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

Diabetes. 2019 Jan;68(1):198-206. doi: 10.2337/db18-0500. Epub 2018 Oct 10.

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 1) identify the genetic determinants influencing circulating PEDF levels in a clinical setting of T2D, 2) examine the relationship between circulating PEDF and diabetes complications, and 3) 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 (n = 2,936) and replication stage (n = 2,449) was performed. The strongest association was detected at SERPINF1 (p.Met72Thr; Pcombined = 2.06 × 10-57; β [SE] -0.33 [0.02]). Two missense variants of SMYD4 (p.Arg131Ile; Pcombined = 7.56 × 10-25; β [SE] 0.21 [0.02]) and SERPINF2 (p.Arg33Trp; Pcombined = 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 (P = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetic Nephropathies / genetics*
  • Exome / genetics*
  • Eye Proteins / genetics*
  • Humans
  • Mendelian Randomization Analysis
  • Mutation, Missense / genetics
  • Nerve Growth Factors / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Serpins / genetics*
  • Tumor Suppressor Proteins / genetics

Substances

  • Eye Proteins
  • Nerve Growth Factors
  • Serpins
  • Tumor Suppressor Proteins
  • pigment epithelium-derived factor