The association study between MTOR and high myopia in a Han Chinese population

Myopia, in particularly high myopia (HM), is a major global ocular disorder and genetic factors playing a crucial role in its development. This study aimed to shed light on the genetic association between candidate single nucleotide polymorphisms (SNPs) and HM, offering insights into the mechanisms underlying of HM. This case-control study involves 1,008 unrelated Han Chinese participants, including 508 HM patients and 500 healthy controls. Eleven candidate SNPs that were previously linked to refractive errors in other populations, were genotyped using multiplex PCR and high-throughput sequencing. We analyzed the associations between SNPs and HM under five genetic models, adjusting for age and sex. Ocular biometrics, such as axial length (AL) and refractive error, were correlated with the significant SNPs identified. We conducted functional annotation of the target SNP using bioinformatic tools. In addition, a form-deprivation myopia (FDM) mouse model was employed to validate the role of the candidate gene through Western blot analysis of retinal proteins. Among the 11 SNPs analyzed, rs17036350 in the MTOR gene showed a significant association with HM in the Southern Han Chinese population. Under the homozygous model, the results for this SNP, after adjusting for age and sex, suggest an association with high myopia. ( p = 0.009, OR = 2.008, 95% CI: 0.611 - 6.596), after Bonferroni multiple-correction ( p = 0.0456). In individuals with HM, carriers of the C allele of rs17036350 (CC + CT genotypes) had a significantly longer AL than those with the TT genotype ( p = 0.015), and the association was more pronounced in female patients ( p = 0.033). Bioinformatics functional analysis revealed that rs17036350 interacts with the MTOR gene in a chromatin regulatory loop, which potentially enhances the transcription factor PBX1 and downstream gene expression. Myopic eyes exhibited significant axial elongation in the FDM mouse model, and elevated levels of phosphorylated mTOR (p-mTOR) were observed in the retina compared to controls ( p =0.0128). This study identified rs17036350 within MTOR as a genetic marker that is associated with HM in the Southern Han Chinese population, specifically linked to AL. Additionally, MTOR activation may contribute to axial elongation in myopia. These findings provide new insights into the genetic regulation of refractive development and support potential targeted strategies for managing myopia.