Redox Genetic Risk Score and the Incidence of End-Stage Kidney Disease in People with Type 1 Diabetes

Abstract

End-stage kidney disease (ESKD) is a multifactorial condition influenced by genetic background, but the extent to which a genetic risk score (GRS) improves ESKD prediction is unknown. We built a redox GRS on the base of previous association studies (six polymorphisms from six redox genes) and tested its relationship with ESKD in three cohorts of people with type 1 diabetes. Among 1012 participants, ESKD (hemodialysis requirement, kidney transplantation, eGFR < 15 mL/min/1.73 m2) occurred in 105 (10.4%) during a 14-year follow-up. High redox GRS was associated with increased ESKD risk (adjusted HR for the upper versus the lowest GRS tertile: 2.60 (95% CI, 1.51–4.48), p = 0.001). Each additional risk-allele was associated with a 20% increased risk of ESKD (95% CI, 8–33, p < 0.0001). High GRS yielded a relevant population attributable fraction (30%), but only a marginal enhancement in c-statistics index (0.928 [0.903–0.954]) over clinical factors 0.921 (0.892–0.950), p = 0.04). This is the first report of an independent association between redox GRS and increased risk of ESKD in type 1 diabetes. Our results do not support the use of this GRS in clinical practice but provide new insights into the involvement of oxidative stress genetic factors in ESKD risk in type 1 diabetes.