Xiaocui Chen

TT genotype of rs2941484 in the human HNF4G gene is associated with hyperuricemia in Chinese Han men

The aim of the study is to investigate the association between the human hepatocyte nuclear factor 4 gamma (HNF4G) gene and hyperuricemia in Chinese Han population. A total of 414 hyperuricemia patients and 406 gender and age-matched normouricemic controls were enrolled. Four single nucleotide polymorphisms were genotyped as genetic markers for the human HNF4G gene (rs2977939, rs1805098, rs2941484, rs4735692). Data were analyzed for two separate groups: men and women. For rs2941484, the genotype distribution frequency in hyperuricemic subjects and was significantly different from that in normouricemic controls in men (P = 0.038). Meanwhile, in recessive model of rs2941484, the distribution frequency of TT genotype and CC+CT genotypes also differed significantly between the hyperuricemia men and normouricemic men (P = 0.011). For the other 3 SNPs in both men and women, there was no difference in the genotype and allele and distribution frequency between the hyperuricemia patients and normouricemic controls. In men, after adjustments for BMI, SBP, DBP, fasting glucose, total cholesterol, triglycerides, low density lipoprotein cholesterol and creatinine, the men with the TT genotype of rs2941484 were found to have significantly higher probability of suffering from hyperuricemia than the ones with CT and CC genotypes (OR = 2.170, P < 0.001). Therefore, TT genotype of rs2941484 in the human HNF4G gene might be a gender-specific genetic marker for hyperuricemia in Chinese Han men.

CYP19A1 polymorphisms associated with coronary artery disease and circulating sex hormone levels in a Chinese population

Background The relationship between CYP19A1 genetic polymorphisms and coronary artery disease (CAD) remains unclear. Thus, the aim of the present study was to investigate the association of CYP19A1 genetic polymorphisms with CAD in Han and Uygur populations and to characterize the association between the levels of sex hormones and aromatase with single-nucleotide polymorphisms (SNPs) in CYP19A1 genes in Chinese women. Results There were significant differences in the genotype distributions of rs2236722 and rs4646 between CAD patients and control subjects in the Uygur population. The rs4646 was found to be associated with CAD in the dominant model (CC vs. CA + AA) and the additive model (CA vs. CC + AA) (both P ≤ 0.001). The difference remained statistically significant after multivariate adjustment (OR = 0.483, 95% CI: 0.338–0.690, P = 0.000; and OR = 1.844, 95% CI: 1.300–2.617, P = 0.001, respectively). In normal Uygur postmenopausal women, there were significant differences in the genotype distributions of rs4646 and the circulating hormone and aromatase levels between CAD patients and control subjects. The differences in estradiol and aromatase levels remained statistically significant after multivariate adjustment (OR = 0.889, 95% CI: 0.817–0.969, P = 0.007; and OR = 0.947, 95% CI: 0.936–0.957, P = 0.000, respectively). Additionally, there were differences in sex hormone levels between the different ethnicities among the Xinjiang Chinese population. Materials and Methods Among a total of 1,064 Han individuals (614 men and 450 women) and 790 Uygur individuals (484 men and 306 women), 498 postmenopausal women (265 Han and 233 Uygur individuals) were selected. Four SNPs (rs2236722, rs2304463, rs4646, and rs4275794) were genotyped using the improved multiplex ligation detection reaction (iMLDR) technique. The estradiol and testosterone levels were determined using a radioimmunoassay based on GC-2016γ. In addition, an enzyme-linked immunosorbent assay (ELISA) was performed to determine the serum P450 aromatase levels. Conclusions The results of this study indicate that the rs2236722 and rs4646 of the CYP19A1 gene are associated with CAD and circulating sex hormone levels in the Xinjiang population of China.

Mutant DD genotype of NFKB1 gene is associated with the susceptibility and severity of coronary artery disease

Nuclear factor κappa B (NF-κB) is an important transcription factor in the development and progression of coronary artery disease (CAD). Recent evidence suggests that -94 ATTG ins/del mutant in the promoter of NFKB1 gene is an essential functional mutant. The present study demonstrated the frequencies of the del/del (DD) genotype and del (D) allele were significantly higher in CAD patients than in controls. CAD patients carrying mutant DD genotype had worse stenosis of diseased coronary arteries compared to those carrying ins/ins (II) or ins/del (ID) genotype. Plasma levels of endothelial nitric oxide synthase (eNOS) were lower, while inflammatory cytokine incnterlukin-6 (IL-6) was higher in CAD patients with DD genotype than those with II or ID genotype (both P<0.05). In vitro study showed that mutant human umbilical vein endothelial cells (DD genotype HUVECs) were more susceptible to H2O2-induced apoptosis, which was accompanied with a decreased Bcl-2 expression. Further, mutant HUVECs had lower eNOS but higher IL-6 mRNA levels and decreased phosphorylation of eNOS under H2O2-stimulation (both P<0.05). Compared to wild type cells (II genotype), significantly downregulated protein expression of total NF-κB p50 subunit were observed in mutant HUVECs with or without oxidative stress, and a lower expression of unclear p50 was associated with a decreased p50 nuclear translocation in mutant HUVECs versus wild type cells under H2O2-stimulation (both P<0.05). In conclusion, mutant DD genotype of NFKB1 gene is associated with the risk and severity of CAD. Dwonregulation of NF-κB p50 subunit leads to exacerbated endothelial dysfunction and apoptosis and enhanced inflammatory response that is the potential underlying mechanism.

Co-expression of Akt1 and Wnt11 promotes the proliferation and cardiac differentiation of mesenchymal stem cells and attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis

Mesenchymal stem cells (MSCs) transplantation has emerged as a promising therapeutic strategy for acute myocardial infarction. However, there are still limitations for this therapy, such as low survival rate and poor cardiac differentiation potential of MSCs. In this study, we genetically engineered MSCs using ex vivo adeno-associated virus (AAV) transduction to overexpress Akt1 and Wnt11, which are well-characterized genes involved in MSC proliferation and cardiac differentiation. Our results showed that infection with AAV-Akt1-Wnt11 significantly upregulated the growth and proliferation of MSCs, as compared with those infected with AAV-Akt1 or AAV-Wnt11. In addition, co-expression of Akt1 and Wnt11 markedly promoted the expression of cardiac markers including NK2 transcription factor related 5, GATA-binding protein 4, α-myosin MHC and brain natriuretic protein. Notably, co-expression of Akt1 and Wnt11 increased cell survival and reduced cell apoptosis of MSCs under hypoxia/reoxygenation (H/R) treatment; however, these effects were blocked by Wnt11 neutralizing antibodies or Akt1 inhibitor. Moreover, co-culture of cardiomyocytes with MSCs infected with AAV-Akt1-Wnt11, in a dual chamber system, significantly reduced H/R-induced cell apoptosis compared with those co-cultured with MSCs infected with AAV-Akt1 or AAV-Wnt11. Overall, our results showed that MSCs, co-expressing Akt1 and Wnt11, showed greater survival and cardiac differentiation under H/R conditions and effectively ameliorated H/R-induced cardiomyocyte apoptosis in vitro. Our study suggests that transplantation of MSCs genetically engineered with AAV-Akt1-Wnt11 is a promising therapeutic strategy for treatment of acute myocardial infarction.