Association of Myopia and Genetic Variants of TGFB2-AS1 and TGFBR1 in the TGF-β Signaling Pathway: A Longitudinal Study in Chinese School-Aged Children

Abstract

BackgroundMyopia is a complex multifactorial condition which involves several overlapping signaling pathways mediated by distinct genes. This prospective cohort study evaluated the associations of two genetic variants in the TGF-β signaling pathway with the onset and progression of myopia and ocular biometric parameters in Chinese school-aged children.MethodsA total of 556 second grade children were examined and followed up for 3.5 years. Non-cycloplegic refraction and ocular biometric parameters were measured annually. Multivariate regression analysis was used to assess the effect of the TGFBR1 rs10760673 and TGFB2-AS1 rs7550232 variants on the occurrence and progression of myopia. A 10,000 permutations test was used to correct for multiple testing. Functional annotation of single nucleotide polymorphisms (SNPs) was performed using RegulomeDB, HaploReg, and rVarBase.ResultsA total of 448 children were included in the analysis. After adjustments for gender, age, near work time and outdoor time with 10,000 permutations, the results indicated that the C allele and the AC or CC genotypes of rs7550232 adjacent to TGFB2-AS1 were associated with a significantly increased risk of the onset of myopia in two genetic models (additive: P’ = 0.022; dominant: P’ = 0.025). Additionally, the A allele and the AA or AG genotypes of rs10760673 of TGFBR1 were associated with a significant myopic shift (additive: P’ = 0.008; dominant: P’ = 0.028; recessive: P’ = 0.027). Furthermore, rs10760673 was associated with an increase in axial length (AL) (P’ = 0.013, β = 0.03) and a change in the ratio of AL to the corneal radius of curvature (AL/CRC) (P’ = 0.031, β = 0.003). Analysis using RegulomeDB, HaploReg, and rVarBase indicated that rs7550232 is likely to affect transcription factor binding, any motif, DNase footprint, and DNase peak.ConclusionThe present study indicated that rs10760673 and rs7550232 may represent susceptibility loci for the progression and onset of myopia, respectively, in school-aged children. Associations of the variants of the TGFBR1 and TGFB2-AS1 genes with myopia may be mediated by the TGF-β signaling pathway; this hypothesis requires validation in functional studies. This trial was registered as ChiCTR1900020584 at www.Chictr.org.cn.

TGFB2-AS1 binding to MED1 promotes doxorubicin-induced cardiomyocyte apoptosis via BMP7 pathway

“…Recent studies found the role of long non-coding RNA in doxorubicin-induced cardiomyopathy, lncRNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocytes apoptosis by regulating the Rab2A-p53 axis [27], METTL14 silencing suppresses the ferroptosis of cardiomyocyte in doxorubicin-induced mice[28].TGFB2-AS1 has been reported in breast cancer, glioma, lung adenocarcinoma, gastric cancer, and other tumor diseases, and more importantly, the limited molecular biological role of TGFB2-AS1 in some diseases has been illustrated [29]. Studies have shown that mutations in the TGFBR1 and TGFB2-AS1 genes were associated with myopia in preschoolers, mediated by the TGF-β signaling pathway [30]; loss of TGFB2-AS1 signi cantly promoted Apoptosis of HepG2 liver cancer cells and inhibited migration and invasion [31], and TGFB2-AS1 interacted with the Core subunit of SWI/SNF complex, SMARCA4 to inhibit the expression of target genes TGFB2 and SOX2, ultimately inhibiting the breast Cancer progression [32]. Evolutionary conservation is widely used as an indicator of the functional signi cance of newly discovered lncRNAs and the evolutionary conservation of lncRNAs is multidimensional including Sequence, structure, function, and syntenic expression, and different from the conserved analysis of coding gene proteins [33].…”

Association of a High Healthy Eating Index Diet with Long-Term Visceral Fat Loss in a Large Longitudinal Study

“…The genetic variants associated with abdominal obesity were identified using the data of the hospital-based KoGES cohort. The best set of genetic variants with interactions influencing abdominal obesity was generated with a sign rank test ( p < 0.05) of trained balanced accuracy (TRBA) and testing balanced accuracy (TEBA), adjusting for the covariates by generalized multifactor dimensionality reduction (GMDR) [ 20 ]. Ten-fold cross-validation (CV) was used to estimate the CV consistency (CVC), because the sample size was larger than 1000 [ 21 ].…”

Crosstalk between heredity and environment in myopia: An overview

“…RSPO1 SNP rs12144790 and WNT7B rs10453441 [ 42 ] are related to children's visual axis length. ZFHX1B rs13382811 [ 34 , 43 ], PTPN5 rs1550870 and RASGRF1 rs6495367 [ 44 ], TGF receptor one rs10760673, and TGF receptor 2-AS1 rs7550232 [ 45 ] are also bound up with myopia in children. MMP-9 rs2236416 is interrelated to myopia in the population, suggesting that the MMP-9 gene locus may play a role in myopia [ 46 ].…”

“… 2020 [ 42 ] ZFHX1B rs13382811 Li, J. 2017 [ 43 ] PTPN5 rs1550870, RASGRF1 rs6495367 Xiao, H. 2021 [ 44 ] TGF receptor one rs10760673, TGF receptor 2-AS1 rs7550232 Liu, L. 2021 [ 45 ] MMP-9 rs2236416 Li, Y. 2022 [ 46 ] 4q25 rs10034228, 15q14 rs524952, MIPEP rs9318086 Liu, J.…”