Family-Based Association Analysis of Hepatocyte Growth Factor ( HGF ) Gene Polymorphisms in High Myopia

Department of Ophthalmology, The First Affiliated Hospital, Medical College, Zhejiang University, Hangzhou, China.
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.4). 06/2006; 47(6):2291-9. DOI: 10.1167/iovs.05-1344
Source: PubMed

ABSTRACT To investigate the association of high myopia with polymorphisms in the hepatocyte growth factor (HGF) gene, a potential candidate for myopia development.
Single nucleotide polymorphisms (SNPs) were screened and identified in the HGF gene region with denaturing high-performance liquid chromatography, and their linkage disequilibrium pattern was established in a Han Chinese population (n=150). Tag SNPs were selected and genotyped using restriction digestion and fluorescence polarization assays for 128 nuclear families with 133 severely myopic (mean spherical equivalent [MSE]<or=-10.0 D) offspring. A family-based association study was performed using FBAT and GenAssoc (Cambridge University, Cambridge, UK).
Of three tag SNPs (HGF5-5b, HGFe9, and HGFe10b) selected for association study, HGF5-5b, located in the upstream region, was found to be associated with high myopia considered as a quantitative trait (MSE) in additive, dominant, and recessive models (P=0.0157, 0.0108, and 0.0108, respectively). The genotype relative risk was 2.19 for the genotype C/T, and 2.14 for T/T with reference to C/C of HGF5-5b. Significantly reduced transmission was demonstrated for the haplotypes C-A-C (HGF5-5b, HGFe9, and HGFe10b; P=0.0031) and C-A (HGF5-5b and HGFe9; P=0.0015) in the recessive model, whereas significantly increased transmission was found for haplotype T-C (HGF5-5b and HGFe10b; P=0.0040) under the dominant model. Preferential transmission of haplotypes remained significant even after correction for multiple comparisons. Analysis gave similar results, with myopia considered to be a qualitative trait.
HGF is a potential locus associated with high myopia in the Han Chinese population. This is the first study reporting the association of an HGF gene polymorphism with high myopia.

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Available from: Shea Ping Yip, Sep 26, 2015
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    • "To date, over 20 genetic loci have been mapped using linkage analysis for both common myopia and high myopia [11-17]. A recent plethora of genome wide association studies have shown positive associations with refractive error [14,18-25]. Of late, large parallel sequencing techniques have been used to identify causal genes for ocular disorders including myopia. "
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    ABSTRACT: Myopia, or nearsightedness, is highly prevalent in Asian countries and is considered a serious public health issue globally. High-grade myopia can predispose individuals to myopic maculopathy, premature cataracts, retinal detachment, and glaucoma. A recent study implicated zinc finger protein 644 isoform 1 (ZNF644) variants with non-syndromic high-grade myopia in a Chinese-Asian population. Herein we focused on investigating the role for ZNF644 variants in high-grade myopia in a United States (US) cohort. DNA from a case cohort of 131 subject participants diagnosed with high-grade myopia was screened for ZNF644 variants. Spherical refractive error of -≤-6.00 diopters (D) in at least one eye was defined as affected. All coding, intron/exon boundaries were screened using Sanger sequencing. Single nucleotide allele frequencies were determined by screening 672 ethnically matched controls. Sequencing analysis did not detect previously reported mutations. However, our analysis identified 2 novel single nucleotide variants (c.725C>T, c.821A>T) in 2 high-grade myopia individuals- one Caucasian and one African American, respectively. These variants were not found in normal controls. A rare variant - dbsSNP132 (rs12117237→c.2119A>G) - with a minor allele frequency of 0.2% was present in 6 additional cases, but was also present in 5 controls. Our study has identified two novel variants in ZNF644 associated with high-grade myopia in a US cohort. Our results suggest that ZNF644 may play a role in myopia development.
    Molecular vision 04/2012; 18:937-44. · 1.99 Impact Factor
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    • "Vitreous chamber is the largest compartment in the eye, and its depth accounts for the largest proportion of axial length. These findings could explain the previous report of HGF as a high myopia-associated gene in the Chinese population [25]. Intriguingly, HGF exhibited significant interaction with another myopia-associated gene GJD2, which also contributed to the genetic association with axial length and vitreous chamber depth. "
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    ABSTRACT: To investigate the association with ocular biometric parameters in myopia-associated single nucleotide polymorphisms (SNPs) of the gap junction protein delta 2 (GJD2), insulin-like growth factor-1 (IGF1) and hepatocyte growth factor (HGF) genes in two geographically different Chinese cohorts. In 814 unrelated Han Chinese individuals aged above 50 years including 362 inland residents and 432 island dwellers, comprehensive ophthalmic examinations were performed. Three SNPs, including GJD2 rs634990, IGF1 rs6214, and HGF rs3735520, were genotyped. Genetic association with ocular biometric parameters was analyzed in individual cohorts, using linear regression controlled for sex and age. Common associations shared by the two cohorts were revealed by meta-analysis. Meta-analysis showed that GJD2 rs634990 alone was not associated with any biometric parameters (adjusted p>0.645). The T allele of IGF1 rs6214 was specifically associated with thicker lens (β±SE=0.055±0.022, adjusted p=0.034). The A allele of HGF rs3735520 was associated with longer vitreous chamber depth (β±SE=0.143±0.060, adjusted p=0.050). Significant interaction between HGF rs3735520 and GJD2 rs634990 was found in association with axial length and vitreous chamber depth (adjusted p=0.003 and 0.033, respectively), and possibly with spherical error (adjusted p=0.056). Our endophenotyping analysis showed differential association between selected myopia-associated genes and ocular biometric parameters in our Chinese cohorts, which may underline substantial but diversified effects of these genes and their interaction on the development of eye structure and etiology of myopia.
    Molecular vision 03/2012; 18:765-78. · 1.99 Impact Factor
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    • "Over the years, various studies have reported associations between numerous nucleotide variants in several genes and HM [30,42,44,80]. However, subsequent studies have failed to confirm and replicate these associations [40,45,81,82]. "
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    ABSTRACT: Recent work has suggested that insulin-like growth factor 1 (IGF-1) gene polymorphisms are genetically linked with high-grade myopia (HM), which is a complex-trait eye disorder in which numerous candidate loci and genes are thought to play a role. We investigated whether the IGF-1 single nucleotide polymorphisms (SNPs) rs6214, rs10860860, and rs2946834 are associated with HM (≤-6.0 diopters [D]) and any myopia (≤-0.5 D) phenotype in Polish families. Forty-two multiplex HM Polish families, of whom 127 had HM, participated in the study. All of the family members (n=306) underwent a detailed ophthalmic examination, including axial length measurements. The IGF-1 SNPs rs6214, rs10860860, and rs2946834 were evaluated by PCR-RFLP and direct sequencing methods. Both Family-Based Association Test (FBAT) and family-based Pedigree Disequilibrium Test (PDT) were used to examine the potential association of the IGF-1 SNPs rs6214, rs10860860, and rs2946834 with HM or any myopia. To determine the distribution of the HM-associated SNPs rs6214 and rs10860860, 543 unrelated individuals from the general Polish population were also analyzed. We found no significant association between the IGF-1 SNPs rs6214, rs10860860, and rs2946834 and HM or any myopia phenotype in Polish HM families. In the general Polish population, the minor allele frequencies of the SNPs rs6214 and rs10860860 did not deviate significantly from the distribution reported for European populations (p=0.629). In the FBAT analysis under the dominant model, the haplotype consisted of T allele of rs10860860, with C allele of rs2946834 of IGF-1 was found less frequently transmitted to HM individuals (p=0.0065), pointing to a nonassociated or protective haplotype. Our results do not support recent studies reporting an association of the SNPs rs6214, rs10860860, and rs2946834 in the IGF-1 gene with HM and any myopia phenotypes. Further replication studies involving other populations are needed to investigate the possible role of IGF-1 as a potential myopia candidate gene.
    Molecular vision 09/2011; 17:2428-39. · 1.99 Impact Factor
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