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Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.

Fan Q, Barathi VA, Cheng CY, Zhou X, Meguro A, Nakata I, Khor CC, Goh LK, Li YJ, Lim W, Ho CE, Hawthorne F, Zheng Y, Chua D, Inoko H, Yamashiro K, Ohno-Matsui K, Matsuo K, Matsuda F, Vithana E, Seielstad M, Mizuki N, Beuerman RW, Tai ES, Yoshimura N, Aung T, Young TL, Wong TY, Teo YY, Saw SM - PLoS Genet. (2012)

Bottom Line: We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)).In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1.This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

View Article: PubMed Central - PubMed

Affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.

ABSTRACT
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

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Transcription quantification of ZC3H11A, SLC30A10, and LYPLAL1 in mouse retina, retinal pigment epithelium, and sclera in induced myopic eyes, fellow eyes, and independent control eyes.Myopia was induced using −15 diopter negative lenses in the right eye of mice for 6 weeks. Uncovered left eyes were served as fellow eyes and age-matched naive mice eyes were controls. Quantification of mRNA expression in mice neural retina (retina), retinal pigment epithelium (RPE) and sclera using quantitative real-time PCR. The bar represents the fold changes of mRNA for each gene after normalization using GAPDH as reference. The mRNA levels of murine ZC3H11A, a gene that is conserved with respect to ZC3H11B in human, SLC30A10 and LYPLAL1 in myopic and fellow retina, RPE and sclera are compared with independent controls with P-values as follows: ZC3H11A (retina/RPE/sclera, P = 2.60×10−5, 2.62×10−6 and 1.08×10−4 respectively), SLC30A10 (P = 2.00×10−4, 2.00×10−4 and 4.02×10−4 respectively) and LYPLAL1 (P = 1.50×10−4, 1.50×10−4, 1.54×10−4 respectively). *P<0.0001.
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pgen-1002753-g004: Transcription quantification of ZC3H11A, SLC30A10, and LYPLAL1 in mouse retina, retinal pigment epithelium, and sclera in induced myopic eyes, fellow eyes, and independent control eyes.Myopia was induced using −15 diopter negative lenses in the right eye of mice for 6 weeks. Uncovered left eyes were served as fellow eyes and age-matched naive mice eyes were controls. Quantification of mRNA expression in mice neural retina (retina), retinal pigment epithelium (RPE) and sclera using quantitative real-time PCR. The bar represents the fold changes of mRNA for each gene after normalization using GAPDH as reference. The mRNA levels of murine ZC3H11A, a gene that is conserved with respect to ZC3H11B in human, SLC30A10 and LYPLAL1 in myopic and fellow retina, RPE and sclera are compared with independent controls with P-values as follows: ZC3H11A (retina/RPE/sclera, P = 2.60×10−5, 2.62×10−6 and 1.08×10−4 respectively), SLC30A10 (P = 2.00×10−4, 2.00×10−4 and 4.02×10−4 respectively) and LYPLAL1 (P = 1.50×10−4, 1.50×10−4, 1.54×10−4 respectively). *P<0.0001.

Mentions: Gene expressions for ZC3H11A, SLC30A10 and LYPLAL1 from the tissues of myopic (with SE<−5.0 D) and fellow non-occluded eyes of the experimental mice were compared with age-matched control tissues (Figure 4). The mRNA levels of ZC3H11A, a gene that is conserved with respect to ZC3H11B in human, were significantly down-regulated in myopic eyes compared to naive controls (retina/RPE/sclera, Fold change = −2.88, −3.24 and −2.07; P = 2.60×10−5, 2.62×10−6 and 1.08×10−4, respectively). At the neighboring gene SLC30A10, there was a similarly significant reduction in the expression of mRNA in the retina tissue of myopic eyes in contrast to independent controls (retina/RPE, Fold change = −2.02, −2.69; P = 2.00×10−4, 2.00×10−4, respectively), with elevated expression in the sclera (Fold change = 4.58; P = 4.02×10−4). Another neighboring gene LYPLAL1 exhibited up-regulation of transcription levels in retina tissue but was down-regulated in the sclera (retina/RPE/sclera, Fold change = 2.71, 3.45 and −2.36; P = 1.50×10−4, 1.50×10−4 and 1.54×10−4, respectively).


Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.

Fan Q, Barathi VA, Cheng CY, Zhou X, Meguro A, Nakata I, Khor CC, Goh LK, Li YJ, Lim W, Ho CE, Hawthorne F, Zheng Y, Chua D, Inoko H, Yamashiro K, Ohno-Matsui K, Matsuo K, Matsuda F, Vithana E, Seielstad M, Mizuki N, Beuerman RW, Tai ES, Yoshimura N, Aung T, Young TL, Wong TY, Teo YY, Saw SM - PLoS Genet. (2012)

Transcription quantification of ZC3H11A, SLC30A10, and LYPLAL1 in mouse retina, retinal pigment epithelium, and sclera in induced myopic eyes, fellow eyes, and independent control eyes.Myopia was induced using −15 diopter negative lenses in the right eye of mice for 6 weeks. Uncovered left eyes were served as fellow eyes and age-matched naive mice eyes were controls. Quantification of mRNA expression in mice neural retina (retina), retinal pigment epithelium (RPE) and sclera using quantitative real-time PCR. The bar represents the fold changes of mRNA for each gene after normalization using GAPDH as reference. The mRNA levels of murine ZC3H11A, a gene that is conserved with respect to ZC3H11B in human, SLC30A10 and LYPLAL1 in myopic and fellow retina, RPE and sclera are compared with independent controls with P-values as follows: ZC3H11A (retina/RPE/sclera, P = 2.60×10−5, 2.62×10−6 and 1.08×10−4 respectively), SLC30A10 (P = 2.00×10−4, 2.00×10−4 and 4.02×10−4 respectively) and LYPLAL1 (P = 1.50×10−4, 1.50×10−4, 1.54×10−4 respectively). *P<0.0001.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3369958&req=5

pgen-1002753-g004: Transcription quantification of ZC3H11A, SLC30A10, and LYPLAL1 in mouse retina, retinal pigment epithelium, and sclera in induced myopic eyes, fellow eyes, and independent control eyes.Myopia was induced using −15 diopter negative lenses in the right eye of mice for 6 weeks. Uncovered left eyes were served as fellow eyes and age-matched naive mice eyes were controls. Quantification of mRNA expression in mice neural retina (retina), retinal pigment epithelium (RPE) and sclera using quantitative real-time PCR. The bar represents the fold changes of mRNA for each gene after normalization using GAPDH as reference. The mRNA levels of murine ZC3H11A, a gene that is conserved with respect to ZC3H11B in human, SLC30A10 and LYPLAL1 in myopic and fellow retina, RPE and sclera are compared with independent controls with P-values as follows: ZC3H11A (retina/RPE/sclera, P = 2.60×10−5, 2.62×10−6 and 1.08×10−4 respectively), SLC30A10 (P = 2.00×10−4, 2.00×10−4 and 4.02×10−4 respectively) and LYPLAL1 (P = 1.50×10−4, 1.50×10−4, 1.54×10−4 respectively). *P<0.0001.
Mentions: Gene expressions for ZC3H11A, SLC30A10 and LYPLAL1 from the tissues of myopic (with SE<−5.0 D) and fellow non-occluded eyes of the experimental mice were compared with age-matched control tissues (Figure 4). The mRNA levels of ZC3H11A, a gene that is conserved with respect to ZC3H11B in human, were significantly down-regulated in myopic eyes compared to naive controls (retina/RPE/sclera, Fold change = −2.88, −3.24 and −2.07; P = 2.60×10−5, 2.62×10−6 and 1.08×10−4, respectively). At the neighboring gene SLC30A10, there was a similarly significant reduction in the expression of mRNA in the retina tissue of myopic eyes in contrast to independent controls (retina/RPE, Fold change = −2.02, −2.69; P = 2.00×10−4, 2.00×10−4, respectively), with elevated expression in the sclera (Fold change = 4.58; P = 4.02×10−4). Another neighboring gene LYPLAL1 exhibited up-regulation of transcription levels in retina tissue but was down-regulated in the sclera (retina/RPE/sclera, Fold change = 2.71, 3.45 and −2.36; P = 1.50×10−4, 1.50×10−4 and 1.54×10−4, respectively).

Bottom Line: We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)).In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1.This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

View Article: PubMed Central - PubMed

Affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.

ABSTRACT
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

Show MeSH
Related in: MedlinePlus