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

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To investigate the association between insulin (INS) pathway related genes, including INS, insulin receptor (INSR), insulin receptor substrate 1 (IRS1), insulin-like growth factor 2 (IGF2), IGF2 receptor (IGF2R) and IGF binding protein 1 (IGFBP1), and high myopia (HM) in a Han Chinese population, we have genotyped 24 single nucleotide polymorphisms (SNPs) of these genes in this cohort by Sequenom MassARRAY method. The genotyping data was analyzed by χ(2) test and the linkage disequilibrium block structure was examined by Haploview software. SNPs in the INS-IGF2 region (rs2070762 and rs1003483), and the INSR gene (rs3745551 and rs2229429) showed significant association with HM (allelic P = 0.0085, 0.0494, 0.0171 and 0.0238, respectively). Under the model of risk genotype combination of INSR and IRS1, carrying the variant allele (A) of the IRS1 Gly972Arg SNP (rs1801278) further increased the risk among the rs2229429T allele carriers (odds ratio 6.865, 95 % confidence interval 1.533-30.745). None of the SNPs in the IGF2R and IGFBP1 genes were found to be significantly associated with HM. Genetic variants in the insulin signaling pathway genes may increase the susceptibility of high myopia in Han Chinese.

Functional studies have suggested the important role of early growth response 1 (EGR1) and Laminin α2-chain (LAMA2) in human eye development. Genetic studies have reported a significant association of the single nucleotide polymorphism (SNP) in the LAMA2 gene with myopia. This study aimed to evaluate the association of the tagging SNPs (tSNPs) in the EGR1 and LAMA2 genes with high myopia in two independent Han Chinese populations. Four tSNPs (rs11743810 in the EGR1 gene; rs2571575, rs9321170, and rs1889891 in the LAMA2 gene) were selected, according to the HapMap database (http://hapmap.ncbi.nlm.nih.gov), and were genotyped using the ligase detection reaction (LDR) approach for 167 Han Chinese nuclear families with extremely highly myopic offspring (<-10.0 diopters) and an independent group with 485 extremely highly myopic cases (<-10.0 diopters) and 499 controls. Direct sequencing was used to confirm the LDR results in twenty randomly selected subjects. Family-based association analysis was performed using the family-based association test (FBAT) software package (Version 1.5.5). Population-based association analysis was performed using the Chi-square test. The association analysis power was estimated using online software (http://design.cs.ucla.edu). The FBAT demonstrated that all four tSNPs tested did not show association with high myopia (P>0.05). Haplotype analysis of tSNPs in the LAMA2 genes also did not show a significant association (P>0.05). Meanwhile, population-based association analysis also showed no significant association results with high myopia (P>0.05). On the basis of our family- and population-based analyses for the Han Chinese population, we did not find positive association signals of the four SNPs in the LAMA2 and EGR1 genes with high myopia.

High myopia, highly prevalent in the Chinese population, is a leading cause of visual impairment worldwide. Genetic factors play a critical role in the development of this visual disorder. Genome-wide association studies in recent years have revealed several chromosomal regions that contribute to its progression. To identify additional genetic variants for high myopia susceptibility, we used a genome-wide meta-analysis to examine the associations between the disease and 286 031 single-nucleotide polymorphisms (SNPs) in a combined cohort of 665 cases and 960 controls. The most significant SNPs (n = 61) were genotyped in a replication cohort (850 cases and 1197 controls), and 14 SNPs were further tested through genotyping in two additional validation cohorts (combined 1278 cases and 2486 controls). As a result of this analysis, four SNPs reached genome-wide significance (P < 2.0 × 10(-7)). The most significantly associated SNP, rs2730260 [overall P = 8.95 × 10(-14); odds ratio (95% CI) =1.33 (1.23-1.44)], is located in the VIPR2 gene, which is located in the MYP4 locus. The other three SNPs (rs7839488, rs4395927 and rs4455882) in the same linkage disequilibrium block are located in the SNTB1 gene, with -P values ranging from 1.13 × 10(-8) to 2.13 × 10(-11). The VIPR2 and SNTB1 genes are expressed in the retina and the retinal pigment epithelium and have been previously reported to have potential functions for the pathogenesis of myopia. Our results suggest that variants of the VIPR2 and SNTB1 genes increase susceptibility to high myopia in Han Chinese.

The correlation of age, axial length, and myopic chorioretinal atrophy with vitreous changes in high myopia were analyzed to investigate the development of posterior vitreous detachment (PVD) in high myopia. The vitreous condition of 329 consecutive eyes with high myopia (more than -8.25 diopters (D) and more than 26.0 mm of axial length) was examined biomicroscopically with a +90-D preset lens and a Goldmann three-mirror contact lens. The prevalence of PVD in high myopia was 12.5% in patients between 20 and 29 years of age, and it increased with age. The incidence of PVD in eyes with axial length of more than 30.0 mm was 60.7% and was statistically higher than the prevalence in eyes with an axial length of less than 29.9 mm (P < 0.01). Multiple logistic regression analysis showed that age and axial length were statistically significant factors in the development of PVD and lacuna formation in high myopia (P < 0.01), but the influence of chorioretinal atrophy was not significant. The results of this study suggest that liquefaction of the vitreous begins at a relatively young age in patients with high myopia and progresses with age and axial elongation, thus resulting in a frequent occurrence of PVD.

Purpose. With an increasing proportion of children with myopia especially in Asia, efforts have been made to reduce chances of preventable sight loss related to high myopia in the future. Orthokeratology lens has been used as one of the modalities not just to correct myopia, but also to slow down myopic progression and axial elongation. This case report reviews a patient with clinically significantly high myopia, whose refractive errors was partially corrected with orthokeratology lens and spectacle lenses. Material and Methods. A now 14-year-old patient with a history of fast progressing myopia, was prescribed and commended orthokeratology to manage myopia, while regularly monitoring her refractive errors, axial length, binocular vision status, corneal topography, and anterior eye health was monitored regularly at the author’s practice. Results. Over a two year follow up period, a partial correction of high myopia with orthokeratology lenses and residual refractive errors with additional spectacle lenses was effective in managing this patient’s myopia, as well as slowing of axial elongation. An updated pair of orthokeratology lens with a steeper back optic zone radii were prescribed to reduce superficial corneal staining and to maintain corneal health. Conclusion. Patient commitment and adherence to close monitoring of eyes in terms refractive errors, axial length, and anterior eye health, are vital in achieving a successful orthokeratology lens wear for high myopia. A dual fitting strategy consisting of orthokeratology lens and spectacle wear can be a safe management strategy that is acceptable for patients with high myopia. It would be helpful for practitioners to be able to rely on robust evidence-based guidance when determining whether lens wear can be ceased, i.e. when further axial elongation and myopic progression are no longer likely.

Objective: Schizophrenia is thought to be a neurodevelopmental disorder. As a key regulator in the development of the central nervous system, transcription factor 4 (TCF4) has been shown to be involved in the pathogenesis of schizophrenia. The aim of our study was to assay the association of TCF4 single nucleotide polymorphisms (SNPs) with schizophrenia and the effect of these SNPs on phenotypic variability in schizophrenia in Southern Chinese Han Population.Methods: Four SNPs (rs9960767, rs2958182, rs4309482, and rs12966547) of TCF4 were genotyped in 1137 schizophrenic patients and 1035 controls in a Southern Chinese Han population using the improved multiplex ligation detection reaction (iMLDR) technique. For patients with schizophrenia, the severity of symptom phenotypes was analyzed by the five-factor model of the Positive and Negative Symptom Scale (PANSS). Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale.Results: The results showed that the genotypes and alleles of the three SNPs (rs2958182, rs4309482, and rs12966547) were not significantly different between the control group and the case group (all P > 0.05). rs9960767 could not be included in the statistics for the extremely low minor allele frequency. However, the genotypes of rs4309482 shown a potential risk in the positive symptoms (P = 0.04) and excitement symptoms (P = 0.04) of the five-factor model of PANSS, but not survived in multiple test correction. The same potential risk was shown in the rs12966547 in positive symptoms of the PANSS (P = 0.03).Conclusion: Our results failed to find the associations of SNPs (rs2958182, rs4309482, and rs12966547) in TCF4 with schizophrenia in Southern Chinese Han Population.

Polymorphisms in the promoter regions of matrix metalloproteinase (MMP) genes can cause variations in the expression of the MMP genes in the sclera that can lead to a greater susceptibility to axial elongation of the eye. The purpose of this study was to determine whether functional single-nucleotide polymorphisms (SNPs) in the MMP1, -2, and -3 promoter regions are associated with high myopia in the Japanese. Seven hundred twenty-five unrelated Japanese patients with high myopia (axial length of >or=26.0 mm in both eyes, or refractive error>or=-6.0 D in phakic cases) and >or=40 years of age were studied. Five hundred forty-six healthy, unrelated Japanese who were >or=40 years of age served as population-based control subjects. All the subjects were genotyped for the four functional SNPs MMP1 -1607 1G/2G, MMP2 C-1306T, MMP2 C-735T, and MMP3 -1612 5A/6A with an SNP assay. The distribution of the genotypes in the cases and control subjects was compared by the chi2 test for trend. No significant difference was detected in the distribution of the four SNPs MMP1 -1607 1G/2G (P=0.92), MMP2 C-1306T (P=0.83), MMP2 C-735T (P=0.10), and MMP3 -1612 5A/6A (P=0.62), between the high myopia cases and the general-population controls. The four functional SNPs in the MMP1, -2, and -3 promoter regions do not play critical roles in the development of high myopia in the Japanese population.

One of the serious challenges facing surgeons after congenital cataract extraction with IOL implantation in infancy is unplanned refractive results revealed in the long-term period, including the cases of myopia higher than 3.0 D in approximately 50 %. Purpose. The study aimed to evaluate the clinical and functional condition of the eyes in children with moderate to high myopia. Material and methods. Our study included a total of 33 patients (61 eyes) with pseudophakia, of which 16 (26 eyes) developed moderate (12 eyes) or high (14 eyes) myopia at the age of 5 to 15 years. Parameters of the anterior and posterior eye segments were evaluated using Galilei Dual Scheimpflug Analyzer and Optical Coherence Tomography RS-3000 Advance 2, and the axial length using Optical Biometer Al-Scan. Results. The central corneal thickness (CCT) was found considerably above the norm (up to 580 ± 35 pm) in most cases of pseudophakic myopia (72.2 %). Anterior chamber depth in children (4.07 ± 0.39 mm) was equal to that in adults with pseudophakia. Astigmatism and axial length in children with highmyopia significantly exceeded those in children with moderate myopia (3.5 and 1.88 D; 23.57 ± 1.31 and 25.04 ± 1.90 mm, respectively), while choroidal thickness and best corrected visual acuity (BCVA) were much lower (268 and 181 pm; 0.1 and 0.3, respectively). There were no variations in spherical equivalent between different axial length in high and moderate myopia. Conclusion. Taken together these results suggest that with the increase of astigmatism axial length elongated and high myopia developed in children with pseudophakia. Choroidal thickness declined due this process and may be a cause of poor functional outcome. Sufficient CCT opens possibilities for refractive surgery in those patients to improve visual outcomes.

Introduction: Targeted single nucleotide polymorphisms (SNPs) have been used in genomic prediction methodologies to enhance the accuracy of associated genetic transmitting abilities in Holstein cows. The objective of this study was to identify and validate SNPs associated with fertility traits impacting early embryo mortality. Methods: The mRNA sequencing data from day 16 normal (n = 9) and embryo mortality (n = 6) conceptuses from lactating multiparous Holstein cows were used to detect SNPs. The selection of specific genes with SNPs as preliminary candidates was based on associations with reproductive and fertility traits. Validation of candidate SNPs and genotype-to-phenotype analyses were conducted in a separate cohort of lactating primiparous Holstein cows (n = 500). After genotyping, candidate SNPs were filtered using a quality control pipeline via PLINK software. Continuous numeric and binary models from reproductive traits were evaluated using the mixed procedure for a generalized linear model-one way ANOVA or logistic regression, respectively. Results: Sixty-nine candidate SNPs were initially identified, but only 23 passed quality control procedures. Ultimately, the study incorporated 466 observations for statistical analysis after excluding animals with missing genotypes or phenotypes. Significant (p <0.05) associations with fertility traits were identified in seven of the 23 SNPs: DSC2 (cows with the A allele were older at first calving); SREBF1 and UBD (cows with the T or G alleles took longer to conceive); DECR1 and FASN (cows with the C allele were less likely to become pregnant at first artificial insemination); SREBF1 and BOLA-DMB (cows with the T allele were less likely to be pregnant at 150 days in milk). It was also determined that two candidate SNPs within the DSC2 gene were tag SNPs. Only DSC2 SNPs had an important allele substitution effect in cows with the G allele, which had a decreased age at first calving by 10days. Discussion: Candidate SNPs found in this study could be used to develop genetic selection tools to improve fertility traits in dairy production systems.

The SNTB1 and ZFHX1B gene have susceptibility in northern Han Chinese populations with high myopia

To investigate whether there are associations of genetic variations in chromosome 15q14 and 15q25, recently shown to confer risk of refractive error and myopia in Caucasians, with high myopia in Japanese. A total of 1125 unrelated Japanese patients with high myopia and two independent control groups were evaluated (366 cataract patients without high myopia and 929 healthy Japanese patients). The four single nucleotide polymorphisms (SNPs) rs634990 and rs524952 at 15q14 and rs8027411 and rs17175798 at 15q25 were genotyped. A significant association with high myopia was observed in 15q14 (P = 0.0035 for rs634990 and P = 0.0017 for rs524952 when evaluated with cataract controls and P = 1.91 × 10(-6) for rs634990 and P = 8.78 × 10(-7) for rs524952 with healthy Japanese controls). When evaluated with cataract controls, the odds ratios (95% confidence intervals) were 1.30 (1.10-1.53) for rs634990 C allele and 1.32 (1.11-1.56) for rs524952 A allele. The population attributable risks were 0.29 and 0.30, respectively. The SNPs in 15q25 did not show a significant association with high myopia when evaluated with cataract control (P > 0.42), while it showed a weak association when evaluated with healthy Japanese controls (P = 0.031 for rs8027411 and P = 0.047 for rs17175798) with odds ratios of 1.17 (1.03-1.33) for rs8027411 T allele and 1.15 (1.02-1.31) for rs17175798 C allele. These findings suggest that a region in 15q14 is susceptibility loci for high myopia. This locus harbor susceptibility genes for not only common myopia but also for high myopia. The 15q25 locus might also have association to myopia.

Genome-wide association studies have established a number of replicated single nucleotide polymorphisms (SNPs) for susceptibility to prostate cancer (CaP), but it is unclear whether these susceptibility SNPs are also associated with disease aggressiveness. This study evaluates whether such replication SNPs or other candidate SNPs are associated with CaP aggressiveness in African-American (AA) and European-American (EA) men. A 1,536 SNP panel which included 34 genome-wide association study (GWAS) replication SNPs, 38 flanking SNPs, a set of ancestry informative markers, and SNPs in candidate genes and other areas was genotyped in 1,060 AA and 1,087 EA men with incident CaP from the North Carolina-Louisiana Prostate Cancer Project (PCaP). Tests for association were conducted using ordinal logistic regression with a log-additive genotype model and a 3-category CaP aggressiveness variable. Four GWAS replication SNPs (rs2660753, rs13254738, rs10090154, rs2735839) and seven flanking SNPs were associated with CaP aggressiveness (P < 0.05) in three genomic regions: One at 3p12 (EA), seven at 8q24 (5 AA, 2 EA), and three at 19q13 at the kallilkrein-related peptidase 3 (KLK3) locus (two AA, one AA and EA). The KLK3 SNPs also were associated with serum prostate-specific antigen (PSA) levels in AA (P < 0.001) but not in EA. A number of the other SNPs showed some evidence of association but none met study-wide significance levels after adjusting for multiple comparisons. Some replicated GWAS susceptibility SNPs may play a role in CaP aggressiveness. However, like susceptibility, these associations are not consistent between racial groups.

Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classical Wnt/β-catenin signaling pathway. Our study was aimed to determine the association between five candidate single nucleotide polymorphisms (SNPs) of LRP5 or AXIN1 and osteoporosis susceptibility in Chinese Han population. A total of 599 osteoporosis patients and 599 healthy individuals were recruited for this case-control study. Agena MassARRAY was used to genotype SNPs. The association between SNPs and osteoporosis susceptibility in different genetic models was analyzed by PLINK software. We used false-positive report probability (FPRP) analysis to detect whether the positive results were just chance or noteworthy observations. Multifactor dimension reduction (MDR) was used to analyze the interaction of SNP-SNP in the osteoporosis risk. Finally, haplotype analysis was performed by plink1.07 and Haploview software. We found that LRP5 rs11228240, AXIN1 rs2301522, and rs9921222 were significantly associated with the osteoporosis susceptibility. The results of subgroup analysis showed that LRP5 rs11228240 (protective factor) and AXIN1 rs2301522 (risk factor) were associated with the susceptibility of osteoporosis among participants who were age >60 years, female or BMI ≤ 24; AXIN1 rs9921222 significantly increased the risk of osteoporosis among participants with BMI ≤ 24. The genotype Ars2301522Crs9921222 could increase the susceptibility of osteoporosis (p = 0.026). The rs11228219LPR5, rs11228240 LPR5, rs2301522AXIN1, and rs9921222AXIN1 four-site model was the best model for predicting the osteoporosis risk (test accuracy = 0.541; CVC = 10/10). The LRP5-rs11228240, AXIN1-rs2301522, and AXIN1- rs9921222 were associated with osteoporosis susceptibility in Chinese Han population.

Glioma is a highly fatal malignant tumor with a high recurrence rate, poor clinical treatment effect, and prognosis. We aimed to determine the association between single nucleotide polymorphisms (SNPs) of NDRG1 and glioma risk and prognosis in the Chinese Han population. 5 candidate SNPs were genotyped by Agena MassARRAY in 558 cases and 503 controls; logistic regression was used to analyze the relationship between SNPs and glioma risk. We used multi-factor dimensionality reduction to analyze the interaction of 'SNP-SNP'; the prognosis analysis was performed by log-rank test, Kaplan-Meier analysis, and Cox regression model. Our results showed that the polymorphisms of rs3808599 was associated with the reduction of glioma risk in all participants (OR 0.41, p = 0.024) and the participants ≤ 40years old (OR 0.30, p = 0.020). rs3802251 may reduce glioma risk in all participants (OR 0.79, p = 0.008), the male participants (OR 0.68, p = 0.033), and astrocytoma patients (OR 0.81, p = 0.023). rs3779941 was associated with poor glioma prognosis in all participants (HR = 2.59, p = 0.039) or astrocytoma patients (HR = 2.63, p = 0.038). We also found that the key factors for glioma prognosis may include surgical operation, radiotherapy, and chemotherapy. This study is the first to find that NDRG1 gene polymorphisms may have a certain association with glioma risk or prognosis in the Chinese Han population.