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Xiangtian Zhou, Wei Chen, Yijin Tao, Miaozhen Pan, Suh-Hang H. Juo, Zhenglin Yang, Jianhong An, Fuxin Zhao, Changiqng Zeng, Jia Qu; PDE4B Is A High Myopia Susceptibility Gene As Revealed By Genome-wide Association Studies In A Chinese Population And In Animal Model Studies. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6293.
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High myopia (HM) is a complex disease and thus far very limited candidate genes were identified. This study performed a genome-wide association (GWA) study followed by replicates and functions analysis the high myopia susceptibility gene.
We performed a GWA study using pooled samples (507 HM and 294 controls) followed by individual verification. Then 2,014 and 1,099 samples from Taiwan and Sichuan province were used as replicates. Functions of a candidate gene phosphodiesterase 4B (PDE4B) were analyzed by immunofluorescence on normal and form-deprived (FD) guinea pig eyes, followed by determination of refraction and ocular biometric parameters on normal and FD animals before and after subconjunctival injection of rolipram, an inhibitor of PDE4. Scleral collagen diameters in those eyes were examined by electron microscopy. Collagen mRNA and secretion of soluble collagen from cultured human scleral fibroblast (HSF) were measured after rolipram treatment.
rs10889602 within the third intron of PDE4B was identified to associate with HM (p=0.0198). Meta-analysis with samples of 3 areas verified this correlation (pcombine=3.7×10-3). PDE4B expression in FD sclera was reduced compared to the fellow sclera, whereas no decrease was seen in the rest of PDE4 family members. Moreover, inhibition of PDE4B induced myopia in normal eyes and exacerbated myopia in FD eyes. Reduction of PDE4B down-regulated collagens I, III, and V transcription as well as decreased collagen secretion by HSFs. Consequently, thinner scleral collagen fibrils were observed in FD eyes treated with rolipram.
PDE4B is a susceptibility gene for high myopia as revealed by GWA study and validated by functional assays. PDE4B contributes to myopia development by down-regulating scleral collagen synthesis.
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