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

Elevated circulating levels of pigment epithelium-derived factor (PEDF) have been reported in patients with type 2 diabetes (T2DM) and its associated microvascular complications. This study aimed to (i) identify the genetic determinants influencing circulating PEDF level in a clinical setting of T2DM; (ii) examine the relationship between circulating PEDF and diabetic complications; and (iii) explore the causal relationship between PEDF and diabetic complications. An exome-chip association study on circulating PEDF leve1 was conducted in 5385 Chinese subjects with T2DM. A meta-analysis of the association results of the discovery stage (n=2936) and replication stage (n=2449) was performed. The strongest association was detected at SERPINF1 (p.Met72Thr; P combined =2.06x10-57 ; β[SE]:-0.33[0.02]). Two missense variants of SMYD4 (p.Arg131Ile; P combined =7.56x10-25 ; β[SE]:0.21[0.02]) and SERPINF2 (p.Arg33Trp; P combined =8.22x10-10 ; β[SE]:-0.15[0.02]) respectively, showed novel associations at genome-wide significance. Elevated circulating PEDF level was associated with increased risks of diabetic nephropathy (DN) and sight-threatening diabetic retinopathy (STDR). Mendelian randomization analysis showed suggestive evidence of a protective role of PEDF on STDR ( P =0.085). Our study had provided new insights into the genetic regulation of PEDF and further support for its potential application as a biomarker for DN and STDR. Further studies to explore the causal relationship of PEDF with diabetic complications are warranted.