Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes.

AIMS/HYPOTHESIS: Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2. Carnosinase degrades carnosine (β-alanyl-L-: histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro- or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (D18S880, five to seven leucine repeats) in CNDP1 and CNDP2 in a case-control set-up including 4,888 unrelated type 2 diabetic patients (with and without nephropathy) from Sweden (Scania Diabetes Registry). RESULTS: Two SNPs, rs2346061 in CNDP1 and rs7577 in CNDP2, were associated with an increased risk of diabetic nephropathy (rs2346061 p = 5.07 × 10(-4); rs7577 p = 0.021). The latter was also associated with estimated GFR (β = -0.037, p = 0.014), particularly in women. A haplotype including these SNPs (C-C-G) was associated with a threefold increased risk of diabetic nephropathy (OR 2.98, 95% CI 2.43-3.67, p < 0.0001). CONCLUSIONS/INTERPRETATION: These data suggest that common variants in CNDP1 and CNDP2 play a role in susceptibility to kidney disease in patients with type 2 diabetes

Cell entry and trafficking of human adenovirus bound to blood factor X is determined by the fiber serotype and not hexon: heparan sulfate interaction

Human adenovirus serotype 5 (HAdV5)-based vectors administered intravenously accumulate in the liver as the result of their direct binding to blood coagulation factor X (FX) and subsequent interaction of the FX-HAdV5 complex with heparan sulfate proteoglycan (HSPG) at the surface of liver cells. Intriguingly, the serotype 35 fiber-pseudotyped vector HAdV5F35 has liver transduction efficiencies 4-logs lower than HAdV5, even though both vectors carry the same hexon capsomeres. In order to reconcile this apparent paradox, we investigated the possible role of other viral capsid proteins on the FX/HSPG-mediated cellular uptake of HAdV5-based vectors. Using CAR- and CD46-negative CHO cells varying in HSPG expression, we confirmed that FX bound to serotype 5 hexon protein and to HAdV5 and HAdV5F35 virions via its Gla-domain, and enhanced the binding of both vectors to surface-immobilized hypersulfated heparin and cellular HSPG. Using penton mutants, we found that the positive effect of FX on HAdV5 binding to HSPG and cell transduction did not depend on the penton base RGD and fiber shaft KKTK motifs. However, we found that FX had no enhancing effect on the HAdV5F35-mediated cell transduction, but a negative effect which did not involve the cell attachment or endocytic step, but the intracellular trafficking and nuclear import of the FX-HAdV5F35 complex. By cellular imaging, HAdV5F35 particles were observed to accumulate in the late endosomal compartment, and were released in significant amounts into the extracellular medium via exocytosis. We showed that the stability of serotype 5 hexon:FX interaction was higher at low pH compared to neutral pH, which could account for the retention of FX-HAdV5F35 complexes in the late endosomes. Our results suggested that, despite the high affinity interaction of hexon capsomeres to FX and cell surface HSPG, the adenoviral fiber acted as the dominant determinant of the internalization and trafficking pathway of HAdV5-based vectors

Sialosyllactotetraosylceramide, a novel ganglioside antigen detected in human carcinomas by a monoclonal antibody

AbstractA novel ganglioside was detected in a small cell lung carcinoma by TLC-immunostaining of gangliosides with a monoclonal antibody, the C-50 MAb. Structural characterization showed this ganglioside to be IV3NeuAc-LcOse4Cer, a hitherto unknown ganglioside. This ganglioside has also been detected as a minor component in many different carcinomas using the C-50 MAb. The normally dominant CA-50 ganglioside antigen is IV3NeuAc. III4Fuc-LcOse4Cer. Based upon solid-phase binding to IV3NeuAc, III4-LcOse4Cer and IV3NeuAc-LcOse4Cer it is concluded that the C-50 MAb recognizes an epitope present in sialylated type I carbohydrate chains

Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy.

Increased production of reactive oxygen species (ROS) has been suggested as a cause of diabetic complications. Uncoupling proteins (UCPs) have been ascribed a role in reducing the formation of ROS, and genetic variation in genes encoding for UCPs could thus be putative candidate genes for diabetic nephropathy. To test this hypothesis we searched for association between the A→G (−3862) variant in UCP1, the insertion/deletion (I/D) polymorphism in exon 8 in UCP2, and the C→T (−55) polymorphism in UCP3 and diabetic nephropathy in 218 diabetic patients with normal urinary albumin excretion rate (AER), 216 with micro- or macroalbuminuria, and in 106 control subjects without a family history of diabetes. We did not find any association between the different polymorphisms and diabetic nephropathy, nor did we observe any difference in AER among carriers of different UCP1–3 genotypes. We could, however, confirm the reported association between BMI and the UCP3 −55 C→T polymorphism; patients carrying the T allele had higher BMI than patients homozygous for the C allele (26.4±4.2 vs. 25.3±4.3 kg/m2; P=.01). We conclude that studied polymorphisms in the UCP1–3 genes do not play a major role in the development of micro- or macroalbuminuria in Scandinavian diabetic patients

Polymorphism in the MHC2TA Gene Is Associated with Features of the Metabolic Syndrome and Cardiovascular Mortality

BACKGROUND: Recently, a -168A→G polymorphism in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to myocardial infarction (MI). AIM: To confirm the association between the MHC2TA -168A→G polymorphism and MI and to study its putative role for microalbuminuria, the metabolic syndrome (MetS) and cardiovascular mortality. MATERIALS AND METHODS: Using an allelic discrimination method we genotyped 11,064 individuals from three study populations: 1) 4,432 individuals from the Botnia type 2 diabetes (T2D) study, 2) 1,222 patients with MI and 2,345 control subjects participating in the Malmö Diet and Cancer study and comprising an MI case-control sample, and 3) 3,065 T2D patients from the Local Swedish Diabetes registry. RESULTS: No association between the -168A→G polymorphism in MHC2TA and MI was observed. However, in the Botnia cohort the AG/GG genotypes were associated with cardiovascular mortality after MI (1.78 [1.09–2.92], p = 0.02). In addition, the AG/GG genotypes were more common in subjects with MetS (40.1% vs. 36.9%, p = 0.03) and in non-diabetic subjects with microalbuminuria (45.4% vs. 36.5%, p = 0.003) compared to control subjects. CONCLUSIONS: A polymorphism in MHC2TA was associated with cardiovascular mortality and predictors of cardiovascular mortality, microalbuminuria and MetS

Cell Entry and Trafficking of Human Adenovirus Bound to Blood Factor X Is Determined by the Fiber Serotype and Not Hexon:Heparan Sulfate Interaction

Human adenovirus serotype 5 (HAdV5)-based vectors administered intravenously accumulate in the liver as the result of their direct binding to blood coagulation factor X (FX) and subsequent interaction of the FX-HAdV5 complex with heparan sulfate proteoglycan (HSPG) at the surface of liver cells. Intriguingly, the serotype 35 fiber-pseudotyped vector HAdV5F35 has liver transduction efficiencies 4-logs lower than HAdV5, even though both vectors carry the same hexon capsomeres. In order to reconcile this apparent paradox, we investigated the possible role of other viral capsid proteins on the FX/HSPG-mediated cellular uptake of HAdV5-based vectors. Using CAR- and CD46-negative CHO cells varying in HSPG expression, we confirmed that FX bound to serotype 5 hexon protein and to HAdV5 and HAdV5F35 virions via its Gla-domain, and enhanced the binding of both vectors to surface-immobilized hypersulfated heparin and cellular HSPG. Using penton mutants, we found that the positive effect of FX on HAdV5 binding to HSPG and cell transduction did not depend on the penton base RGD and fiber shaft KKTK motifs. However, we found that FX had no enhancing effect on the HAdV5F35-mediated cell transduction, but a negative effect which did not involve the cell attachment or endocytic step, but the intracellular trafficking and nuclear import of the FX-HAdV5F35 complex. By cellular imaging, HAdV5F35 particles were observed to accumulate in the late endosomal compartment, and were released in significant amounts into the extracellular medium via exocytosis. We showed that the stability of serotype 5 hexon∶FX interaction was higher at low pH compared to neutral pH, which could account for the retention of FX-HAdV5F35 complexes in the late endosomes. Our results suggested that, despite the high affinity interaction of hexon capsomeres to FX and cell surface HSPG, the adenoviral fiber acted as the dominant determinant of the internalization and trafficking pathway of HAdV5-based vectors

Novel subgroups of adult-onset diabetes and their association with outcomes : a data-driven cluster analysis of six variables

Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA(1c), and homoeostatic model assessment 2 estimates of beta-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. Interpretation We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.Peer reviewe

Association between LTA, TNF and AGER Polymorphisms and Late Diabetic Complications

BACKGROUND: Several candidate genes on the short arm of chromosome 6 including the HLA locus, TNF, LTA and AGER could be associated with late diabetic complications. The aim of our study was therefore to explore whether polymorphisms (TNF -308 G-->A, LTA T60N C-->A and AGER -374 T-->A) in these genes alone or together (as haplotypes) increased the risk for diabetic complications. METHODOLOGY/PRINCIPAL FINDINGS: The studied polymorphisms were genotyped in 742 type 1 and 2957 type 2 diabetic patients as well as in 206 non-diabetic control subjects. The Haploview program was used to analyze putative linkage disequilibrium between studied polymorphisms. The TNF, LTA and AGER polymorphisms were associated with the HLA-DQB1 risk genotypes. The AGER -374 A allele was more common in type 1 diabetic patients with than without diabetic nephropathy (31.2 vs. 28.4%, p = 0.007). In a logistic regression analysis, the LTA but not the AGER polymorphism was associated with diabetic nephropathy (OR 2.55[1.11-5.86], p = 0.03). The AGER -374 A allele was associated with increased risk of sight threatening retinopathy in type 2 diabetic patients (1.65[1.11-2.45], p = 0.01) and also with increased risk for macrovascular disease in type 1 diabetic patients (OR 2.05[1.19-3.54], p = 0.01), but with decreased risk for macrovascular disease in type 2 diabetic patients (OR 0.66[0.49-0.90], p = 0.009). The TNF A allele was associated with increased risk for macrovascular complications in type 2 (OR 1.53 [1.04-2.25], p = 0.03, but not in type 1 diabetic patients. CONCLUSIONS/SIGNIFICANCE: The association between diabetic complications and LTA, TNF and AGER polymorphisms is complex, with partly different alleles conferring susceptibility in type 1 and type 2 diabetic patients. We can not exclude the possibility that the genes are part of a large haplotype block that also includes HLA-DQB1 risk genotypes