Genetic variants in the epithelial sodium channel associate with oedema in type 2 diabetic patients receiving the peroxisome proliferator-activated receptor gamma agonist farglitazar (original) (raw)
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Clinical Chemistry, 2002
Background: The epithelial sodium channel (ENaC) is composed of three homologous subunits: α, β, and γ. Mutations in the Scnn1b and Scnn1g genes, which encode the β and the γ subunits of ENaC, cause a severe form of hypertension (Liddle syndrome). The contribution of genetic variants within the Scnn1a gene, which codes for the α subunit, has not been investigated. Methods: We screened for mutations in the COOH termini of the α and β subunits of ENaC. Blood from 184 individuals from 31 families participating in a study on the genetics of hypertension were analyzed. Exons 13 of Scnn1a and Scnn1b, which encode the second transmembrane segment and the COOH termini of α- and β-ENaC, respectively, were amplified from pooled DNA samples of members of each family by PCR. Constant denaturant capillary electrophoresis (CDCE) was used to detect mutations in PCR products of the pooled DNA samples. Results: The detection limit of CDCE for ENaC variants was 1%, indicating that all members of any ...
Clinical chemistry, 2002
The epithelial sodium channel (ENaC) is composed of three homologous subunits: alpha, beta, and gamma. Mutations in the Scnn1b and Scnn1g genes, which encode the beta and the gamma subunits of ENaC, cause a severe form of hypertension (Liddle syndrome). The contribution of genetic variants within the Scnn1a gene, which codes for the alpha subunit, has not been investigated. We screened for mutations in the COOH termini of the alpha and beta subunits of ENaC. Blood from 184 individuals from 31 families participating in a study on the genetics of hypertension were analyzed. Exons 13 of Scnn1a and Scnn1b, which encode the second transmembrane segment and the COOH termini of alpha- and beta-ENaC, respectively, were amplified from pooled DNA samples of members of each family by PCR. Constant denaturant capillary electrophoresis (CDCE) was used to detect mutations in PCR products of the pooled DNA samples. The detection limit of CDCE for ENaC variants was 1%, indicating that all members o...
Journal of Human Genetics, 2012
Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria-and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at À1254 G4A showed significantly higher frequency compared with NC (P ¼ 0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P ¼ 0.031). In vitro functional study demonstrated that the À1254 G allele had lower luciferase activity (Po0.001) in HMC-1 cells. EMSA finding showed that PTGER4 À1254 G produced a specific band. Significantly decreased PTGER4 expression (P ¼ 0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P ¼ 0.001). The PTGER4 À1254 G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.
The Journal of Clinical Endocrinology & Metabolism, 2006
Context: Activation of peroxisome proliferator-activated receptors (PPARs)-␥ by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPAR␣/␥ agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema are worrying side effects with these drugs. Objective: The objective of the present study was to investigate any variation in the PPARG and PPARA genes associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPAR␣/␥ agonist ragaglitazar. Design: Single-nucleotide polymorphism and haplotype analyses of the PPARA and PPARG genes were performed on DNA obtained from 345 type 2 diabetic patients randomized to 26-wk monotherapy with the dual-acting PPAR␣/␥ agonist ragaglitazar. Results: At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar, and Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as biologically the most important risk factor (hazard ratio 4.42, P ϭ 0.0081) for edema. Other risk factors included female gender (hazard ratio 3.34, P ϭ 0.0005) and weight change during treatment (hazard ratio 1.20, P ϭ 0.0017). Conclusions: A population-attributable risk of approximately 50% for the Pro12Pro genotype indicates that testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPAR␥ agonist-induced fluid retention and edema in patients with type 2 diabetes.
The Pharmacogenomics Journal
Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p
Clinical and experimental nephrology, 2002
Mutations have been found only in exons 8 and 12 of the β-subunit of the epithelial sodium channel (βENaC), but the presence of other mutations in the remaining exons remains to be determined in the Japanese population. New cases with the V434M mutation should be identified because the identified individuals have high plasma sodium concentration Exons 1 to 7 and 9 to 11 were screened by using single-strand conformational polymorphism (SSCP) in 200 subjects (100 normotensive and 100 hypertensive) randomly selected from 1245 participants in a community-based cohort study (Ohasama study) in northern Japan Four novel mutations were detected in exons 5, 6, and 7, and one of them was the novel missense mutation, P369H in exon 6. Then extended investigation of this mutation, together with those of V434M and P592S, which were identified in our previous studies, was performed in 1245 subjects. The final frequency of these mutations was 1/1245 for P369H, 5/1245 for V434M, and 5/1245 for P592S...
The pharmacogenomics journal, 2016
We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a β-blocker-based strategy (β-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10(-)(8)). rs11124945 G allele carriers had lower odds for NOD when exposed to the β-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10(-)(5)), whereas A/A homozygotes exposed to the β-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10(-)(4))...
American Journal of Hypertension, 2000
We evaluated the association of a common polymorphism in ␥ENaC, consisting in a C to G transversion in codon 649, with essential hypertension and to the pressor response to salt in whites. Two hundred fifteen essential hypertensive patients, and 137 normotensive controls were genotyped for the ␥649 ENaC polymorphism by polymerase chain reaction method and diagnostic restriction enzyme digestion. The genotype distribution of the ␥649 ENaC polymorphism in the hypertensives, 129 CC (60%) and 86 CG/GG (40%) was not significantly different from that of the control group, 84 CC (61%) and 53 CG/GG (39%) (P ؍ ؍ .81). Salt sensitivity was assessed in a group of 48 patients by 24-h mean blood pressure response to changes in salt intake. Nineteen patients were diagnosed as salt sensitive, whereas 29 had salt-resistant hypertension. The ␥649 ENaC genotype distribution in salt-sensitive patients was 12 CC (63%) and 7 CG/GG (37%), not significantly different from the distribution in the salt-resistant group, 19 CC (65%) and 10 CG/GG (35%), P ؍ ؍ .87. The changes in systolic, diastolic, and mean blood pressure as measured by ambulatory blood pressure monitoring, and in plasma renin activity and plasma aldosterone induced by high salt diet were not different among the ␥649 ENaC genotypes. In the present study we found no association between the ␥649 ENaC polymorphism and essential hypertension or salt sensitivity. Although these data do not support a major causative role for this polymorphism, we cannot exclude that a functional mutation elsewhere in ENaC might be associated with essential hypertension.
The Journal of Membrane Biology, 2010
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARc) agonists used to treat type 2 diabetes. TZD treatment induces side effects such as peripheral fluid retention, often leading to discontinuation of therapy. Previous studies have shown that PPARc activation by TZD enhances the expression or function of the epithelial sodium channel (ENaC) through different mechanisms. However, the effect of TZDs on ENaC activity is not clearly understood. Here, we show that treating Xenopus laevis oocytes expressing ENaC and PPARc with the TZD rosiglitazone (RGZ) produced a twofold increase of amiloride-sensitive sodium current (Iam), as measured by two-electrode voltage clamp. RGZinduced ENaC activation was PPARc-dependent since the PPARc antagonist GW9662 blocked the activation. The RGZ-induced Iam increase was not mediated through direct serum-and glucocorticoid-regulated kinase (SGK1)dependent phosphorylation of serine residue 594 on the human ENaC a-subunit but by the diminution of ENaC ubiquitination through the SGK1/Nedd4-2 pathway. In accordance, RGZ increased the activity of ENaC by enhancing its cell surface expression, most probably indirectly mediated through the increase of SGK1 expression.