GENETICS RESEARCH PROGRAM
Diabetic kidney disease is a devastating disease affecting one third of the individuals with diabetes.
Elevated urinary albumin excretion rate (AER) is an early sign of diabetic kidney disease. We previously identified variants in the GLRA3 gene genome-wide significantly associated with AER in Finnish individuals with type 1 diabetes, but replication attempt in non-Finnish Europeans showed association in the opposite direction; we hypothesized a population-specific association, but the finding remained controversial. In this study, we confirmed the association in the GLRA3 locus in 1295 additional Finnish individuals with type 1 diabetes, with p=0.0013 for replication, and genome-wide significant p=4.2×10-10 after meta-analysis. Association was particularly strong in patients with elevated blood glucose levels (HbA1c ≥7%), suggesting a diabetes-specific association for albuminuria. In whole exome sequencing data (WES) for 328 individuals with type 1 diabetes, missense variants in the nearby ADAM29 gene were associated with AER (p=0.009) and modified the association between AER and rs10011025 (GLRA3). Even though further studies are needed to pinpoint the causal variants, dissecting the association at the GLRA3 locus may uncover novel molecular mechanisms for diabetic albuminuria irrespective of population background.
Sandholm N, Haukka J, Toppila I, Valo E, Harjutsalo V, Forsblom C, Groop P-H. Confirmation of GLRA3 as a susceptibility locus for albuminuria in Finnish patients with type 1 diabetes. Sci Rep 8: 12408, 2018 (doi: 10.1038/s41598-018-29211-1)