Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes

Abstract

Elevated circulating levels of pigment epithelium-derived factor (PEDF) have been reported in patients with type 2 diabetes (T2D) and its associated microvascular complications. This study aimed to <i>1</i>) identify the genetic determinants influencing circulating PEDF levels in a clinical setting of T2D, <i>2</i>) examine the relationship between circulating PEDF and diabetes complications, and <i>3</i>) explore the causal relationship between PEDF and diabetes complications. An exome-chip association study on circulating PEDF levels was conducted in 5,385 Chinese subjects with T2D. A meta-analysis of the association results of the discovery stage (<i>n</i> = 2,936) and replication stage (<i>n</i> = 2,449) was performed. The strongest association was detected at <i>SERPINF1</i> (p.Met72Thr; <i>P_combined</i> = 2.06 × 10^-57; β [SE] -0.33 [0.02]). Two missense variants of <i>SMYD4</i> (p.Arg131Ile; <i>P_combined</i> = 7.56 × 10^-25; β [SE] 0.21 [0.02]) and <i>SERPINF2</i> (p.Arg33Trp; <i>P_combined</i> = 8.22 × 10^-10; β [SE] -0.15 [0.02]) showed novel associations at genome-wide significance. Elevated circulating PEDF levels were associated with increased risks of diabetic nephropathy and sight-threatening diabetic retinopathy. Mendelian randomization analysis showed suggestive evidence of a protective role of PEDF on sight-threatening diabetic retinopathy (<i>P</i> = 0.085). Our study provided new insights into the genetic regulation of PEDF and further support for its potential application as a biomarker for diabetic nephropathy and sight-threatening diabetic retinopathy. Further studies to explore the causal relationship of PEDF with diabetes complications are warranted.