Exome-chip association analysis on a multifunctional anti-tumor factor, pigment epithelium-derived factor (PEDF), in patients with type 2 diabetes

Abstract

Objectives: Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein that belongs to the serine protease inhibitor (serpin) superfamily. It possesses diverse biological functions in different tissues, including anti-angiogenesis, retina protection, inflammation, stem cell renewal, neurogenesis and neuroprotection, and has been variably reported to ameliorate or induce insulin resistance. The anti-tumor effects of PEDF have been extensively reported. However, little is known of its genetic regulation. No genome-wide or exome-wide association studies on circulating PEDF level have been published to date. This study aimed to identify the genetic determinants influencing circulating PEDF level. Methods: An exome-chip association study on circulating PEDF level was conducted using a custom designed exome array in Chinese subjects with T2DM recruited from the Hong Kong West Diabetes Registry. Single-variant association analysis was conducted on a total of 76,951 polymorphic single nucleotide polymorphisms (SNPs) in the discovery stage, which involved 2936 Chinese subjects with T2DM. Eight SNPs with Pdiscovery<5x10-5 were subsequently genotyped for replication analysis in another 2449 subjects with T2DM. A meta-analysis of the association results of the two stages was then conducted. Results: The strongest association with circulating PEDF level was detected at SERPINF1 (rs1135287; p.Met72Thr; Pcombined=2.06x10-57; β[SE]: -0.33[0.02]). Two missense variants of SMYD4 (rs7224496; p.Arg131Ile; Pcombined=7.56x10-25; β[SE]: 0.21[0.02]) and SERPINF2 (rs2070863; p.Arg33Trp; Pcombined=8.22x10-10; β[SE]: -0.15[0.02]) showed novel associations with circulating PEDF level at genome-wide significance after adjustment for age, gender and the first two principal components in the combined analysis. Similar findings were obtained on further adjustment for body mass index. Conclusions: We have identified three missense variants of SERPINF1, SMYD4 and SERPINF2 significantly associated with circulating PEDF level in an exome-chip association study among Chinese subjects with T2DM. Our findings have shed light on the genetic regulation of circulating PEDF level. Acknowledgements: This work was supported by the Hong Kong Research Grant Council: Theme Based Research Scheme (T12-705/11).