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Hepatocyte growth factor and myopia: genetic association analyses in a Caucasian population.

Yanovitch T, Li YJ, Metlapally R, Abbott D, Viet KN, Young TL - Mol. Vis. (2009)

Bottom Line: A total of 146 multiplex families consisting of 649 Caucasian subjects were included.A promising association between extreme high myopia and the HGF SNP, rs2286194, was also found (APL p=0.005763 for SPH and 0.004103 for SE).No evidence of association was found in the SNPs tested for C-MET.

View Article: PubMed Central - PubMed

Affiliation: Duke University Center for Human Genetics, 595 La Salle Street, Durham, NC 27710, USA.

ABSTRACT

Introduction: Hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (C-MET) genes have previously been reported to be associated with myopia in Asian family-based and case-control association studies, respectively. We examined whether these genes were associated with myopia in a Caucasian family dataset biased towards high myopia.

Methods: Participating families had at least one offspring with high myopia (< or = -5.00 diopters [D]). Genotyping was performed with tagging single nucleotide polymorphisms (SNPs) for each candidate gene using Taqman allelic discrimination assays. The data were analyzed with two family-based association methods, the pedigree disequilibrium test (PDT) and the association in the presence of linkage (APL) test. Analyses compared 1) high myopia (<-5.00 D), 2) mild to moderate myopia (-0.50 to -5.00 D), 3) any myopia (<-0.50 D) and 4) extreme high myopia (< or =-10.00 D) versus emmetropia using refractive error as either sphere (SPH) or spherical equivalent (SE=sphere + [cylinder/2]). Bonferroni correction was applied to adjust for multiple testing leading to significance levels of 0.0125 for HGF and 0.008 for C-MET. Two and three-marker sliding window haplotype association tests using APL were also performed for HGF markers. Significance levels for haplotype association testing were set at 0.01 for the global tests, and 0.007 for the three marker haplotype specific tests and 0.0125 for the two marker haplotype specific tests.

Results: A total of 146 multiplex families consisting of 649 Caucasian subjects were included. The HGF SNP, rs3735520 (APL p=0.002768 for SPH and 0.005609 for SE), and the haplotypes, rs2286194-rs3735520-rs17501108 (APL p=0.007403 for SPH and 0.062685 for SE) and rs12536657-rs2286194 (APL p=0.004219 for SPH and 0.00518 for SE), showed significant association with mild to moderate myopia versus emmetropia. A promising association between extreme high myopia and the HGF SNP, rs2286194, was also found (APL p=0.005763 for SPH and 0.004103 for SE). No evidence of association was found in the SNPs tested for C-MET.

Conclusions: This study supports a strong association between the mild to moderate myopia group and the HGF SNP rs3735520 and the HGF haplotypes rs2286194-rs3735520-rs17501108 and rs12536657-rs2286194, and a moderate association of the extreme high myopia with rs2286194. C-MET polymorphism statistical associations with myopia in an Asian study were not replicated in our Caucasian cohort. HGF may be a potential myopia candidate gene for further investigation.

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Related in: MedlinePlus

Schematic representations of the SNPs selected for the HGF (1A) and C-MET (1B) genes (source UCSC genome browser). A total of 4 SNPs were selected for HGF and 6 were selected for C-MET. The SNPs highlighted in yellow have previously been associated with high myopia as reported by Han et al. [16] for HGF and Khor et al. [Personal communication, Khor CC] for C-MET. All of the SNPs are intronic with the exception of rs3735520 which is located 1.5KB upstream from HGF and rs17501108 which is located 4.5KB upstream from HGF.
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f1: Schematic representations of the SNPs selected for the HGF (1A) and C-MET (1B) genes (source UCSC genome browser). A total of 4 SNPs were selected for HGF and 6 were selected for C-MET. The SNPs highlighted in yellow have previously been associated with high myopia as reported by Han et al. [16] for HGF and Khor et al. [Personal communication, Khor CC] for C-MET. All of the SNPs are intronic with the exception of rs3735520 which is located 1.5KB upstream from HGF and rs17501108 which is located 4.5KB upstream from HGF.

Mentions: For the candidate genes, HGF and C-MET, the SNPSelector® program [18] was used to choose tagging SNPs that met the criteria of a Pearson squared correlation (r2) threshold of 0.76 in the linkage disequilibrium bins and a minor allele frequency (MAF) greater than 5% in the Caucasian population. The SNPs that Han et al. [16] and Khor C.C. (Personal communication) reported to have significant association with myopia were included. Sufficient tagging SNPs were selected to provide full gene coverage. The SNPs chosen for the candidate genes are shown in Figure 1.


Hepatocyte growth factor and myopia: genetic association analyses in a Caucasian population.

Yanovitch T, Li YJ, Metlapally R, Abbott D, Viet KN, Young TL - Mol. Vis. (2009)

Schematic representations of the SNPs selected for the HGF (1A) and C-MET (1B) genes (source UCSC genome browser). A total of 4 SNPs were selected for HGF and 6 were selected for C-MET. The SNPs highlighted in yellow have previously been associated with high myopia as reported by Han et al. [16] for HGF and Khor et al. [Personal communication, Khor CC] for C-MET. All of the SNPs are intronic with the exception of rs3735520 which is located 1.5KB upstream from HGF and rs17501108 which is located 4.5KB upstream from HGF.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2684748&req=5

f1: Schematic representations of the SNPs selected for the HGF (1A) and C-MET (1B) genes (source UCSC genome browser). A total of 4 SNPs were selected for HGF and 6 were selected for C-MET. The SNPs highlighted in yellow have previously been associated with high myopia as reported by Han et al. [16] for HGF and Khor et al. [Personal communication, Khor CC] for C-MET. All of the SNPs are intronic with the exception of rs3735520 which is located 1.5KB upstream from HGF and rs17501108 which is located 4.5KB upstream from HGF.
Mentions: For the candidate genes, HGF and C-MET, the SNPSelector® program [18] was used to choose tagging SNPs that met the criteria of a Pearson squared correlation (r2) threshold of 0.76 in the linkage disequilibrium bins and a minor allele frequency (MAF) greater than 5% in the Caucasian population. The SNPs that Han et al. [16] and Khor C.C. (Personal communication) reported to have significant association with myopia were included. Sufficient tagging SNPs were selected to provide full gene coverage. The SNPs chosen for the candidate genes are shown in Figure 1.

Bottom Line: A total of 146 multiplex families consisting of 649 Caucasian subjects were included.A promising association between extreme high myopia and the HGF SNP, rs2286194, was also found (APL p=0.005763 for SPH and 0.004103 for SE).No evidence of association was found in the SNPs tested for C-MET.

View Article: PubMed Central - PubMed

Affiliation: Duke University Center for Human Genetics, 595 La Salle Street, Durham, NC 27710, USA.

ABSTRACT

Introduction: Hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (C-MET) genes have previously been reported to be associated with myopia in Asian family-based and case-control association studies, respectively. We examined whether these genes were associated with myopia in a Caucasian family dataset biased towards high myopia.

Methods: Participating families had at least one offspring with high myopia (< or = -5.00 diopters [D]). Genotyping was performed with tagging single nucleotide polymorphisms (SNPs) for each candidate gene using Taqman allelic discrimination assays. The data were analyzed with two family-based association methods, the pedigree disequilibrium test (PDT) and the association in the presence of linkage (APL) test. Analyses compared 1) high myopia (<-5.00 D), 2) mild to moderate myopia (-0.50 to -5.00 D), 3) any myopia (<-0.50 D) and 4) extreme high myopia (< or =-10.00 D) versus emmetropia using refractive error as either sphere (SPH) or spherical equivalent (SE=sphere + [cylinder/2]). Bonferroni correction was applied to adjust for multiple testing leading to significance levels of 0.0125 for HGF and 0.008 for C-MET. Two and three-marker sliding window haplotype association tests using APL were also performed for HGF markers. Significance levels for haplotype association testing were set at 0.01 for the global tests, and 0.007 for the three marker haplotype specific tests and 0.0125 for the two marker haplotype specific tests.

Results: A total of 146 multiplex families consisting of 649 Caucasian subjects were included. The HGF SNP, rs3735520 (APL p=0.002768 for SPH and 0.005609 for SE), and the haplotypes, rs2286194-rs3735520-rs17501108 (APL p=0.007403 for SPH and 0.062685 for SE) and rs12536657-rs2286194 (APL p=0.004219 for SPH and 0.00518 for SE), showed significant association with mild to moderate myopia versus emmetropia. A promising association between extreme high myopia and the HGF SNP, rs2286194, was also found (APL p=0.005763 for SPH and 0.004103 for SE). No evidence of association was found in the SNPs tested for C-MET.

Conclusions: This study supports a strong association between the mild to moderate myopia group and the HGF SNP rs3735520 and the HGF haplotypes rs2286194-rs3735520-rs17501108 and rs12536657-rs2286194, and a moderate association of the extreme high myopia with rs2286194. C-MET polymorphism statistical associations with myopia in an Asian study were not replicated in our Caucasian cohort. HGF may be a potential myopia candidate gene for further investigation.

Show MeSH
Related in: MedlinePlus