[Activation of renal outer medullary potassium channel in the renal distal convoluted tubule by high potassium diet].

Renal outer medullary potassium (ROMK) channel is an important K+ excretion channel in the body, and K+ secreted by the ROMK channels is most or all source of urinary potassium. Previous studies focused on the ROMK channels of thick ascending limb (TAL) and collecting duct (CD), while there were few studies on the involvement of ROMK channels of the late distal convoluted tubule (DCT2) in K+ excretion. The purpose of the present study was mainly to record the ROMK channels current in renal DCT2 and observe the effect of high potassium diet on the ROMK channels by using single channel and whole-cell patch-clamp techniques. The results showed that a small conductance channel current with a conductance of 39 pS could be recorded in the apical membrane of renal DCT2, and it could be blocked by Tertiapin-Q (TPNQ), a ROMK channel inhibitor. The high potassium diet significantly increased the probability of ROMK channel current occurrence in the apical membrane of renal DCT2, and enhanced the activity of ROMK channel, compared to normal potassium diet (P < 0.01). Western blot results also demonstrated that the high potassium diet significantly up-regulated the protein expression levels of ROMK channels and epithelial sodium channel (ENaC), and down-regulated the protein expression level of Na+-Cl- cotransporter (NCC). Moreover, the high potassium diet significantly increased urinary potassium excretion. These results suggest that the high potassium diet may activate the ROMK channels in the apical membrane of renal DCT2 and increase the urinary potassium excretion by up-regulating the expression of renal ROMK channels.

The association of six non-synonymous variants in three DNA repair genes with hepatocellular carcinoma risk: a meta-analysis.

Hepatocellular carcinoma is a complex polygenic disease. Despite the huge advances in genetic epidemiology, it still remains a challenge to unveil the genetic architecture of hepatocellular carcinoma. We, therefore, decided to meta-analytically assess the association of six non-synonymous coding variants from XRCC1, XRCC3 and XPD genes with hepatocellular carcinoma risk by pooling the results of 20 English articles. This meta-analysis was conducted according to the PRISMA statement, and data collection was independently completed in duplicate. In overall analyses, the minor alleles of four variants, Arg280His (odds ratio, 95% confidence interval, P: 1.37, 1.13-1.66, 0.001), Thr241Met (1.93, 1.17-3.20, 0.011), Asp312Asn (1.22, 1.08-1.38, 0.001) and Lys751Gln (1.42, 1.02-1.97, 0.038), were associated with the significant risk for hepatocellular carcinoma. There were low probabilities of publication bias for all variants. Subgroup analyses revealed significant association of XRCC1 gene Arg399Gln with hepatocellular carcinoma in Chinese especially from south China (odds ratio, 95% confidence interval, P: 1.57, 1.16-2.14, 0.004), in larger studies (1.48, 1.11-1.98, 0.007) and in studies with population-based controls (1.33, 1.06-1.68, 0.016). Taken together, our findings demonstrated that XPD gene Asp312Asn and XRCC1 gene Arg399Gln might be candidate susceptibility loci for hepatocellular carcinoma. Considering the ubiquity of genetic heterogeneity, further validation in a broad range of ethnic populations is warranted.

Fasting blood soluble RAGE may be causally implicated in impaired glucose metabolism in Chinese patients with primary hypertension.

We prepared to investigate the association of four well-defined polymorphisms in the receptor for advanced glycation end-products (RAGE) gene with the changes of fasting blood soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) and the risk for impaired glucose metabolism (IGM) in 1704 patients with primary hypertension, aiming to infer possible causality between sRAGE/esRAGE and IGM. This was a hospital-based case-control study, including 848 patients coexisting with IGM (the case group) and 856 patients with normal glucose tolerance (the control group). Fasting blood sRAGE and esRAGE concentrations were measured in 300 cases and 300 controls. There were significant differences in the genotypes/alleles of T-429C (rs1800625) and T-374A (rs1800624) polymorphisms between the case and control groups after Bonferroni correction (P<0.05/8). Adjusted estimates of above two polymorphisms for IGM risk were remarkably significant, especially under the recessive model (odd ratio [OR], 95% confidence interval [CI], P: 3.57, 1.95-5.18, 0.002 for T-429C and 3.49, 1.42-8.58, 0.007 for T-374A). Mean sRAGE and esRAGE concentrations were significantly higher in controls than in cases (P<0.001). Participants with the rs1800625 -429CC and -429TC genotypes had significantly lower sRAGE (417.3 and 473.6 vs. 502.3pg/mL, P<0.01) and esRAGE (230.1 and 298.0 vs. 340.4pg/mL, P<0.05) concentrations than those with the -429TT genotype in primary hypertensive patients with IGM. Further Mendelian randomization analysis revealed that per 100pg/mL reduction in fasting blood sRAGE and esRAGE was causally associated with 2.40-fold (95% CI: 1.46-3.94) and 2.65-fold (95% CI: 1.24-5.13) increased IGM risk, respectively. Our findings collectively demonstrate that fasting blood sRAGE and esRAGE may be causally implicated in IGM in primary hypertensive patients.

Genetic susceptibility of eight nonsynonymous polymorphisms in HLA-DRB1 gene to hepatocellular carcinoma in Han Chinese.

Backgrounds and Objective: Mounting evidence suggests that human leukocyte antigen (HLA) plays a central role in anti-virus and tumor defense. To test whether genetic variation in HLA-DRB1 gene, a key component of HLA system, can predict its predisposition to hepatocellular carcinoma (HCC), we thereby conducted an association study by genotyping 8 nonsynonymous polymorphisms in HLA-DRB1 gene among 257 HCC patients and 264 controls. RESULTS: All polymorphisms respected the Hardy-Weinberg equilibrium. The genotypes and alleles of rs17879599 differed significantly between patients and controls after Bonferroni correction (both P < 0.001), and the power to detect this significance was 94.4%. After adjusting for age, gender, smoking, drinking and hepatitis infection, the mutant allele of rs17879702 was significantly associated with an increased risk for HCC under additive (odds ratio [OR] = 2.12, 95% confidence interval [CI]: 1.20-4.02, P = 0.004) and dominant (OR = 2.51, 95% CI: 1.39-2.96, P = 0.004) models. Haplotype analysis indicated that haplotype A-T-C-T-G-C-T-A (alleles ordered by rs199514452, rs201540428, rs201614260, rs17879702, rs17880292, rs17879599, rs17424145 and rs35445101) was overrepresented in patients and enhanced predisposition to HCC (adjusted OR = 2.72, 95% CI: 1.24-5.78, P = 0.004). In cumulative analysis, carriers of 7-9 unfavorable alleles had a 2.41-fold (95% CI: 1.18-4.92, P = 0.016) increased risk for HCC after adjusting for confounding factors relative to those possessing 4 or less unfavorable alleles. MATERIALS AND METHODS: Genotypes were determined by ligase detection reaction. HCC patients were newly diagnosed, histopathologically confirmed or previously untreated and controls were cancer-free. CONCLUSIONS: Our findings suggest an independent leading contribution of rs17879599 in the 2nd exon of HLA-DRB1 gene to HCC risk in Han Chinese.

The association of three promoter polymorphisms in interleukin-10 gene with the risk for colorectal cancer and hepatocellular carcinoma: A meta-analysis.

Mounting evidence supports a potent inhibitory role of interleukin-10 (IL-10) in tumor carcinogenesis, angiogenesis and metastasis. This meta-analysis was designed to examine the association of three promoter polymorphisms (-592C > A, -819C > T and -1082G > A) in IL-10 gene with the risk for colorectal cancer and hepatocellular carcinoma. Qualification assessment and data collection were completed by two authors independently. The random-effects model using the DerSimonian and Laird method was fitted by the STATA software. Twenty-five articles involving 5933 cases and 9724 controls were meta-analyzed. Overall comparisons of the mutant alleles (-592A, -819T and -1082A) of three promoter polymorphisms with alternative wild alleles failed to reveal any statistical significance for both colorectal cancer and hepatocellular carcinoma (P > 0.05), and the likelihood of heterogeneity was low (I(2) < 50%). For -592C > A polymorphism, a significant risk for colorectal cancer was identified when analysis was restricted to East Asians (odds ratio or OR = 1.41, 95% confidence interval or CI: 1.18-1.68, P < 0.001) and retrospective studies (OR = 1.23, 95% CI: 1.09-1.39, P = 0.001). As weighed by the Egger's test and the fill-and-trim method, there was a low probability of publication bias for all studied polymorphisms. Our findings collectively suggest that the -592C > A polymorphism in IL-10 gene might be a susceptibility locus for colorectal cancer in East Asians.

The relationship between three X-linked genes and the risk for hypertension among northeastern Han Chinese.

BACKGROUND AND OBJECTIVE: Incidences of hypertension are increasing and this condition is more common in men than in women. We selected six well-characterized polymorphisms from three X-linked genes (ACE2, AGTR2, apelin) aiming to investigate their interactive association with hypertension among northeastern Han Chinese. METHODS AND RESULTS: This was a case-control study involving 1009 hypertensive patients and 756 normotensive controls. All polymorphisms except rs3761581 in the apelin gene satisfied the Hardy-Weinberg equilibrium in females. The genotype and allele distributions of rs1403543 in the AGTR2 gene and rs56204867 in the apelin gene differed significantly between patients and controls for both genders, even after the Bonferroni correction (P<0.05/6). The risk prediction was significant for rs1403543 and rs56204867 under both additive and dominant models for both genders. In haplotype analysis, significance was seen for haplotype G-T-G-G-A (alleles in order of rs1978124, rs2106809, rs1403543, rs5194 and rs56204867), which was overrepresented in patients (5.15% versus 1.10% in controls, PSim=0.004). Interaction analysis indicated that all derived multifactor dimensionality reduction (MDR) models were non-significant for both genders. CONCLUSION: Our findings demonstrate that genetic defects in AGTR2 and apelin genes by themselves may play an independent leading role in determining susceptibility to hypertension in both genders.

Genetic variants of the matrix metalloproteinase family genes and risk for hypertension: a case-control study among northeastern Han Chinese.

In this study, we sought to examine the association between 10 genetic variants in the matrix metalloproteinase (MMP) family genes and the risk of hypertension among northeastern Han Chinese. This was a hospital-based case-control study involving 1009 sporadic hypertensive patients and 756 age-, gender- and ethnicity-matched normotensive controls. The genotypes of the 10 examined variants were determined by PCR-ligase detection reaction method. The genotype/allele distributions of rs3025058 and rs679620 differed significantly between patients and controls, with a Bonferroni corrected α of 0.05/10. The probability of having hypertension was significant for rs3025058 under the additive (odds ratio; 95% confidence interval; P: 1.33; 1.16-1.53; <0.001) and dominant (1.43; 1.18-1.73; <0.001) models and was significant for rs679620 under the additive (1.27; 1.1-1.46; <0.001) model after adjusting for confounders. In a combined analysis, when compared with the reference group (score<3.5 for unfavorable genotypes), participants in the medium- and high-risk groups had odds ratios that increased to 1.61 (95% CI: 1.25-2.51; P<0.001) and 1.92 (95% CI: 1.54-2.39; P<0.001) after adjustment, respectively. Interaction analysis showed that a three-locus model including rs3025058, rs679620 and rs243865 was the best, with a maximum testing accuracy of 0.6605 and a cross-validation consistency of 10 (P=0.0022). Taken together, our findings suggest that the true association between individual variants and the risk of hypertension may not be revealed until combined analyses of multiple variants from genes involving a specific physiological or cellular function are performed. Moreover, we propose a three-locus model that can best characterize the genetic interactions of the MMP multiple gene family.

Interactive contribution of serine/threonine kinase 39 gene multiple polymorphisms to hypertension among northeastern Han Chinese.

Serine/threonine kinase 39 (STK39) gene has been reported to be a hypertension-susceptibility gene by a recent genome-wide association study in Western populations. To validate this finding in Chinese, we focused on five well-characterized common polymorphisms in STK39 gene to examine their potential association with hypertension in a large northeastern Han population. This is a hospital-based case-control study involving 1009 hypertensive patients and 756 normotensive controls. Data were analyzed by the Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. The genotype and allele distributions of rs6749447, rs3754777 and rs6433027 differed significantly between patients and controls (P < 0.001) even after the Bonferroni correction. The majority of derived haplotypes also showed remarkable differences between the two groups (P ≤ 0.001). As indicated by MDR analysis, a three-locus model including rs6749447, rs35929607 and rs3754777 was selected as the overall best with a larger testing accuracy of 0.7309 and a maximum cross-validation consistency of 10 (P < 0.001). The utility of this model was reinforced by a Logistic regression analysis. Taken together, our findings suggest the potential interactive role of STK39 gene multiple polymorphisms in the development of hypertension among northeastern Han Chinese.

Replication of the top 10 most significant polymorphisms from a large blood pressure genome-wide association study of northeastern Han Chinese East Asians.

The replication of genome-wide significant association signals in independent populations is a practical approach for characterizing gene-disease relationships. Therefore, we sought to explore the top 10 polymorphisms from a large blood pressure genome-wide association study of northeastern Han Chinese East Asians. This was a hospital-based study involving 1009 patients with essential hypertension and 756 normotensive controls from Qiqihar city, China. Genotyping was conducted with a polymerase chain reaction-ligase detection reaction method. All polymorphisms except for rs6825911 satisfied Hardy-Weinberg equilibrium. Overall, the genotype differences between the patients and controls were significant for rs35444 (P<0.001), rs11191548 (P=0.017) and rs17249754 (P=0.017). The per-minor-allele odds ratios of rs35444, rs11191548 and rs17249754 were 0.54 (95% confidence interval (95% CI): 0.46-0.62; P<0.01), 1.23 (95% CI: 1.07-1.43; P=0.005) and 1.23 (95% CI: 1.07-1.41; P=0.004), respectively. Similarly, the carriers of minor homozygotes had a significant reduction in adjusted systolic and diastolic blood pressure for rs35444 (P<0.01) but an increase for both rs11191548 (P<0.01) and rs17249754 (P<0.04). Further application of the genetic risk score method indicated that subjects with risk scores of 8, 10 and 12-16 had 1.66-fold (95% CI: 1.01-2.72), 1.72-fold (95% CI: 1.03-2.86) and 1.97-fold (95% CI: 1.12-3.46) increases, respectively, in the odds of developing hypertension, and similar increases were also observed for blood pressure. Taken together, our findings demonstrate that although only three of the top 10 polymorphisms were successfully validated in the northeastern Han Chinese population, the genetic risk score analyses led us to more profound insights into the possible joint effects of multiple polymorphisms on hypertension risk and blood pressure variation.

The contributory role of angiotensin receptor-like 1 gene multiple polymorphisms in hypertension among northeastern Han Chinese.

BACKGROUND AND OBJECTIVE: Via direct sequencing, we have recently identified six common polymorphisms in angiotensin receptor-like 1 (AGTRL1) gene, and found only two polymorphisms were significantly associated with hypertension in a family-based analysis on 1,015 southern Han Chinese. Extending our previous work and considering the ubiquity of epistasis in determining disease susceptibility, we, in this study, sought to explore the potential interaction of AGTRL1 gene six polymorphisms with hypertension in a large northeastern Han Chinese population. METHODS AND RESULTS: This was a case-control study involving 1,009 sporadic hypertensive patients and 756 normotensive controls. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. There were no deviations from Hardy-Weinberg equilibrium for all polymorphisms. The genotypes and alleles of rs7119675 and rs11544374 differed significantly between the two groups (P<0.0005), even after the Bonferroni correction. Under three genetic models, significant association was consistently observed for rs7119675 and rs11544374, and this association was independent of confounding factors. Taking rs7119375 as an example, the odds of having hypertension was 2.46 (95% confidence interval (95% CI): 2.06-2.94), 2.82 (95% CI: 2.29-3.46) and 3.97 (95% CI: 2.37-6.64) under additive, dominant and recessive models (P<0.001), respectively, whereas the adjusted risk estimates were slightly attenuated but still significant. The frequencies of most derived haplotypes differed significantly between patients and controls. Haplotype-phenotype analyses indicated marginal association for triglyceride (P(Sim)  = 0.011) and total cholesterol (P(Sim)  = 0.025) in patients and for triglyceride in controls (P(Sim) = 0.023). The overall best MDR model included rs11544374, rs7119375 and rs948847 with the maximal testing accuracy of 0.737 and cross-validation consistency of 10 out of 10 (P<0.0001). Further interaction entropy graph suggested that the interaction of rs7119375 with rs11544374 and rs948847 was strongly antagonized. CONCLUSIONS: Our findings demonstrate that AGTRL1 genetic polymorphisms might contribute to the development of hypertension independently and/or through complex interaction.

Synergistic association between two alcohol metabolism relevant genes and coronary artery disease among Chinese hypertensive patients.

OBJECTIVE: Coronary artery disease (CAD) is a multifactorial and polygenic disease. The aim of this study was to examine the association between six polymorphisms of four alcohol metabolism relevant genes (ADH1B, ADH1C, ALDH1b1, ALDH2) and the risk of CAD in Han Chinese. METHODS AND RESULTS: This was a hospital-based case-control study involving 1365 hypertensive patients. All study subjects were angiographically confirmed. Genotypes were determined with ligase detection reaction method. There was no observable deviation from the Hardy-Weinberg equilibrium for six examined polymorphisms in controls. The genotype and allele distributions of ALDH1b1 rs2073478 and ALDH2 rs671 polymorphisms differed significantly between the two groups (P≤0.005), even after the Bonferroni correction. The most common allele combination was A-C-C-G-C-G (alleles in order of rs1229984, rs1693482, rs2228093, rs2073478, rs886205, rs671) and its frequency was slightly higher in controls than in CAD patients (P = 0.067). After assigning the most common allele combination as a reference, allele combination A-C-C-T-C-A, which simultaneously possessed the risk alleles of rs2073478 and rs671 polymorphisms, was associated with a 1.80-fold greater risk of CAD. Further, a two-locus model including rs2073478 and rs671 that had a maximal testing accuracy of 0.598 and a cross-validation consistency of 10 (P = 0.008) was deemed as the overall best MDR model, which was further validated by classical Logistic regression model. CONCLUSION: Our findings provide clear evidence for both individual and interactive associations of ALDH1b1 and ALDH2 genes with the development of CAD in Han Chinese.

[Study on protective effect of vitamin E for ovarian grandlose cells and its mechanism in aged rats].

AIM: To observe the effect of vitamin E (VE) on ovarian apoptosis-related protein Bcl-2 and Bax and its impact on antioxidant capacity in aged female rats and to study the senility-delaying effect and mechanism of VE on ovary. METHODS: Natural aging female rats were given different doses of exogenous VE. Then apoptosis regulatory protein Bcl-2, Bax expression in ovarian grandlose cells were detected by using immunohistochemical methods and Western blot. The contents of serum total superoxide dismutase (SOD) activity and malondialdehyde (MDA) were detected by using biochemical methods. RESULTS: Contrasted with adult control group, the level of Bcl-2 expression in Senile control group was lower and the level of Bax expression was higher (P < 0.01), Serum SOD activity decreased and the level of MDA significantly increased (P < 0.01). Contrasted with senile control group, the level of Bcl-2 expression increased in VE group, the level of Bax expression decreased (P < 0.05), the level of MDA expression significantly decreased (P < 0.01). CONCLUSION: VE can regulate apoptosis-related protein Bcl-2, Bax expression and confront free radical damage which contribute to a protective effect for ovarian grandiose cells.

[Effects of vitamin E on expression of PS-1 and production of Abeta in the hippocampus of female senile rats].

AIM: To observe the expression of Presenilin-1 (PS-1) and production of amyloid beta-protein (Abeta) in hippocampus of female senile rats and to investigate the effect of vitamin E(VE) on preventing Alzheimer's disease after menopause. METHODS: The animal model was established using female senile rats. Experimental groups (n=8) were respectively given different doses of VE(5 mg/kg, 15 mg/kg, 60 mg/kg) per day. The expression of PS-1 in hippocampus was detected by immunohistochemistry, the level of Abeta in hippocampus was measured by Radioimmunoassay, and neuronal ultrastructure in hippocampal DG area was observed using transmission electron microscope. RESULTS: The expression of PS-1 in rat hippocampus of senile control group was stronger than that of adult control group. PS-1 expressed weakly in three medication groups along with augmentation of dosage. The levels of Abeta were found to correlate statistically with the expression of PS-1. The content of Abeta in VE groups was significantly decreased compared to that in senile control group (P < 0.01). There were some changes in the neuronal ultrastructure of senile rats. Neurons were gradually recovered in VE groups. CONCLUSION: VE may depress the production of Abeta by regulating the expression of PS-1, reducing neuronal injuries. VE may play a role in neuronal protection.