Investigation into the genetic cause of high myopia by a candidate-gene approach

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Investigation into the genetic cause of high myopia by a candidate-gene approach


Author: Mak, Ying-ying
Title: Investigation into the genetic cause of high myopia by a candidate-gene approach
Degree: M.Phil.
Year: 2011
Subject: Myopia -- Genetic aspects.
Hong Kong Polytechnic University -- Dissertations
Department: Dept. of Health Technology and Informatics
Pages: xxii, 242 p. : ill. (some col.) ; 30 cm.
Language: English
Abstract: Myopia is the most common eye disorder worldwide. It involves both genetic and environmental factors. In Hong Kong, more than 70% of young adults are myopic. The severe form, high myopia, may lead to blinding disorders such as premature cataract, glaucoma and retinal detachment. This study investigated the genetic association between high myopia and the following genes: insulin-like growth factor 1 (IGF1), insulin-like growth factor 2 (IGF2), insulin-like growth factor binding protein 3 (IGFBP3), insulin-like growth factor binding protein 4 (IGFPB4), retinaldehyde dehydrogenase 2 (ALDH1A2), retinoic acid receptor alpha (RARA), retinoid X receptor alpha (RXRA) and retinoid X receptor beta (RXRB). This aims to provide insight into the genetic basis of myopia that may aid in developing therapy for high myopia in the long run. IGF1 and retinoic acid (RA) have been shown to be effective in altering the synthesis of scleral extracellular matrix components. They contribute to the active remodeling of sclera and facilitate an increase in eye size, the major cause of high myopia. IGF1 is the protein encoded by the IGF1 gene while the IGFBP3 gene encodes a binding protein that has an antagonistic effect on IGF1. IGF2, a protein encoded by the IGF2 gene, was also implicated to have an important local regulatory role in ocular development. Similarly, the IGFBP4 gene produces a binding protein that has a regulatory action on IGF1 and IGF2. The protein product of the ALDH1A2 gene is an enzyme for RA synthesis, while RARA, RXRA and RXRB genes encode the receptors for RA. Tag single nucleotide polymorphisms (SNPs; n=41) in the candidate genes, except the IGF2 gene, were genotyped for 300 highly myopic (-8.00 diopters, D or worse) and 300 unaffected (± 0.75 D) Hong Kong Chinese individuals. Seven tag SNPs in the IGF2 gene were genotyped for 220 Hong Kong Chinese nuclear families with one to three myopic (-5.00 D or worse) offspring. Genotyping was performed by restriction fragment length polymorphism or unlabeled probe melting analysis.
Single-marker and haplotype analyses were carried out in both case-control and family-based association studies. Interaction among candidate genes that might contribute to myopia susceptibility was also investigated. In case-control association study, the haplotype IGF1-S4-5-6 (rs12423791, rs7956547 and rs5742632) of the IGF1 gene showed impressive p value (p=2.66×10⁻⁴), and the haplotype RXRA-S5-7-8 (rs3118571, rs1045570 and rs4842196) of the RXRA gene showed significant association (p=0.029) with high myopia even after correction of multiple comparisons by permutations. Positive signals in these haplotypes are novel findings not reported before. Other candidate genes showed negative signal in both single-marker and haplotype analyses. In the family-based association study, the IGF2 gene showed no association with high myopia in both single-marker and haplotype analyses. The results from gene × gene interaction analysis showed no significant interaction among the candidate genes in contributing to myopia development. In conclusion, the IGF1 and RXRA genes were found to be associated with high myopia. The SNPs of significant haplotypes in IGF1 and RXRA genes and other SNPs in strong linkage disequilibrium with them are probable candidates for altering the risk for myopia, and are suggested for further replication and association study.

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