AUTHOR=Xiao Haishao , Lin Shudan , Jiang Dandan , Lin Yaoyao , Liu Linjie , Zhang Qiqi , He Juan , Chen Yanyan 

TITLE=Association of Extracellular Signal-Regulated Kinase Genes With Myopia: A Longitudinal Study of Chinese Children

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.654869

DOI=10.3389/fgene.2021.654869

ISSN=1664-8021

ABSTRACT=<sec><title>Objective</title><p>The present study was designed to investigate whether the extracellular signal-regulated kinase (ERK) signaling pathway, a downstream component of dopamine signaling, is involved in myopia among Chinese children.</p></sec><sec><title>Methods</title><p>During a 3.5-year follow-up, 488 primary school students were enrolled in this study. Non-cycloplegic spherical equivalent refraction (SE) and other ocular parameters were assessed. Four variants of four genes in the ERK signaling pathway were selected: <italic>RASGRF1</italic> rs6495367, <italic>PTPN5</italic> rs1550870, <italic>PTPRR</italic> rs11178469, and <italic>PDGFRA</italic> rs6554163. SNPscan was used to genotype single-nucleotide polymorphisms (SNPs). PLINK software was used to assess the associations of the genetic variants with the occurrence or development of myopia, SE, and other ocular parameters. We created a protein-protein interaction (PPI) network and microRNA (miRNA)-gene network using String and Cytoscape and conducted enrichment analyses on the genes in these networks.</p></sec><sec><title>Results</title><p>In total, 426 children (baseline age: 7.28 ± 0.26 years; 236 (55.4%) boys and 190 girls) wereenrolled. After adjusting for confounding factors with 10,000 permutations, children with the CT or TT genotype of <italic>PTPN5</italic> rs155087<italic>0</italic> were more susceptible to myopia than those with the CC genotype (adjusted <italic>p</italic> = 0.011). Additionally, <italic>PTPN5</italic> rs155087<italic>0</italic> was correlated with significant myopic shift and increasing axial length (AL) and lens thickness (LT) but had a negative effect on central corneal thickness (CCT). <italic>RASGRF1</italic> rs6495367 was negatively associated with myopic shift (additive: adjusted <italic>p</italic> = 0.034; dominant: adjusted <italic>p</italic> = 0.020), myopic SE and AL. <italic>PDGFRA</italic> rs6554163 TA or AA was negatively associated with increasing LT (adjusted <italic>p</italic> = 0.033). Evaluation of the effects of SNP-SNP combinations on incident myopia revealed a statistically significant one-locus model: <italic>PTPN5</italic> rs1550870 [cross-validation consistency (CVC) = 10/10, adjusted <italic>p</italic> = 0.0107]. The genes in the PPI and miRNA-gene interaction networks were subjected to enrichment analyses, which suggested that these genes are involved mainly in eye development and dopaminergic synapse-related processes.</p></sec><sec><title>Conclusion</title><p>We identified genetic variants of crucial ERK signaling pathway genes that were significantly correlated with myopia and ocular parameter alterations in Chinese children. A combination of gene and miRNA functional analyses with enrichment analyses highlights the regulatory effects associated with ocular development and dopamine biological functions. This study offers novel clues to understand the role of dopamine in the molecular mechanisms of myopia.</p></sec>