Pathogenesis Of High Myopia Research Articles

A novel variant in the keratin 12 gene in a four-generation Chinese family with high myopia.

High myopia is a major cause of visual impairment, and genetic factors play crucial roles in the pathogenesis. We performed this study to identify candidate genes for the development of high myopia in a four-generation Chinese family with myopia. All family members with myopia and 100 healthy participants were included in this study. Data were obtained on demographics, disease history, and ocular examination results. We performed whole exome sequencing of the genomic DNA and Sanger sequencing to verify the variants. Functional analyses of the variant were performed using software programmes. Nine of thirteen family members were found to have high myopia, amongst which two members were also diagnosed keratoconus. A missense variant in the keratin 12 gene (KRT12, p.Val410Gly) was detected in all high myopia cases but not in other family members without high myopia or the controls. The variant was predicted to be benign by online software programmes. However, modelling of the three-dimensional structure of the protein clearly revealed conformational changes caused by the mutation. A missense mutation in the KRT12 gene was identified in this Chinese family, which may be associated with the pathogenesis of high myopia.

Exploration of the pathophysiology of high myopia via proteomic profiling of human corneal stromal lenticules

This study aimed to investigate the underlying pathophysiology of high myopia by analyzing the proteome of human corneal stromal lenticule samples obtained through small incision lenticule extraction (SMILE). A total of thirty-two patients who underwent SMILE were included in the study. Label-free quantitative proteomic analysis was performed on corneal stromal lenticule samples, equally representing high myopia (n = 10) and low myopia (n = 10) groups. The identified and profiled lenticule proteomes were analyzed using in silico tools to explore biological characteristics of differentially expressed proteins (DEPs). Additionally, LASSO regression and random forest model were employed to identify key proteins associated with the pathophysiology of high myopia. The DEPs were found to be closely linked to immune activation, extracellular matrix, and cell adhesion-related pathways according to gene ontology analysis. Specifically, decreased expression of COL1A1 and increased expression of CDH11 were associated with the pathogenesis of high myopia and validated by western blotting (n = 6) and quantitative real time polymerase chain reaction (n = 6). Overall, this study provides evidence that COL1A1 and CDH11 may contribute to the pathophysiology of high myopia based on comparative proteomic profiling of human corneal stromal lenticules obtained through SMILE.

Assessment of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with high myopia

BackgroundPrevious reports have suggested that inflammation levels play a crucial role in the pathogenesis of high myopia (HM). This study aimed to investigate the relationship between HM and systemic inflammation using the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).MethodsOverall, 100 age- and sex-matched participants were recruited for the study, including 50 participants each in the non-HM (NHM) and HM groups. Ocular examinations and blood tests were performed. The NLR and PLR values were calculated from complete blood counts. Receiver operating characteristic (ROC) curves and optimal cut-off values were used to determine the optimal values of the NLR and PLR to distinguish between the HM and NHM groups.ResultsThe values of NLR and PLR were significantly elevated in the HM group compared with those in the NHM group (P < 0.001 and P = 0.010, respectively). Axial length (AL) was significantly correlated with the NLR (r = 0.367, P < 0.001) and PLR (r = 0.262, P = 0.009). In the ROC analysis, the NLR value to distinguish between the HM and NHM groups was 0.728; the best cut-off value was 2.68, with 76% sensitivity and 62% specificity. The PLR value to distinguish between the HM and NHM groups was 0.650; the best cut-off value was 139.69, with 52% sensitivity and 76% specificity.ConclusionThe findings of this study indicate that the development of HM may be associated with systemic inflammation measured using the NLR and PLR.Trial registrationThe study was registered on December 28, 2021 (http://www.chictr.org.cn; ChiCTR2100054834).

The plasminogen protein is associated with high myopia as revealed by the iTRAQ-based proteomic analysis of the aqueous humor

To explore the pathogenesis of high myopia (HM) using quantitative proteomics. The aqueous humor of patients with simple nuclear cataract and nuclear cataract complicated with HM (hereinafter referred to as “C” and “HM” groups, respectively) were collected. The isobaric tags for relative and absolute quantitation (iTRAQ)-based liquid chromatography–tandem mass spectrometry (LC–MS/MS) proteomics approach was employed to explore differentially expressed proteins (DEPs). Bioinformatics was used to interpret the proteomic results. Furthermore, the plasminogen (PLG) protein was confirmed by enzyme-linked immunosorbent assay (ELISA) as the candidate biomarker for HM through a receiver operating characteristic curve analysis. The study showed 32 upregulated and 26 downregulated proteins. The gene ontology analysis demonstrated that 58 DEPs corresponded to 325 biological processes, 33 cell components, and 45 molecular functional annotations. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the upregulated DEPs were highly enriched in the coagulation and complement cascades, consistent with the gene set enrichment analysis. Our data suggested that some DEPs might be hallmarks of the development of HM. ELISA confirmed that the PLG expression levels were significantly upregulated in HM. This was a new study investigating alterations in protein levels and affected pathways in HM using iTRAQ-based quantitative proteomics. Our study provided a comprehensive dataset on overall protein changes and shed light on its potential molecular mechanism in human HM.

Efficacy and safety of Bu Jing Yi Shi tables for high myopia: A protocol of systematic review and meta-analysis.

Background:High myopia is a kind of ametropia with diopter more than −6.00D or axial length ≥26 mm. With the change of the modern environment, the incidence rate is increasing year by year. At present, the pathogenesis of high myopia is not clear. Some current studies indicate that it may be related to the environment and genetics. A Chinese patent medicine named Bu Jing Yi Shi Tablets (BJYST) has many functions including anti-oxidation, expansion of blood vessels, anti-inflammatory, immune regulation, inhibition of retinal photoreceptor cell apoptosis, and promotion of retinal repair. A large number of existing studies have shown that this prescription can relieve the clinical manifestations of high myopia and its complications, but its true efficacy and safety are still unclear. To certify this point, a protocol for a systematic review and meta-analysis of BJYST for high myopia will be performed.Methods and analysis:Articles that have been identified by electronically searching of 9 English and 5 Chinese databases from their inception to December 4, 2020 will be incorporated into the study. This study only adopts Chinese and English. Two researchers will take charge of completing the selection of research, the extraction of data as well as the assessment of research quality independently. The primary outcomes will be an average change in refractive error measured in diopters and an average change in axial length measured in millimeters. Data analysis will be performed via the RevMan 5.3 software, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will help to assess the evidence level.Results:The results of this study will be published in a peer-reviewed journal.Conclusion:This study will conclude whether BJYST is safe and effective in treating high myopia on the basis of evidence-based medicine.Registration:The Open Science Framework (OSF) registration number is osf.io/dpk5b.

Genome-Wide Association Study in Asians Identifies Novel Loci for High Myopia and Highlights a Nervous System Role in Its Pathogenesis

To identify novel susceptibility loci for high myopia. Genome-wide association study (GWAS) followed by replication and meta-analysis. A total of 14 096 samples from East and Southeast Asian populations (2549 patients with high myopia and 11 547 healthy controls). We performed a GWAS in 3269 Japanese individuals (1668 with high myopia and 1601 control participants), followed by replication analysis in a total of 10 827 additional samples (881 with high myopia and 9946 control participants) from Japan, Singapore, and Taiwan. To confirm the biological role of the identified loci in the pathogenesis of high myopia, we performed functional annotation and Gene Ontology (GO) analyses. We evaluated the association of single nucleotide polymorphisms with high myopia and GO terms enriched among genes identified in the current study. We identified 9 loci with genome-wide significance (P < 5.0× 10-8). Three loci were previously reported myopia-related loci (ZC3H11B on 1q41, GJD2 on 15q14, and RASGRF1 on 15q25.1), and the other 6 were novel (HIVEP3 on 1p34.2, NFASC/CNTN2 on 1q32.1, CNTN4/CNTN6 on 3p26.3, FRMD4B on 3p14.1, LINC02418 on 12q24.33, and AKAP13 on 15q25.3). The GO analysis revealed a significant role of the nervous system related to synaptic signaling, neuronal development, and Ras/Rho signaling in the pathogenesis of high myopia. The current study identified 6 novel loci associated with high myopia and demonstrated an important role of the nervous system in the disease pathogenesis. Our findings give new insight into the genetic factors underlying myopia, including high myopia, by connecting previous findings and allowing for a clarified interpretation of the cause and pathophysiologic features of myopia at the molecular level.

Differential expression of connective tissue growth factor and hepatocyte growth factor in the vitreous of patients with high myopia versus vitreomacular interface disease

BackgroundTo determine the levels of connective tissue growth factor (CTGF) and hepatocyte growth factor (HGF) in the vitreous of patients with high myopia, in comparison with those with a vitreomacular interface disease (VMID).MethodsPatients with either high myopia (high myopia group) or a VMID (VMID group) were included in this study. Each of the two groups were further subdivided into two subgroups: group A (high myopia with macular hole), group B (high myopia with macular retinoschisis), group C (idiopathic macular hole), and group D (idiopathic epiretinal membrane). Vitreal specimens were collected during vitrectomy, and enzyme-linked immunosorbent assay was used to quantitatively measure the CTGF and HGF levels in the vitreous.ResultsThe average axial length was markedly longer in the high myopia group than in the VMID group. The vitreal CTGF level was significantly higher in the high myopia group than in the VMID group. Subgroup analysis revealed significantly higher vitreal CTGF in group A than in the other three subgroups. The vitreal HGF level was not significantly different between the high myopia and VMID groups, but was significantly higher in group D than in group C in the subgroup analysis. Correlation analysis showed that the vitreal CTGF level was positively correlated with the axial length.ConclusionsThe vitreal CTGF level is elevated in highly myopic eyes and may be related to the pathogenesis of high myopia, whereas increased expression of HGF may be involved in the development of idiopathic epiretinal membrane.

Genetic association between corneal curvature-related genes and high myopia in Chinese Han population

Background High myopia is one of the primary factors of visual impairment, and its prevention and management are researching hot topics.Corneal curvature (CC) measures the steepness of the cornea which is an important parameter leading to myopia.Genome-wide association study (GWAS) showed that several genes are associated with CC in Asian populations.However, the association of corneal curvature-related genes with high myopia is unclear up to now. Objective This study was to investigate the association between single nucleotide polymorphism (SNP) in the rs74225573 (mechanistic target of rapamycin [MTOR]), rs60078183 (cytidine/uridine monophosphate kinase 1[CMPK1]), rs1800813 (platelet derived growth factor receptor alpha[PDGFRA]), rs11204213 (retinol binding protein 3[RBP3]) and high myopia in Chinese Han population. Methods A prospective cohort study was performed.Four hundreds and eighty-three patients with high myopia were collected in Sichuan Provincial People's Hospital from February 2012 to August 2013, with the diopter (-10.84±4.69)D in the right eyes and (-10.35±4.67)D in the left eyes or ocular axial length of (28.15±2.27)mm in the right eyes and (27.72±2.51)mm in the left eyes.Five hundreds and nineteen normal volunteers matched in age and gender were included in the same period as controls, and all the subjects were Chinese Han people without genetic relationship.The periphery blood of 4 ml was obtained for the DNA extraction from each subject under the written informed consent.The primers of rs74225573, rs60078183, rs1800813 and rs11204213 were designed based on the information of NCBI website.The four SNPs were amplified by real-time PCR and genotyped by SNaPshot method. Results All the genotype frequencies of these four SNPs were in Hardy-Weinberg equilibrium (HWE). There are no significant differences in minor allele frequency (MAF) distribution of rs74225573, rs60078183 and rs11204213 between high myopia group and normal control group (rs74225573: Page-corrected =0.935, OR=0.98; rs60078183: Page-corrected =0.782, OR=1.04; rs11204213: Page-corrected=0.058, OR=1.66), and the MAF of rs1800813 was significantly higher in the high myopia group than that in the normal control group (Page-corrected=0.001, OR=0.64). The genotype frequency of rs74225573, rs60078183 and rs11204213 was not evidently different in additive model 1(AB vs.BB), additive model 2 (AA vs.BB), dominant model (AA+ AB vs.BB) and recessive model (AA vs.AB+ BB) (all at P>0.05), while significant differences were found in genotype frequency of rs1800813 both in additive model 1 and dominant model (additive model 1: P=0.002, OR=0.59; dominant model: P=0.001, OR=0.58). Conclusions The SNP of rs1800813 in the PDGFRA gene is associated with the pathogenesis of high myopia in the Chinese Han population, but the SNPs of rs74225573 (MTOR gene), rs60078183 (CMPK1 gene) and rs11204213 (RBP3 gene) appear to be not associated with high myopia. Key words: High myopia; Corneal curvature; Single nucleotide polymorphism; Platelet derived growth factor receptor alpha gene

Exome Sequence Analysis of 14 Families With High Myopia

PurposeTo identify causal gene mutations in 14 families with autosomal dominant (AD) high myopia using exome sequencing.MethodsSelect individuals from 14 large Caucasian families with high myopia were exome sequenced. Gene variants were filtered to identify potential pathogenic changes. Sanger sequencing was used to confirm variants in original DNA, and to test for disease cosegregation in additional family members. Candidate genes and chromosomal loci previously associated with myopic refractive error and its endophenotypes were comprehensively screened.ResultsIn 14 high myopia families, we identified 73 rare and 31 novel gene variants as candidates for pathogenicity. In seven of these families, two of the novel and eight of the rare variants were within known myopia loci. A total of 104 heterozygous nonsynonymous rare variants in 104 genes were identified in 10 out of 14 probands. Each variant cosegregated with affection status. No rare variants were identified in genes known to cause myopia or in genes closest to published genome-wide association study association signals for refractive error or its endophenotypes.ConclusionsWhole exome sequencing was performed to determine gene variants implicated in the pathogenesis of AD high myopia. This study provides new genes for consideration in the pathogenesis of high myopia, and may aid in the development of genetic profiling of those at greatest risk for attendant ocular morbidities of this disorder.

Impaired vitreous composition and retinal pigment epithelium function in the FoxG1::LRP2 myopic mice

High myopia (HM) is one of the main causes of visual impairment and blindness all over the world and an unsolved medical problem. Persons with HM are predisposed to other eye pathologies such as retinal detachment, myopic retinopathy or glaucomatous optic neuropathy, complications that may at least partly result from the extensive liquefaction of the myopic vitreous gel. To identify the involvement of the liquid vitreous in the pathogenesis of HM we here analyzed the vitreous of the recently described highly myopic low density lipoprotein receptor-related protein 2 (Lrp2)-deficient eyes. Whereas the gel-like fraction was not apparently modified, the volume of the liquid vitreous fraction (LVF) was much higher in the myopic eyes. Biochemical and proteome analysis of the LVF revealed several modifications including a marked decrease of potassium, sodium and chloride, of proteins involved in ocular tissue homeostasis and repair as well as of ADP-ribosylation factor 4 (ARF4), a protein possibly involved in LRP2 trafficking. A small number of proteins, mainly comprising known LRP2 ligands or proteins of the inflammatory response, were over expressed in the mutants. Moreover the morphology of the LRP2-deficient retinal pigment epithelium (RPE) cells was affected and the expression of ARF4 as well as of proteins involved in degradative endocytosis was strongly reduced. Our results support the idea that impairment of the RPE structure and most likely endocytic function may contribute to the vitreal modifications and pathogenesis of HM.

Construction of adenovirus vectors encoding the lumican gene by gateway recombinant cloning technology.

To construct adenovirus vectors of lumican gene by gateway recombinant cloning technology to further understand the role of lumican gene in myopia. Gateway recombinant cloning technology was used to construct adenovirus vectors. The wild-type (wt) and mutant (mut) forms of the lumican gene were synthesized and amplified by polymerase chain reaction (PCR). The lumican cDNA fragments were purified and ligated into the adenovirus shuttle vector pDown-multiple cloning site (MCS)-/internal ribozyme entry site (IRES)/enhanced green fluorescent protein (EGFP). Then the desired DNA fragments were integrated into the destination vector pAV.Des1d yielding the final expression constructs pAV.Ex1d-cytomegalovirus (CMV)>wt-lumican/IRES/EGFP and pAV.Ex1d-CMV>mut-lumican/IRES /EGFP, respectively. The adenovirus plasmids pAV.Ex1d-CMV>wt-lumican/IRES/EGFP and pAV.Ex1d-CMV>mut-lumican/IRES/EGFP were successfully constructed by gateway recombinant cloning technology. Positive clones identified by PCR and sequencing were selected and packaged into recombinant adenovirus in HEK293 cells. We construct adenovirus vectors containing the lumican gene by gateway recombinant cloning technology, which provides a basis for investigating the role of lumican gene in the pathogenesis of high myopia.

Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia.

High myopia is one of the leading causes of blindness worldwide, with high heritability. However, only a few causative genes have been identified, and the pathogenesis is still unclear. Our aim was to identify a novel causative gene in a family with autosomal-dominant, nonsyndromic high myopia. Whole-genome linkage and whole-exome sequencing were conducted on the family. Real-time quantitative polymerase chain reaction and immunoblotting were applied to test the functional consequence of the candidate mutation. Sanger sequencing was performed to screen for the candidate gene in other families or sporadic cases. A heterozygous missense mutation, c.871G>A (p.Glu291Lys), within P4HA2 was cosegregating with the phenotype in the family. The segregating mutation caused premature degradation of unstable messenger RNA. Subsequent screening for P4HA2 in 186 cases identified an additional four mutations in 5 cases, including the frameshift mutation c.1349_1350delGT (p.Arg451Glyfs*8), the nonsense mutation c.1327A>G (p.Lys443*), and two deleterious missense mutations, c.419A>G (p.Gln140Arg) and c.448A>G (p.Ile150Val). The missense mutation c.419A>G (p.Gln140Arg) was recurrently identified in a sporadic case and was segregating in a three-generation family. P4HA2 was identified as a novel causative gene for nonsyndromic high myopia. This study also indicated that the disruption of posttranslational modifications of collagen is an important factor in the pathogenesis of high myopia.

A case-controlled study on the single nucleotide polymorphism of the CTNND2 gene between high myopia and the normal population in Han Chinese

Background High myopia is one of leading causes of blindness,so far the pathogenesis remains unclear.Two single-nucleotide polymorphisms (SNPs) of rs6885224 and rs12716080 in CTNND2 gene were recently found to be associated with high myopia in Singaporean Chinese.But whether these SNPs are related with the pathogenesis of high myopia in Han Chinese is worth studying, Objective This study was to investigate the relationship between the genetic variations of the CTNND2 gene and high myopia in Han Chinese. Methods A case-controlled association study was designed.Nine hundred and thirty-three individuals with high myopia and 1227age- and gender-matched normal subjects were included in this study.The 5 ml of periphery blood was obtained from all subjects for the extraction of genomic DNA.The target DNA was amplified using PCR and purified by the SNaPshot method.Four SNPs rs12716080,rs917012,rs6885224 and rs16901340 in the CTNND2 gene were genotyped.This study was approved by the Ethic Committee of Sichuan Provincial People Hospital.Written informed consent was obtained from each subject before his/her enrollment. Results The frequencies of the genotypes rs6885224,rs12716080,rs917012,rs16901340 SNPs were in Hardy-Weinberg equilibrium (HWE) ( P=0.181,0.085,0.732,0.313,0.264,0.663,0.084,0.196).There were no significant differences in genotypes frequency distribution ( in turn P =0.654,0.406,0.828,0.403 ) and allele frequency distribution of the CTNND2 gene ( in turn P =0.377,0.209,0.743,0.198) between the high myopia group and normal control group.The haplotypes (TA and GA)frequencies of rs12716080 and rs917012 in the high myopia group were significantly different from those of the normal control group(TA:0.784 vs.0.719;GA:0.087 vs.0.136) (x2 =6.115,P=0.013 ;x2 =6.634,P=0.010),but those of GG were similar between the high myopia group and normal control group ( 0.123 vs.0.143,x2 =0.889,P =0.346). Conclusions The SNPs rs12716080,rs917012,rs6885224 and rs16901340 in CTNND2 gene were not responsible for high myopia,however,the haplotypes of rs12716080 and rs917012 are susceptible for high myopia in Han Chinese. Key words: CTNND2 gene; Single nucleotide polymorphism; Haplotype; High myopia; Han nationality

Scleral Reinforcement for High Myopia

This paper reviews the scleral reinforcement procedure for high myopia. A discussion of the indications and operative technique is presented with postoperative results and complications in 191 cases performed by one surgeon over the last 14 years. A discussion of the history of scleral reinforcement, modification of technique, and pathogenesis of high myopia is presented.