Elevated levels of plasma Leucine Rich α-2-Glycoprotein 1 (LRG1), a component of TGF-ß signalling, 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.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.We performed a genome-wide association study (GWAS) of plasma LRG1 among 3,694 T2D individuals [1,881(983 Chinese, 420 Malay and 478 Indian) discovery from SMART2D cohort and 1,813 (Chinese) validation from DN cohort]. One- sample Mendelian randomization analysis was performed among 1,337 T2D Chinese participants with preserved glomerular filtration function (baseline estimated glomerular filtration rate (eGFR) >60ml/min/1.73m 2). RDKF was defined as an eGFR decline of 3 mL/min/1.73 m 2/year or greater.We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (MetaP=6.66x10 -16). Among 1,337 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 randomisation analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P<0.05).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 DKD prevention.
Resham Lal Gurung, Rajkumar Dorajoo, M Yiamunaa, 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, Jian-Jun Liu, Su Chi Lim