Association of Genetic Variants for Plasma LRG1 with Rapid Decline in Kidney Function in Patients with Type 2 Diabetes

Abstract

Context: Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. Objectives: To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. Design and participants: We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater. Results: We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P=6.66×10-16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio=1.23, P=0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P<0.05). Conclusion: We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention.