Genome-wide characterization of 54 urinary metabolites reveals molecular impact of kidney function.

Dissecting the genetic mechanisms underlying urinary metabolite concentrations can provide molecular insights into kidney function and open possibilities for causal assessment of urinary metabolites with risk factors and disease outcomes. Proton nuclear magnetic resonance metabolomics provides a high-throughput means for urinary metabolite profiling, as widely applied for blood biomarker studies. Here we report a genome-wide association study meta-analysed for 3 European cohorts comprising 8,011 individuals, covering both people with type 1 diabetes and general population settings.

Whole-exome and whole-genome sequencing of 1064 individuals with type 1 diabetes reveals novel genes for diabetic kidney disease.

Aims/hypothesis: Diabetic kidney disease (DKD) is a severe diabetic complication that affects one third of individuals with type 1 diabetes. Although several genes and common variants have been shown to be associated with DKD, much of the predicted inheritance remains unexplained. Here, we performed next-generation sequencing to assess whether low-frequency variants, extending to a minor allele frequency (MAF) ≤10% (single or aggregated) contribute to the missing heritability in DKD.

Medication profiling in women with type 1 diabetes highlights the importance of adequate, guideline-based treatment in low-risk groups.

Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map.

Rate of Kidney Function Decline is Associated With Kidney and Heart Failure in Individuals With Type 1 Diabetes.

Introduction: Diabetes is the most common cause of chronic kidney disease (CKD). Urinary albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR) are commonly used to monitor the onset and progression of diabetic kidney disease (DKD). We studied if the preceding rate of kidney function decline, that is, the eGFR slope, is independently associated with incident clinical cardiorenal events.

Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease.

Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome.

Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations.

Background: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism.

Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes.

Objective: Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D).

Research Design And Methods: We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.

Effect of serum sample storage temperature on metabolomic and proteomic biomarkers.

Prospective biomarker studies can be used to identify biomarkers predictive of disease onset. However, if serum biomarkers are measured years after their collection, the storage conditions might affect analyte concentrations. Few data exists concerning which metabolites and proteins are affected by storage at - 20 °C vs - 80 °C.

Genetic Risk Score Enhances Coronary Artery Disease Risk Prediction in Individuals With Type 1 Diabetes.

Objective: Individuals with type 1 diabetes are at a high lifetime risk of coronary artery disease (CAD), calling for early interventions. This study explores the use of a genetic risk score (GRS) for CAD risk prediction, compares it to established clinical markers, and investigates its performance according to the age and pharmacological treatment.

Research Design And Methods: This study in 3,295 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study (467 incident CAD, 14.

Urinary metabolite profiling and risk of progression of diabetic nephropathy in 2670 individuals with type 1 diabetes.

Aims/hypothesis: This prospective, observational study examines associations between 51 urinary metabolites and risk of progression of diabetic nephropathy in individuals with type 1 diabetes by employing an automated NMR metabolomics technique suitable for large-scale urine sample collections.

Methods: We collected 24-h urine samples for 2670 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy study and measured metabolite concentrations by NMR. Individuals were followed up for 9.

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 () with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (=1072 cases, 752 controls).

Novel Linkage Peaks Discovered for Diabetic Nephropathy in Individuals With Type 1 Diabetes.

Genome-wide association studies (GWAS) and linkage studies have had limited success in identifying genome-wide significantly linked regions or risk loci for diabetic nephropathy (DN) in individuals with type 1 diabetes (T1D). As GWAS cohorts have grown, they have also included more documented and undocumented familial relationships. Here we computationally inferred and manually curated pedigrees in a study cohort of >6,000 individuals with T1D and their relatives without diabetes.

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes.

Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict.

Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline.

Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus.

Aims: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied.

Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy.

Background: Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated.

Methods: We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years.

Biomarker panels associated with progression of renal disease in type 1 diabetes.

Aims/hypothesis: We aimed to identify a sparse panel of biomarkers for improving the prediction of renal disease progression in type 1 diabetes.

Methods: We considered 859 individuals recruited from the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) and 315 individuals from the Finnish Diabetic Nephropathy (FinnDiane) study. All had an entry eGFR between 30 and 75 ml min[1.

Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes.

Glycated hemoglobin (HbA) is an important measure of glycemia in diabetes. HbA is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA in a Finnish type 1 diabetes (T1D) cohort, FinnDiane.

Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy.

Objective: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts.

Research Design And Methods: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.

Confirmation of GLRA3 as a susceptibility locus for albuminuria in Finnish patients with type 1 diabetes.

Urinary albumin excretion is an early sign of diabetic kidney disease, affecting every third individual with diabetes. Despite substantial estimated heritability, only variants in the GLRA3 gene have been genome-wide significantly associated (p-value < 5 × 10) with diabetic albuminuria, in Finnish individuals with type 1 diabetes; However, replication attempt in non-Finnish Europeans with type 1 diabetes showed nominally significant association in the opposite direction, suggesting a population-specific effect, but simultaneously leaving the finding controversial. In this study, the association between the common rs10011025 variant in the GLRA3 locus, and albuminuria, was confirmed in 1259 independent Finnish individuals with type 1 diabetes (p = 0.

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

Identification 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).

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes.

Early Trichinella spiralis and Trichinella nativa infections induce similar gene expression profiles in rat jejunal mucosa.

Trichinella spiralis causes a significantly higher parasite burden in rat muscle than Trichinella nativa. To assess whether the difference in infectivity is due to the early intestinal response, we analyzed gene expression changes in the rat jejunum during Trichinella infection with a whole-genome microarray. The rats were euthanized on day five of infection, and their jejunal mucosa was sampled for microarray analysis.

ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression.

Aberrant ErbB2 receptor tyrosine kinase activation in breast cancer is strongly linked to an invasive disease. The molecular basis of ErbB2-driven invasion is largely unknown. We show that cysteine cathepsins B and L are elevated in ErbB2 positive primary human breast cancer and function as effectors of ErbB2-induced invasion in vitro.