G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) (P = 1.0 × 10⁻⁴). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30–2.05], P = 2.3 × 10⁻⁵).CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.Diabetic nephropathy, characterized by persistent albuminuria, a relentless decline in glomerular filtration rate and raised arterial blood pressure, affects approximately one-third of patients with diabetes (1). Nephropathy accounts for 40% of end-stage renal disease and is associated with high cardiovascular morbidity and mortality (2). Epidemiological and familial studies suggest that genetic factors influence the risk of diabetic nephropathy in both type 1 and type 2 diabetic patients (3–6). Despite rapid research progress, robust predictors of this complication are still lacking.Phenotypic characterization of nephropathy is more accurate in patients with type 1 diabetes than in those with type 2 diabetes, where the kidney failure may often be caused by nondiabetic factors, mainly hypertension. Using a concerted effort including 2,499 patients with type 1 diabetes from the Danish, Finnish, and French populations, the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) consortium has established a large study for association with diabetic nephropathy that includes 1,176 case subjects and 1,323 control subjects (7). Single nucleotide polymorphisms (SNPs) located in 127 candidate genes selected through assessment of linkage studies, knowledge of metabolic pathways, and animal models were sought for association with nephropathy.     

Deficit of NMDA receptor activation in CA1 hippocampal area of aged rats is rescued by D-cycloserine

Activation of the glycine modulatory site of the N-methyl-D-aspartate glutamate receptor (NMDAR) may reduce cognitive impairments associated with normal ageing. In order to test this hypothesis, we assessed the effects of the partial agonist D-cycloserine (DCS) on cellular activities involved in memory formation. This was performed in CA1 cellular networks of adult and aged Sprague-Dawley rat hippocampal slices using extracellular field excitatory postsynaptic potential recordings. Synaptic potentials specifically mediated by NMDAR were significantly reduced in aged animals. DCS increased the magnitude of these responses in both adult and old rats but this effect was significantly higher in the latter, thus reversing the age-related decrease in NMDAR synaptic potentials. NMDAR-mediated theta burst long-term potentiation (TBS-LTP) as well as long-term depression (LTD) of synaptic transmission, prominent models for the cellular basis of learning and memory, were also weakened in aged animals. Age-related alterations of both forms of synaptic plasticity were rescued by DCS. In addition, the DCS-induced decrease in basal fast glutamatergic neurotransmission involving the activation of inhibitory glycinergic receptors, previously reported in young rats (Rouaud & Billard, 2003), was severely attenuated in aged animals. In summary, our results indicate that the facilitation of NMDAR activation through its glycine-binding site rescues the age-related deficit of cellular mechanisms of learning and memory. Such physiological evidences suggest that this modulation site of NMDAR represents an important target to alleviate cognitive deficits associated with normal ageing.     

Comparison of weight gain and energy intake after subthalamic versus pallidal stimulation in Parkinson's disease

To compare body mass index (BMI) and daily energy intake (DEI) after subthalamic versus pallidal deep brain stimulation (DBS). Weight gain following DBS in Parkinson's disease patients remains largely unexplained and no comparison of subthalamic and pallidal (GPi) stimulation has yet been performed. BMI and DEI, dopaminergic drug administration and motor scores were recorded in 46 patients with PD before STN (n = 32) or GPi (n = 14) DBS and 3 and 6 months after. At M6, BMI had increased by an average of 8.4% in the STN group and 3.2% in the GPi group. BMI increased in 28 STN and 9 GPi patients. This increase was significantly higher in the STN group (P < 0.048) and the difference remained significant after adjustment for reduced dopaminergic medication; 28.6% of GPi patients were overweight at 6 months (14.3% preoperatively) versus 37.5% of STN patients (21.9% preoperatively). Changes in BMI were negatively correlated with changes in dyskinesia in the GPi–DBS group. Food intake did not change in the two groups, either quantitatively or qualitatively. Frequent weight gain, inadequately explained by motor improvement or reduced dopaminergic drug dosage, occurred in subthalamic DBS patients. The difference between groups suggests additional factors in the STN group, such as homeostatic control center involvement. © 2009 Movement Disorder Society