metabolism pathways. The purpose of our study is to assess the contribution of GCK methylation to type 2 diabetes (T2D).nnnMETHODS AND RESULTSnGCK methylation was evaluated in 48 T2D cases and 48 age- and gender-matched controls using the bisulphite pyrosequencing technology. Among the four CpG sites in the methylation assay, CpG4 and the other three CpGs (CpG1-3) were not in high correlation (r<0.5). Significantly elevated methylation levels of GCK CpG4 methylation were observed in T2D patients than in the healthy controls (P=0.004). A breakdown analysis by gender indicated that the association between CpG4 methylation and T2D was specific to males (P=0.002). It is intriguing that another significant male-specific association was also found between GCK CpG4 methylation and total cholesterol (TC) concentration (r=0.304, P=0.036).nnnCONCLUSIONnOur results showed that elevated GCK CpG4 methylation might suggest a risk of T2D in Chinese males. Gender disparity in GCK CpG4 methylation might provide a clue to elaborate the pathogenesis of T2D.

Genetic Associations with Diabetes: Meta-Analyses of 10 Candidate Polymorphisms

Aims The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility. Methods Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes. Results A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): NLRP1 rs12150220 (ORu200a=u200a0.71, 95% CIu200a=u200a0.55–0.92, Pu200a=u200a0.01), IL2RA rs11594656 (ORu200a=u200a0.86, 95% CIu200a=u200a0.82–0.91, P<0.00001), and CLEC16A rs725613 (ORu200a=u200a0.71, 95% CIu200a=u200a0.55–0.92, Pu200a=u200a0.01). APOA5 −1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes (T2D, ORu200a=u200a1.27, 95% CIu200a=u200a1.03–1.57, Pu200a=u200a0.03). No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C. Conclusion Our results demonstrated that IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 −1131T/C are risky factors of T1D and T2D, respectively.

The effect of environmental factors and DNA methylation on type 2: The effect of environmental factors and DNA methylation on type 2

Type 2 diabetes mellitus (T2DM) is a glucose metabolic disorder driven by both genetic and environmental factors. Recent DNA methylation studies have established that T2DM may be contributed by environmental factors through the regulation of DNA methylation. Human and animal model studies have made much progress on the interaction between DNA methylation of T2DM genes and environmental factors in multiple tissues. Current studies on DNA methylation of T2DM genes mainly focus on glucose and energy metabolism, inflammation, and so on. This review comprehensively introduces the DNA methylation studies for the genes involved in T2DM and its related environmental factors.

Landscape of the relationship between type 2 diabetes and coronary heart disease through an integrated gene network analysis.

Type 2 diabetes (T2D) and coronary artery disease (CAD) are closely related chronic diseases with high prevalence and morbidity. However, a comprehensive comparison of the two diseases is lacking. Recent genome-wide association studies (GWAS) have identified a handful of single nucleotide polymorphisms (SNPs) that are significantly associated with the risk of T2D and CAD. These most significant findings may help interpret the pathogenesis of T2D and CAD. However, tremendous results from these GWAS are ignored. Here we revisited the raw datasets of these GWAS and performed an integrated gene network analysis to unveil the relationship between T2D and CAD by combining multiple datasets including protein-protein interaction (PPI) database, publication libraries, and pathway datasets. Our results showed that majority of genes were involved in the first module (1122 genes in T2D and 895 in CAD). Four pathways were found to be common in both T2D and CAD, including regulation of actin cytoskeleton, calcium signaling pathway, MAPK signaling pathway and focal adhesion (all P<0.00001). MAX which was involved in small cell lung cancer pathway was a hub gene unique to T2D (OR=1.2, P=0.006) but not in CAD. In contrast, three hub genes including PLEKHG5 (T2D: OR=1, P=1; CAD: OR=1.12, P=0.006), TIAM1 (T2D: OR=1, P=1; CAD: OR=1.48, P=0.004) and AKAP13 (T2D: OR=1, P=1; CAD: OR=1.38, P=0.001) were hub genes unique to CAD. Moreover, for some hub genes (such as SMAD3) that were susceptible to both T2D and CAD, their associated polymorphisms were unique to each of the two diseases. Our findings might provide a landscape of the relationship between T2D and CAD.

Gender-dependent miR-375 promoter methylation and the risk of type 2 diabetes

Promoter DNA methylation may reflect the interaction between genetic background and environmental factors in the development of metabolic disorders, including type 2 diabetes (T2D). As an epigenetic factor of T2D, miR-375 plays an important role in the functional accommodation of islet cells. In the present study, we investigated the association of promoter DNA methylation of the miR-375 gene with the risk of T2D. Using bisulfite pyrosequencing technology, the DNA methylation levels of eight CpG dinucleotides on the miR-375 promoter were measured in 48 T2D cases and 48 healthy controls. The majority of CpGs (with the exception of CpG7) had significantly higher methylation levels in women compared with those in men (P<0.05). The methylation levels of the eight CpGs were significantly correlated with each other (P<0.001). No significant association between miR-375 gene promoter methylation and the risk of T2D was identified (P=0.417). Similar results were observed in the breakdown analysis by gender (men, P=0.844; women, P=0.234). In addition, although a correlation between the CpG8 methylation level of miR-375 and total triglyceride level was identified in women (P=0.009), DNA methylation of the majority of CpGs in the miR-375 gene promoter was not associated with the clinical metabolic features of the individuals.

Investigation into the promoter DNA methylation of three genes (CAMK1D, CRY2 and CALM2) in the peripheral blood of patients with type 2 diabetes.

Promoter DNA methylation may reflect the interaction between genetic backgrounds and environmental factors in the development of metabolic disorders, including type 2 diabetes (T2D). Calcium/calmodulin-dependent protein kinase 1D (CAMK1D), cryptochrome 2 (CRY2) and calmodulin 2 (CALM2) genes have been identified to be associated with a risk of T2D. Therefore, the aim of the present study was to investigate the contribution of promoter DNA methylation of these genes to the risk of T2D. Using bisulfite pyrosequencing technology, the DNA methylation levels of the CpG dinucleotides within the CAMK1D, CRY2 and CALM2 gene promoters were measured in 48 patients with T2D and 48 age- and gender-matched healthy controls. The results demonstrated that the promoters of these three genes were hypomethylated in the peripheral blood of all the subjects, and DNA methylation of these three genes did not contribute to the risk of T2D.

Meta-analyses between 18 candidate genetic markers and overweight/obesity

AimsThe goal of our study is to investigate the associations between 18 candidate genetic markers and overweight/obesity.MethodsA total of 72 eligible articles were retrieved from literature databases including PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. Meta-analyses of 18 genetic markers among 56,738 controls and 48,148 overweight/obese persons were done by Review Manager 5.0.ResultsOur results showed that SH2B1 rs7498665 polymorphism was significantly associated with the risk of overweight/obesity (overall odds ratio (OR)u2009=u20091.21, 95% confidence interval (CI)u2009=u20091.09-1.34, Pu2009=u20090.0004). Increased risk of overweight/obesity was also observed in FAIM2 rs7138803 polymorphism (overall ORu2009=u20091.11, 95% CIu2009=u20091.01-1.22, Pu2009=u20090.04).ConclusionOur meta-analyses have shown the important role of 2 polymorphisms (SH2B1 rs7498665 and FAIM2 rs7138803) in the development of overweight/obesity. This study highlighted the importance of above two candidate genes (SH2B1 and FAIM2) in the risk of overweight/obesity.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2785487401176182.

Population difference in the association of BDNF promoter methylation with mild cognitive impairment in the Xinjiang Uygur and Han populations

BACKGROUNDnMild cognitive impairment (MCI) is a clinical transitional stage between normal aging and Alzheimer disease, which leads to memory loss and a reduction in cognitive function. Brain derived neurotrophic factor (BDNF) plays an important role in neuronal development and plasticity. The aim of this study was to explore the association between BDNF promoter methylation and MCI in the Xinjiang Uygur and Han populations.nnnMETHODSnA DNA methylation assay using bisulfite pyrosequencing technology was performed on 96 Uygur and 96 Han Chinese individuals from Xinjiang province, China.nnnRESULTSnWe found a significantly higher BDNF methylation level in Han MCI cases than in Uygur MCI cases in males from Xinjiang province (p=0.022). In addition, the methylation level was significantly higher in Xinjiang Han healthy Chinese individuals (Northwestern China) than in Ningbo Han healthy Chinese individuals (Southeastern China) (Female and Male: p=1.17E-05; Female: p=0.020; Male: p=1.37E-04). But our results showed no significant association of BDNF methylation with MCI in either the Uygur or Han Chinese populations (p>0.05). Further gender-based subgroup analyses did not find any significant results (p>0.05).nnnCONCLUSIONnOur results indicate that different levels of BDNF methylation may be present in different populations and environments. This study also provides further information regarding the relationship between BDNF methylation levels and MCI in Xinjiang Uygur and Han ethnic groups.