Genetic Risk Factors for Kidney Function in Individuals with Type 1 Diabetes

BACKGROUND: Genetic risk factors underlying kidney disease in type 1 diabetes (T1D) remain poorly understood. We examined whether previously-established polygenic risk scores (PRS) for estimated glomerular filtration rate (eGFR) and albuminuria are associated with these measures in adults with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. METHODS: We applied eGFR and albuminuria PRS derived in general population cohorts to 1,304 DCCT/EDIC participants with genome-wide genotyping. We tested PRS associations with eGFR and urine albumin excretion rate (AER) as well as incident eGFR <60ml/min/1.73m2, AER >30mg/24h, and AER >300mg/24h. For consistency, PRS values were linearly transformed so higher scores corresponded to higher eGFR and AER. We also examined associations of kidney outcomes with rs55703767 in COL4A3, which has previously been associated with CKD in T1D. RESULTS: At DCCT baseline, participants had mean age 27 years; 53% were male. 49% of participants were randomized to intensive versus conventional glucose-lowering therapy. Participants were followed for median of (1st,3rd quartiles) 35 (33,37) years. The eGFR PRS was significantly associated with continuous eGFR (per 1 SD higher PRS 2.72 ml/min/1.73m2 higher [95% CI 2.05; 3.40]) and incident eGFR <60 ml/min/1.73m2 (HR=0.82 [95% CI 0.73,0.92]), but not consistently with albuminuria. There was no association with quantitative AER (2.42mg/24h [95% CI -1.86,6.89]) or sustained AER > 30mg/24h (HR=1.03. [95% CI 0.94,1.14]). The albuminuria PRS was significantly associated with incident AER >30mg/24h (HR=1.12 [95% CI 1.02,1.22]) but not continuous eGFR (0.49 ml/min/1.73m2 higher [95% CI -0.23,1.21]) or incident eGFR <60 ml/min/1.73m2 (HR=0.96 [95% CI 0.85,1.08]). Associations were similar in analyses stratified by DCCT treatment group assignment. rs55703767 was associated with lower incident macroalbuminuria in the overall cohort (HR=0.77 per minor allele [95% CI 0.59,0.99]), and upon stratification by DCCT treatment group assignment, only within the conventional and not intensive glucose-lowering therapy group. CONCLUSIONS: PRS associated with eGFR and albuminuria in the general population were associated with corresponding measures in adults with T1D. Results suggest shared genetic risk factors for kidney disease between T1D and the general population but different genetic risk factors for albuminuria and eGFR in T1D. CLINICAL TRIALS REGISTRATION NUMBERS: NCT00360893, NCT00360815.