1695-P: Genetic Determinants of Estimated Glomerular Filtration Rate (eGFR) in Type 1 Diabetes

Background and Aims: Diabetic kidney disease (DKD) is known to be heritable but few genetic determinants have been found. We performed a GWAS of eGFR in a large nationally representative cohort of people with type 1 diabetes (T1D): the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO).

Materials and Methods: The study included 5368 unrelated people with T1D. Samples were genotyped using the Illumina Human CoreExome array and imputed using the online service of the Sanger Institute. eGFR was calculated using the CKD-EPI equation. We modelled the most recent eGFR adjusted for age, sex and duration of diabetes. GWAS was performed with SNPTEST, adjusting for and first three principal components. The FUMA and GENOSCORES platforms were used to annotate GWAS findings.

Results: We identified two novel loci with GWAS significance for eGFR at p< 5x 10-8 and three suggestive loci at p<1x10-6. The GRM7 locus (lead SNP rs342036, p=1.2x10^-9) has previously been reported as a susceptibility locus for acute kidney injury in a GWAS of 1253 individuals of European ancestry. Multiple suggestive SNPs in this locus are QTL’s for EMILIN-3 protein and IGP63 IgG Glycan. The XRCC4 locus (SNP rs72767159, p=4.2x10^-8), involved in DNA repair, has not been reported associated with eGFR. The three suggestive loci were at the RBP7 (rs112409036, p=5.2x10^-7), PIP5K1B (rs10117043, p=4.4x10^-7) and LINC00871 (rs74891506, p=4.6x10^-7) genes. The lead SNP at RBP7 is a methylation QTL for RBP7. PIP5K1B was previously reported as a locus for diabetic nephropathy and the lead SNP is a QTL for the succinylcarnitine metabolite, previously associated with glycaemic control.

Conclusion: We identified two genome wide significant and three suggestive eGFR loci. Further functional analyses will including testing the utility of potential biomarkers in these pathways, such as EMILIN-3, IGP63 and succinylcarnitine, for DKD.