Mapping shared genetic determinants of eGFR and albuminuria with a focus on type 2 diabetes: a large-scale European study

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) is a global health and economic burden, particularly among individuals with type 2 diabetes (T2D). According to Kidney Disease: Improving Global Outcomes guidelines, key CKD indicators include urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Although independent genetic loci for these traits have been reported, their shared genetic architecture remains insufficiently understood. We hypothesized that there are shared genetic markers of kidney function (eGFR) and albuminuria generally, but also specific to the T2D population.

METHODS: We conducted a cross-sectional observational study including 432 451 UK Biobank participants of primarily European descent (94%), with a subgroup of 16 265 with T2D after data quality control. We examined whether 423 single-nucleotide polymorphisms previously associated with eGFR in a large genome-wide association study meta-analysis were associated with (a) eGFR estimated using the 2021 race-free CKD-Epidemiology Collaboration creatinine equation (eGFR2021) and (b) UACR. Multiple linear regression models were adjusted for systolic blood pressure, age, sex, and the first 10 genetic principal components to account for population stratification. Analyses were performed using Python and R. Bonferroni correction (BC) was performed. For the T2D subgroup, the models were additionally adjusted for body mass index and glycated hemoglobin.

RESULTS: In the overall population, 422 loci were nominally associated with eGFR2021, of which 75 were nominally associated with UACR (p≤0.05); 12 remained significant after BC (Pb ≤ [Formula: see text]). In the T2D subgroup, 76 loci nominally associated with eGFR2021, six also associated nominally with UACR (p≤0.05), and one remained significant after BC (Pb ≤ [Formula: see text]). Two pleiotropic loci (GSTA2, USP2-AS1) suggested diabetes-specific effects.

CONCLUSION: This study identifies several shared genetic loci underlying eGFR and UACR in both general and T2D European populations. These findings highlight common pathobiological pathways between albuminuria and reduced kidney function and provide a genetic map that may inform future CKD risk stratification and towards the development of therapeutic targets.