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- Title
Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes.
- Authors
Resham Lal Gurung; Rajkumar Dorajoo; Yiamunaa M; Jian-Jun Liu; Sharon Li Ting Pek; Jiexun Wang; Ling Wang; Xueling Sim; Sylvia Liu; Yi-Ming Shao; Keven Ang; Tavintharan Subramaniam; Wern Ee Tang; Chee Fang Sum; Su Chi Lim; Gurung, Resham Lal; Dorajoo, Rajkumar; Yiamunaa, M; Liu, Jian-Jun; Pek, Sharon Li Ting
- Abstract
<bold>Context: </bold>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.<bold>Objectives: </bold>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.<bold>Design and Participants: </bold>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.<bold>Results: </bold>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).<bold>Conclusion: </bold>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.
- Subjects
GENETIC variation; TYPE 2 diabetes; KIDNEY physiology; GENOME-wide association studies; CHRONIC kidney failure; GLOMERULAR filtration rate; DISEASE progression; RESEARCH; GENETICS; KIDNEYS; SEQUENCE analysis; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; GLYCOPROTEINS; RESEARCH funding; DIABETIC nephropathies
- Publication
Journal of Clinical Endocrinology & Metabolism, 2021, Vol 106, Issue 8, p2384
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/clinem/dgab268