A Functional Polymorphism at the FGF10 Gene Is Associated With Extreme Myopia

Abstract

PURPOSE. Fibroblast growth factor-10 (FGF10) can modulate extracellular matrix associated genes and, therefore, it could be a myopia susceptibility gene. This study used an animal model, single nucleotide polymorphisms (SNPs) association, and genetic functional assay to evaluate FGF10 gene for myopia. METHODS.The expression levels of FGF10 gene were compared among the form deprivation myopic (FDM) eyes, the fellow eyes of the FDM group, and the healthy eyes of experimental mice. In the present study 1020 cases ( À6.0 diopters [D]) and 960 controls ( ‡À1.5 D) were enrolled from a Chinese population. Eight tagging SNPs were genotyped to test for an association between genotypes and myopia. The luciferase reporter assay was conducted for the particular SNP to assess the allelic effect on gene expression. RESULTS.The sclera of FDM eyes had a 2.57-fold higher level of FGF10 mRNA (P ¼ 0.018) than the fellow eyes. Although no SNP was associated with high myopia, SNP rs339501 was significantly associated with extreme myopia ( À10 D, P ¼ 0.008) and the odds ratio (OR) was 1.58 for G allele carriers. The luciferase assay showed that the risk G allele significantly caused a higher expression level than the A allele (P ¼ 0.011).CONCLUSIONS. The evidence suggested FGF10 to be a risk factor for myopia. The sclera of myopic eyes had higher FGF10 levels. The risk G allele of SNP rs339501 was associated with extreme myopia in human and caused a higher gene expression in the luciferase assay. It is concluded that the FGF10 could have been involved in the development of myopia.Keywords: FDM, myopia, FGF10 M yopia is a common eye condition worldwide, and its prevalence varies widely among populations and ages and between the sexes.1-3 When the definition of less than À6 diopters (D) was used, the prevalence of high myopia was found to be 18% among young Taiwanese men and 24% among young Taiwanese women 1 ; both of which are higher than the 13.1% reported among young men in Singapore.2 Furthermore, an increased frequency of high myopia (<À6.0 D) was found in young Taiwanese people: 10.9% in 1983 and 21% in 2000. 4 Myopia progresses quickly in childhood, especially around the teenage years. By early adulthood, the rate of change in ocular refraction tends to decline and the prevalence of myopia stabilizes. 5 Several studies have also shown the family history of myopia to be a significant risk factor. 6,7 Recently, genetic association studies including genome-wide association studies (GWAS) have reported several susceptibility genes to nonsyndromic myopia. 8-17Scleral remodeling is one of the important mechanisms for the development of myopia, 18 Several genes are associated with the scleral remodeling including sulfated glycosaminoglycans (GAGs), 19 matrix metalloproteinases (MMPs), 20 tissue inhibitors of metalloproteinases (TIMPs), 20 and TGF-b. 21 The expression of fibroblast growth factor 10 (FGF10) has been shown to be abundant in the murine retina and sclera. 22,23 FGF10 plays a pivotal role in controlling elongation of lacrima...

Rapid, Accurate, and Non-Invasive Measurement of Zebrafish Axial Length and Other Eye Dimensions Using SD-OCT Allows Longitudinal Analysis of Myopia and Emmetropization

“…Investigation of genetic or environmental causes of myopia and the extent of their contribution requires isolation of each potential factor, as well as comparison with an appropriate control group. Animal models have provided valuable information on how individual genes are associated with myopic eye growth [21] – [23] [24] , while form-deprivation using light-diffusing goggles or eyelid suturing [25] , [26] [27] , [28] , or inducing optical defocus by applying positive or negative lenses have demonstrated the importance of correct visual cues to instruct emmetropic eye growth [29] – [31] . Dark-rearing is also used to induce refractive error, though interestingly, the direction of ametropia (hyperopia vs myopia) following dark-rearing has been found to differ between species, and the direction of refractive error induced may depend on whether the animal is visually experienced before the onset of dark-rearing [32] , [33] .…”

The Fibroblast Growth Factor signaling pathway

“…Both ALSG and LADD syndromes are caused by FGF10 mutations (Table (a)). Severe myopia (nearsightedness) is associated with a single nucleotide polymorphism in FGF10 (Table (a)). In strong support of an FGF10‐FGFR2b signal, loss‐of‐function mutations in FGFR2 are also a cause of LADD syndrome (see below).…”

Cytokine fibroblast growth factor 10 (FGF10) polymorphisms are associated with risk of myopia in young children

“…7,14 Candidate gene approaches have been used to explore the genetic architecture of myopia and some possible susceptibility genes have been reported. 13 His et al 18 first evaluated eight SNPs in FGF10 and found rs339501 was significantly associated with extreme myopia among Chinese Taiwan adults. Then, Yoshida et al 19 replicated the findings in Japanese adults and found rs339501, rs12517396, and rs10462070 (in complete linkage disequilibrium) were associated with extreme myopia.…”