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Genome-wide association studies have shown that the rs340874 single nucleotide polymorphism (SNP) in PROX1 is a genetic susceptibility factor for type 2 diabetes. We conducted genetic and molecular studies to better understand the role of PROX1 in type 2 diabetes. We assessed the impact of the whole common genetic variability of PROX1 (80 SNPs) on type 2 diabetes--related biochemical traits in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study (n = 1,155). Three SNPs (rs340838, rs340837, and rs340836) were significantly associated with fasting plasma insulin levels (P ≤ 0.00295). We evaluated the impact of nine PROX1 SNPs (the three insulin-associated SNPs plus six SNPs in strong linkage disequilibrium) on luciferase reporter gene expression. The insulin-lowering alleles of rs340874, rs340873, and rs340835 were associated with lower luciferase activity in MIN6 and HepG2 cells (except for rs340874, which was in HepG2 cells only). Electrophoretic mobility shift assays indicated that specific nuclear protein bindings occur at the three SNPs in HepG2 cells, with allele-binding differences for rs340874. We also showed that the knockdown of Prox1 expression by small interfering RNAs in INS-1E cells resulted in a 1.7-fold reduction in glucose-stimulated insulin secretion. All together, we propose that reduced expression of PROX1 by cis-regulatory variants results in altered β-cell insulin secretion and thereby confers susceptibility to type 2 diabetes., Type 2 diabetes is a major public health issue that will affect >439 million people worldwide by 2030 (1) and is characterized by impaired β-cell function and insulin resistance, leading [...]

Previous studies have clearly demonstrated the beneficial effect of -blockers in patients with stable congestive heart failure (CHF). -blockers improve left ventricular ejection fraction (LVEF) and reduce cardiac mortality. However, there is an interindividual variability in the response to these agents. Two studies have suggested a possible impact of some functional AR gene polymorphisms on the effects of -blockade. The objective of the study is to analyse the association between genetic variations in the 1or the 2adrenoreceptor (AR) gene and the effects of -blockade in patients with stable CHF. We studied 199 consecutive patients with stable CHF not treated with -blockers. Before introduction of -blockers and 3 months after the maximal tolerated dose was reached, patients underwent an echocardiography and a radionuclide angiography. The 1ARGly389Arg, 1ARSer49Gly, 2ARGly16Arg, 2ARGln27Glu and 2ARThr164Ile polymorphisms were determined -blockade resulted in a significant decrease in heart rate, a significant increase in LVEF (from 30±10 to 40±13, P<0.0001). There was no association between the five polymorphisms and heart rate or LVEF, either before or after -blockade. Heart rate and LVEF responses to -blockade were not associated with the 1AR or the 2AR polymorphisms. AR polymorphisms did not explain the interindividual variability in the response to -blockers.

Background: The DD genotype for the angiotensin-I converting enzyme (ACE I) deletion allele (D) polymorphism is a possible genetic risk factor for restenosis after coronary stent implantation. We aimed to establish whether or not blockade of ACE with high doses of ACE inhibitors could reduce this risk of angiographic restenosis. Methods: We characterised the ACE I/D polymorphism in 345 consecutive patients who were undergoing coronary stenting. 115 had the DD genotype. We assigned 91 of these 115 patients to quinapril 40 mg daily (n=46) or placebo (n=45). Treatment was started within 48 h after stent implantation and continued for 6 months. 79 patients complied with the protocol and underwent follow-up angiography after 6 months. Findings: Our primary endpoint of late loss in minimum lumen diameter (a quantitative index of restenosis) was significantly higher in the quinapril group than in the controls (mean 1-11 mm [SD 0-70] vs 0-76 mm [0-60]; p=0-018). Secondary endpoints also showed consistent trends towards increased angiographic restenosis in the treatment group. Interpretation: Contrary to our expectations, ACE inhibitor treatment did not reduce restenosis after coronary stent implantation in patients with DD genotype, but was associated with an exaggerated restenotic process when compared with administration of placebo.