Polymorphisms of the glucose transporter (GLUT1) gene are associated with diabetic nephropathy

Polymorphisms of the glucose transporter (GLUT1) gene are associated with diabetic nephropathy.BackgroundDiabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with type 1 diabetes mellitus. Recent studies suggest that genetic factors, including polymorphisms in the flanking region of the aldose reductase gene (5′ALR2), play an important role in the pathogenesis of nephropathy. Glucose transporter (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. The aim was to investigate the frequency of a polymorphism within the GLUT1 gene in 186 Caucasoid patients with type 1 diabetes and 104 normal controls.MethodsAmplimers flanking the Xba-I polymorphic site in the second intron were employed to amplify DNA from subjects. The amplified DNA was restricted with endonuclease Xba-I, separated by gel electrophoresis, and visualized. In the absence of an Xba-I site, a fragment of 1.1 kilobase was seen, whereas fragments of 0.9 and 0.2 were generated if the Xba-I site was present.ResultsThere was a highly significant increase in the frequency of the 1.1 allele in those patients with nephropathy (N = 70) compared with those with no proteinuria or retinopathy after 20 years of diabetes (uncomplicated N = 44, 61.4 vs. 40.9%, respectively, P < 0.001). The 1.1/1.1 genotype was also significantly increased in the nephropathy group compared with the uncomplicated group of patients (37.1 vs. 13.6%, respectively, P < 0.01). The frequency of the 1.1/1.1 genotype was similar in 30 patients with retinopathy but not nephropathy when compared with the uncomplicated group of patients (13.6 vs. 16.7%). Furthermore, only 8 out of 49 patients with DN had the Z+2 5′ALR2 DN “protective” allele and the 0.9 GLUT1 allele in contrast to 21 out of 39 uncomplicated patients (P < 0.0002).ConclusionThese results suggest that the GLUT1 gene together with the aldose reductase gene are associated with susceptibility to DN in patients with type 1 diabetes

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Cytokine Gene Polymorphisms in Acute Pancreatitis

Context Pro-inflammatory and regulatory cytokines play a key role in the pathogenesis of acute pancreatitis. Genetic loci encoding cytokines have been shown to be polymorphic, in some cases influencing protein expression. Objective To investigate if TNF and IL-10 gene loci are associated with the occurrence or severity of acute pancreatitis. Setting Acute surgical unit within large district hospital serving a population of 500,000. Methods Three TNF microsatellite loci (TNFa, TNFb, TNFc), the TNF-308 polymorphism, the IL-10.G microsatellite locus, and 3 bi-allelic polymorphisms in the IL-10 5’ region were typed using PCR in 135 acute pancreatitis patients and ethnically matched normal controls (n=107). Aetiology of disease was determined and patients grouped according to disease severity by assigning an organ failure score or classification according to the Atlanta system. Main outcome measures Allelic frequency of polymorphic loci in patients with different aetiology and disease course in acute pancreatitis. Results No difference was noted in allelic frequency of any of the cytokine gene loci between groups stratified according to disease severity. When aetiology was studied again there was no significant difference in allelic frequency. Conclusions The cytokine gene polymorphisms studied play no part in determination of disease severity or susceptibility to acute pancreatitis.Image: Structural formula of Tumor necrosis factor-alpha (TNF-alpha) (Author: Doxepine; Wikimedia Commons

A predominantly Neolithic origin for European paternal lineages.

none16The relative contributions to modern European populations of Paleolithic hunter-gatherers and Neolithic farmers from the Near East have been intensely debated. Haplogroup R1b1b2 (R-M269) is the commonest European Y-chromosomal lineage, increasing in frequency from east to west, and carried by 110 million European men. Previous studies suggested a Paleolithic origin, but here we show that the geographical distribution of its microsatellite diversity is best explained by spread from a single source in the Near East via Anatolia during the Neolithic. Taken with evidence on the origins of other haplogroups, this indicates that most European Y chromosomes originate in the Neolithic expansion. This reinterpretation makes Europe a prime example of how technological and cultural change is linked with the expansion of a Y-chromosomal lineage, and the contrast of this pattern with that shown by maternally inherited mitochondrial DNA suggests a unique role for males in the transition.noneBalaresque P.; Bowden G.R.; Adams S.M.; Leung H-Y.; King T.E.; Rosser Z.H.; Goodwin J.; Moisan J-P.; Richard C.; Millward A.; Demaine A.G.; Barbujani G.; Previderè C.; Wilson I.J.; Tyler-Smith C.; and Jobling M.A.Balaresque, P.; Bowden, G. R.; Adams, S. M.; Leung, H. Y.; King, T. E.; Rosser, Z. H.; Goodwin, J.; Moisan, J. P.; Richard, C.; Millward, A.; Demaine, A. G.; Barbujani, Guido; Previderè, C.; Wilson, I. J.; Tyler Smith, C.; Jobling, M. A