PDE4B Proposed as a High Myopia Susceptibility Gene in Chinese Population.

Wei Chen,Changqing Zeng,Anquan Xue,Peter S Reinach,Zhenglin Yang,Suh-Hang H Juo,Fuxin Zhao,Xiangtian Zhou,Yi Shi,Yuhan Wang,Jia Qu,Hui Zhou,Chung-Ling Liang

doi:10.3389/fgene.2021.775797

Abstract

Myopia is the most common cause of refractive error worldwide. High myopia is a severe type of myopia, which usually accompanies pathological changes in the fundus. To identify high myopia susceptibility genes, DNA-pooling based genome-wide association analysis was used to search for a correlation between single nucleotide polymorphisms and high myopia in a Han Chinese cohort (cases vs. controls in discovery stage: 507 vs. 294; replication stage 1: 991 vs. 1,025; replication stage 2: 1,021 vs. 52,708). Three variants (rs10889602T/G, rs2193015T/C, rs9676191A/C) were identified as being significantly associated with high myopia in the discovery, and replication stage. rs10889602T/G is located at the third intron of phosphodiesterase 4B (PDE4B), whose functional assays were performed by comparing the effects of rs10889602T/T deletion of this risk allele on PDE4B and COL1A1 gene and protein expression levels in the rs10889602T/Tdel/del, rs10889602T/Tdel/wt, and normal control A549 cell lines. The declines in the PDE4B and COL1A1 gene expression levels were larger in the rs10889602T/T deleted A549 cells than in the normal control A549 cells (one-way ANOVA, p < 0.001). The knockdown of PDE4B by siRNA in human scleral fibroblasts led to downregulation of COL1A1. This correspondence between the declines in rs10889602 of the PDE4B gene, PDE4B knockdown, and COL1A1 protein expression levels suggest that PDE4B may be a novel high myopia susceptibility gene, which regulates myopia progression through controlling scleral collagen I expression levels. More studies are needed to determine if there is a correlation between PDE4B and high myopia in other larger sample sized cohorts.

Highlights

Myopia is the most common cause of refractive error, which leads to visual impairment and even blindness (Cho et al, 2016; Flitcroft et al, 2019)
To minimize sample heterogeneity in the discovery phase of the GWA study, High myopia (HM) subjects were only included if their refractive errors were ≤ −8.00 D
Most of these HM patients presented with degenerative changes specific to pathological myopia in the ocular fundus

Summary

Introduction

Myopia is the most common cause of refractive error, which leads to visual impairment and even blindness (Cho et al, 2016; Flitcroft et al, 2019). Its prevalence can even exceed more than 80% in young people in China and Singapore (Sun et al, 2012; Saw et al, 2016). High myopia (HM), is defined as a refractive error that is either equal to or less than -6.00 diopters (D), which is commonly accompanied by excessive axial elongation (≥26 mm). This condition can involve other complications, including retinal detachment, macular degeneration, cataract, and glaucoma. It is predicted that the prevalence of HM will progressively increase to reach 9.8% worldwide by 2050, which creates a substantial burden on providing effective health care (Holden et al, 2016). This limitation hinders development of innovative procedures that improve therapeutic management of this sight compromising condition

Methods

Results

Conclusion