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). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. 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 'EGFR'. 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.</p

Prognostic Factors for the Course of β Cell Function in Autoimmune Diabetes1

This study presents a 2-yr follow-up of 281 patients, aged 15–34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As); the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0.27; 0.16–0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51; 0.28–0.78 nmol/L; P &amp;lt; 0.001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20; 0.10–0.37 nmol/L; P = 0.0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2.6; 95% confidence interval, 1.7–4.0) and a high level of GADAs (odds ratio, 2.5; 95% confidence interval, 1.1–5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in β-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained β-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased β-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in β-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.</jats:p

Changes in 65-Kilodalton Glutamate Decarboxylase Antibody-Specific Antiidiotypic Antibody Levels Correlate with Changes in C-Peptide Levels and Progression to Islet Cell Autoimmunity

This article appears in The Journal of Clinical Endocrinology &amp; Metabolism. 10.1210/jc.2010-0785</jats:p