Abstract
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 × 10−8) 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 = 0.0013), and meta-analysis of all Finnish individuals yielded a genome-wide significant association. The association was particularly pronounced in subjects not reaching the treatment target for blood glucose levels (HbA1c > 7%; N = 2560, p = 1.7 × 10−9). 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.
Highlights
Diabetic nephropathy (DN) is a devastating disease affecting one third of the individuals with diabetes, with up to 20% of subjects with type 1 diabetes developing end-stage renal disease (ESRD) requiring dialysis treatment or renal transplantation for survival[1]
We previously selected for replication three SNPs genome-wide significantly associated with albuminuria (p < 5 × 10−8), plus rs11725853 (p = 1.8 × 10−7), from the GLRA3 locus
We have previously identified genetic variants in the GLRA3 gene to be genome-wide significantly associated with AER in a Finnish genome-wide association studies (GWAS) discovery population, but we were not able to replicate the signal in 598 additional Finnish individuals with type 1 diabetes
Summary
Diabetic nephropathy (DN) is a devastating disease affecting one third of the individuals with diabetes, with up to 20% of subjects with type 1 diabetes developing end-stage renal disease (ESRD) requiring dialysis treatment or renal transplantation for survival[1]. Our previous GWAS on albuminuria, as measured by 24-hour AER, identified five single nucleotide polymorphisms (SNPs) in the GLRA3 gene that were associated with albuminuria with genome-wide significance (p-value = 1.5 × 10−9 for rs10011025) in Finnish individuals with type 1 diabetes in the Finnish Diabetic Nephropathy Study (FinnDiane). A replication attempt in 3152 non-Finnish European individuals with type 1 diabetes reached a nominally-significant p-value of 0.03 for a directly genotyped SNP, rs1564939 in the GLRA3 gene, but with the opposite allele associated with albuminuria than in the Finnish subjects. In order to study this topic further, we here assessed the associations of the previously identified genetic variants in additional Finnish individuals recently recruited into the FinnDiane study in order to confirm or to refute the role of these variants for AER in Finnish patients with type 1 diabetes. We further dissected the flanking region to detect low frequency and rare variants contributing to the association seen at the common rs10011025 variant
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