Genetic risk score for plasma uric acid levels is associated with early rapid kidney function decline in type 2 diabetes

• Main Authors: Gurung, Resham Lal, Yiamunaa, M., Liu, Jian-Jun, Dorajoo, Rajkumar, Wang, Jiexun, Wang, Ling, Liu, Sylvia, Chan, Clara, Ang, Keven, Shao, Yi-Ming, Subramaniam, Tavintharan, Tang, Wern E., Sum, Chee Fang, Lim, Su Chi
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Medicine; Uric Acid; Genetic Risk Score
• Online Access: https://hdl.handle.net/10356/163889
• Institution: Nanyang Technological University

Context: Observational studies have shown that elevated uric acid (UA) is associated with chronic kidney disease (CKD). However, whether the relationship is causal remains unclear. Objective: To determine the association of plasma UA and incident CKD and the causal relationship between plasma UA and rapid decline in kidney function (RDKF) in patients with type 2 diabetes (T2D). Methods: Multivariable Cox regression was conducted to evaluate the hazard ratio (HR) between plasma UA and incident CKD among 1300 normoalbuminuric patients in 2 T2D study cohorts (DN, n = 402; SMART2D, n = 898). A weighted genetic risk score (wGRS) was calculated based on 10 single nucleotide polymorphism (SNPs) identified in genome-wide association studies of UA in East Asians. Mendelian randomization (MR) analysis was performed among 1146 Chinese T2D patients without CKD (estimated glomerular filtration rate [eGFR] > 60 mL/ min/1.73m2 ) at baseline (DN, 478; SMART2D, 668). The wGRS and individual SNPs were used as genetic instruments and RDKF was defined as eGFR decline of 5 mL/min/1.73m2 /year or greater. Results: During mean follow-up of 5.2 and 5.4 years, 81 (9%) and 46 (11%) participants in SMART2D and DN developed CKD, respectively. A 1-SD increment in plasma UA conferred higher risk of incident CKD (DN, adjusted-HR = 1.40 [95% CI, 1.02-1.91], P = 0.036; SMART2D, adjusted-HR = 1.31 [95% CI, 1.04-1.64], P = 0.018). Higher wGRS was associated with increased odds for RDKF (meta-adjusted odds ratio = 1.12 [95% CI, 1.01-1.24], P = 0.030, Phet = 0.606). Conclusion: Elevated plasma UA is an independent risk factor for incident CKD. Furthermore, plasma UA potentially has a causal role in early eGFR loss in T2D patients.