Associations between CRYBA4 gene variants and high myopia in a Japanese population.
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ABSTRACT:
SUBMITTER: Kawagoe T
PROVIDER: S-EPMC5724408 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: Myopia is the most common ocular disorder worldwide and imposes tremendous burden on the society. It is a complex disease. The MYP6 locus at 22 q12 is of particular interest because many studies have detected linkage signals at this interval. The MYP6 locus is likely to contain susceptibility gene(s) for myopia, but none has yet been identified. METHODOLOGY/PRINCIPAL FINDINGS: Two independent subject groups of southern Chinese in Hong Kong participated in the study an initial study using a discovery sample set of 342 cases and 342 controls, and a follow-up study using a replication sample set of 316 cases and 313 controls. Cases with high myopia were defined by spherical equivalent ? -8 dioptres and emmetropic controls by spherical equivalent within ±1.00 dioptre for both eyes. Manual candidate gene selection from the MYP6 locus was supported by objective in silico prioritization. DNA samples of discovery sample set were genotyped for 178 tagging single nucleotide polymorphisms (SNPs) from 26 genes. For replication, 25 SNPs (tagging or located at predicted transcription factor or microRNA binding sites) from 4 genes were subsequently examined using the replication sample set. Fisher P value was calculated for all SNPs and overall association results were summarized by meta-analysis. Based on initial and replication studies, rs2009066 located in the crystallin beta A4 (CRYBA4) gene was identified to be the most significantly associated with high myopia (initial study: P?=?0.02; replication study: P?=?1.88e-4; meta-analysis: P?=?1.54e-5) among all the SNPs tested. The association result survived correction for multiple comparisons. Under the allelic genetic model for the combined sample set, the odds ratio of the minor allele G was 1.41 (95% confidence intervals, 1.21-1.64). CONCLUSIONS/SIGNIFICANCE: A novel susceptibility gene (CRYBA4) was discovered for high myopia. Our study also signified the potential importance of appropriate gene prioritization in candidate selection.
| S-EPMC3389832 | biostudies-literature
Project description:PurposeMany studies have investigated the relationship of the lumican gene (LUM) rs3759223 variant with the risk of high myopia, but the results have been inconsistent and inconclusive. In this study, we investigated whether LUM rs3759223 is associated with high myopia in a Japanese population.MethodsWe recruited 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE ≥-1.00 D). The rs3759223 variant was genotyped using the TaqMan assay, and the allelic and genotypic diversity among cases and controls was analyzed according to the SE level.ResultsIn the allelic tests, the odds ratio (OR) for the T allele of rs3759223 tended to increase with the progression of SE, and the highest OR (1.56) was found in patients with SE <-15 D in both eyes. The OR of the T allele tended to increase with the progression of SE in the additive, dominant, and recessive inheritance models. However, we found no significant associations for any of the alleles or genotype models.ConclusionThese data support the possibility that the LUM rs3759223 T allele accelerates the progression of SE in the Japanese population, although no significant associations were observed in this study. Additional genetic studies with larger samples that take into account the degree of SE are needed to clarify the contribution of rs3759223 to the risk of high myopia.
| S-EPMC5096747 | biostudies-literature
Project description:PurposePolymorphisms in the insulin-like growth factor 1 (IGF1) gene were previously associated with high or extreme myopia in Caucasian and Chinese populations. In the present study, we investigated whether IGF1 polymorphisms are associated with high myopia in a Japanese population.MethodsA total of 446 Japanese patients with high myopia (≤-9.00 diopters) and 481 Japanese healthy controls (+1.50 diopters to -1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs) in IGF1 and assessed allelic and haplotypic diversity in cases and controls.ResultsThere were no statistically significant differences in the allele frequencies of IGF1 SNPs and genotypes between cases and controls (P>0.05). However, the A allele of rs5742629 and the G allele of rs12423791 were associated with a moderately increased risk of high myopia (odds ratio [OR] =1.20 and OR =1.21, respectively) with borderline statistical significance (P=0.0502, corrected P (Pc) =0.21 and P=0.064, Pc=0.29, respectively). The haplotype consisting of the A allele of rs5742629 and the G allele of rs12423791 was marginally associated with the risk of high myopia (P=0.041; OR =1.21); this association was not significant after correction (Pc=0.19).ConclusionWe found that the IGF1 SNPs are not significantly associated with high myopia in our Japanese population. Our results are in contrast to a previous study in which extreme myopia cases had significantly higher frequencies of the G allele of rs5742629 and the C allele of rs12423791 than controls. Therefore, the IGF1 SNPs may not be important factors for susceptibility to high myopia in all populations. Further genetic studies are needed to elucidate the possible contributions of the IGF1 region to the development of high myopia.
| S-EPMC3804590 | biostudies-literature
Project description:PURPOSE:Many studies have investigated the relationship of paired box 6 (PAX6) gene polymorphisms with the risk of high myopia, but the results across studies remain inconsistent and ambiguous. In the present work, we investigated whether PAX6 polymorphisms are associated with high myopia in a Japanese population. METHODS:A total of 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE?-1.00 D) were recruited. To compare genotype frequencies between cases and controls, we genotyped five single nucleotide polymorphisms in the PAX6 gene that are reportedly associated with high/extreme myopia: rs662702, rs3026393, rs644242, rs3026390, and rs667773. RESULTS:For rs662702, rs644242, and rs667773, odds ratios (ORs) for their risk alleles tended to increase with the progression of SE and axial length in the additive and recessive models. Of these, rs644242 had the highest OR (2.56) in patients with SE<-15 D in both eyes in the recessive model. On the other hand, for rs3026393 and rs3026390, the ORs for their risk alleles tended to increase according to the progression of SE and axial length in the dominant model. Of the two, rs3026393 had the highest OR (2.32) in patients with SE<-15 D in both eyes in the dominant model. However, no significant associations were identified in this study. CONCLUSION:We found that these PAX6 single nucleotide polymorphisms were associated with an increased risk of extreme myopia. Although the results, which are in agreement with some previous studies, did not reach statistical significance, PAX6 single nucleotide polymorphisms may be important risk factors for the development of extreme myopia. Further genetic studies with larger sample sizes and taking into account the degree of myopia are needed to clarify the contribution of PAX6 variants in myopia development.
| S-EPMC4629984 | biostudies-literature
Project description:AIM:To investigate the association between lumican gene -1554 T/C polymorphism and high myopia susceptibility. METHODS:We searched the published literature in the Medline, Embase, and CBM databases from inception to July 2013. A meta-analysis was performed by the programs RevMan 5.1 and Stata 12.0, and the odds ratio (OR) with 95% confidence interval (CI) was calculated in fixed or random effect model based on heterogeneity test among studies. RESLUTS:Seven case-control studies with a total of 1 233 cases and 936 controls were included. A statistical significant association with high myopia was observed in the recessive model (TT vs CT+CC: OR=1.92; 95%CI=1.14-3.23) and codominant model (TT vs CT: OR=1.81, 95%CI=1.19-2.75). CONCLUSION:The present meta-analysis suggested that lumican -1554 T/C polymorphism might be moderately associated with high myopia susceptibility. This conclusion warrants confirmation by further studies.
| S-EPMC3808924 | biostudies-literature
Project description:Myopia is the most common cause of refractive error worldwide. High myopia is a severe type of myopia, which usually accompanies pathological changes in the fundus. To identify high myopia susceptibility genes, DNA-pooling based genome-wide association analysis was used to search for a correlation between single nucleotide polymorphisms and high myopia in a Han Chinese cohort (cases vs. controls in discovery stage: 507 vs. 294; replication stage 1: 991 vs. 1,025; replication stage 2: 1,021 vs. 52,708). Three variants (rs10889602T/G, rs2193015T/C, rs9676191A/C) were identified as being significantly associated with high myopia in the discovery, and replication stage. rs10889602T/G is located at the third intron of phosphodiesterase 4B (PDE4B), whose functional assays were performed by comparing the effects of rs10889602T/T deletion of this risk allele on PDE4B and COL1A1 gene and protein expression levels in the rs10889602T/Tdel/del, rs10889602T/Tdel/wt, and normal control A549 cell lines. The declines in the PDE4B and COL1A1 gene expression levels were larger in the rs10889602T/T deleted A549 cells than in the normal control A549 cells (one-way ANOVA, p < 0.001). The knockdown of PDE4B by siRNA in human scleral fibroblasts led to downregulation of COL1A1. This correspondence between the declines in rs10889602 of the PDE4B gene, PDE4B knockdown, and COL1A1 protein expression levels suggest that PDE4B may be a novel high myopia susceptibility gene, which regulates myopia progression through controlling scleral collagen I expression levels. More studies are needed to determine if there is a correlation between PDE4B and high myopia in other larger sample sized cohorts.
| S-EPMC8804583 | biostudies-literature
Project description:High myopia, which is extremely prevalent in the Chinese population, is one of the leading causes of blindness in the world. Genetic factors play a critical role in the development of the condition. To identify the genetic variants associated with high myopia in the Han Chinese, we conducted a genome-wide association study (GWAS) of 493,947 SNPs in 1088 individuals (419 cases and 669 controls) from a Han Chinese cohort and followed up on signals that were associated with p < 1.0 × 10(-4) in three independent cohorts (combined, 2803 cases and 5642 controls). We identified a significant association between high myopia and a variant at 13q12.12 (rs9318086, combined p = 1.91 × 10(-16), heterozygous odds ratio = 1.32, and homozygous odds ratio = 1.64). Furthermore, five additional SNPs (rs9510902, rs3794338, rs1886970, rs7325450, and rs7331047) in the same linkage disequilibrium (LD) block with rs9318086 also proved to be significantly associated with high myopia in the Han Chinese population; p values ranged from 5.46 × 10(-11) to 6.16 × 10(-16). This associated locus contains three genes-MIPEP, C1QTNF9B-AS1, and C1QTNF9B. MIPEP and C1QTNF9B were found to be expressed in the retina and retinal pigment epithelium (RPE) and are more likely than C1QTNF9B-AS1 to be associated with high myopia given the evidence of retinal signaling that controls eye growth. Our results suggest that the variants at 13q12.12 are associated with high myopia.
| S-EPMC3113245 | biostudies-literature
Project description:Although a myopia susceptibility gene has not yet been elucidated, ten candidate regions (MYP1-MYP10) have been associated with myopia by linkage analysis employing large pedigrees. We report herein on the results of our analysis pertaining to polymorphisms of LAMA1 (alpha subunit of laminin), a promising candidate gene for high myopia present in the MYP2 region of Japanese subjects with high myopia. Three hundred and thirty Japanese subjects with high myopia at a level of greater than -9.25 D and ethnically and sex matched 330 normal controls without high myopia was enrolled in this study. The thirteen SNPs located on the LAMA1 gene were analyzed using PCR and SNP-specific fluorogenic probes. Two of the SNPs were monomorphic and none of the 11 SNPs showed statistically significant association with high myopia in the Japanese population. There is no convincing evidence to prove a connection between nucleotide sequence variations in LAMA1 and high myopia. The pairwise linkage disequilibrium (LD) mapping disclosed a strong value (D' > 0.8) and narrow ranged block within these SNPs.
| S-EPMC2701124 | biostudies-literature
Project description:AIM:To explore whether genetic variations in the MFN1 gene are associated with low to moderate myopia in Chinese population. METHODS:The case-control association analysis was used. The study included 100 independent myopia patients (-0.75 D ? spherical refraction ?-8.00 D) and 100 sex-matched healthy controls (with binocular spherical equivalent ranges between -0.50 D and +0.50 D). Four single nucleotide polymorphism (SNP) tags (rs3976523, rs13098637, rs6762399 and rs7618348) were selected for genotyping by direct sequencing. The frequencies of genotypes and their alleles were calculated based on the number of SNP genotypes in each sample. The Chi-square test was used to examine the difference in the frequency between the myopia cases and controls. RESULTS:Genotype distributions in the four SNPs were all in accordance with the Hardy-Weinberg equilibrium; analysis showed that rs13098637 was significantly associated with low to moderate myopia (P=0.003 and empirical P=0.010). There were no statistically significant differences observed for the genotype or allele frequencies of the other three SNPs between the myopia cases and controls in the Chinese population in this study. CONCLUSION:The current study has revealed that the C allele of rs13098637 in MFN1 had a significant association with low to moderate myopia.
| S-EPMC4651875 | biostudies-literature
Project description:The objective of this study was to investigate whether genetic variations in the paired box 6 (PAX6) gene are associated with high myopia in Japanese subjects.A total of 1,307 unrelated Japanese patients with high myopia (axial length ?26 mm in both eyes) and two independent control groups were evaluated (333 cataract patients without high myopia and 923 age-matched healthy Japanese individuals). We genotyped three tag single-nucleotide polymorphisms (SNPs) in PAX6: rs2071754, rs644242, and rs3026354. These SNPs provided 100% coverage of all phase II HapMap SNPs within the PAX6 region (minor allele frequency ?0.10; r(2) threshold: 0.90). Chi-square tests for trend and multivariable logistic regression were conducted.Genotype distributions in the three SNPs were in accordance with the Hardy-Weinberg equilibrium. After adjusting for age and sex, evaluation of cataract control showed a marginal association with high myopia in rs644242 (odds ratio [95% confidence interval]=0.69 [0.49-0.96], p=0.026), and a significant association was observed in healthy Japanese controls (0.79 [0.66-0.96], p=0.015). We pooled two control cohorts to evaluate the association. This analysis revealed a strong association between rs644242 and high myopia (0.78 [0.65-0.92], p=0.0045). The rs644242 A allele was a protective allele for development of high myopia. Subanalysis also revealed that rs644242 was significantly associated with extreme high myopia (0.78 [0.64-0.95], p=0.0165). The other two SNPs did not show a significant association with this condition.The current study showed a significant association of PAX6 with high and extreme myopia in Japanese participants. The A allele of rs644242 is a protective allele.
| S-EPMC3513191 | biostudies-literature