3.3
TIGR, TGFB1, cMET, HGF, Collagen Genes,
and Myopia
Chiea-Chuen Khor*
The candidate gene approach is a feasible and widely employed method in our search for disease genes. This approach has resulted in the identification of many putative ‘susceptibility genes’ of which a majority could not be subsequently replicated. This chapter summarizes recent findings in the field of refractive error genetics, and proceeds to highlight some of the prominent findings, which include the successful validation of MYP2, MYP3, and COL2A1 as myopia susceptibility loci. The inherent weaknesses of this approach, as well as the caveats to be mindful of in future studies, are touched upon in the discussion.
Introduction
Myopia is a very common health problem in today’s developed world. The prevalence varies significantly between ethnic groups, but individuals of Asian descent, especially Chinese, have been shown to display a markedly increased prevalence of myopia compared to Western populations. It affects up to 40% of Chinese between the ages of 40 to 79 years. This phenomenon is despite differing environmental and lifestyle conditions in various ‘predominantly Chinese’ countries such as China, Singapore, and Taiwan.1,3–6
There are two forms of myopia that are distinguishable by aetiology. The commoner ‘axial myopia’ results from a disproportionately rapid increase of eye globe length during an individual’s growth phase.
*Division of Infectious Diseases, Genome Institute of Singapore, 60 Biopolis Street, Genome, Singapore 138672; +65 64788200. E-mail: khorcc@gis.a-star.edu.sg.
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‘Refractive myopia’ is less common comparatively, and is primarily due to abnormal light diffraction caused by pathological changes in the refractive elements of the eye: extreme corneal curvature, changes in lens density, or increased refractive index of the ocular media (aqueous and vitreous humor). For all forms of myopia, the image is focused in front of (rather than exactly on) the retina; corrective lenses are thus necessarily convex in nature.
The mechanism of disease pathogenesis for myopia has not been clearly defined to date. However, it is generally agreed that whilst environmental factors (e.g. near work, location of homestead) contribute strongly to the disease process, there appears to be a considerable genetic contribution to disease susceptibility and progression. Firstly, high hereditability estimates for myopia related traits, such as spherical equivalent (SE, measured in Diopters) and axial (eye-globe) length (AL, measured in millimeters) have been previously shown.7 Indeed, epidemiologic8 and twin studies have demonstrated a markedly increased risk between related individuals and myopia (an increase in susceptibility of between 2.5 to 5.5 fold).9–13 Secondly, family segregation studies also report a strong association between parental myopia and myopia in their offspring.14–17 Taken together, all these data strongly implicate the contribution of genetic factors to the pathogenesis of myopia.
To date, more than 14 genetic loci (with each locus implicating the involvement of a genomic region larger than a million base pairs) have been found to be tightly linked to myopia-related phenotypes via family-based linkage studies. These have been designated as MYP loci and numbered according to the chronological timeline of their discovery.18,19 One of these loci (MYP1, located on Chromosome Xq28) has been implicated in Bornholm’s eye disease. Here, patients exhibit X-linked high myopia, mild cone dysfunction, and color vision defects. Other loci that appear to be highly penetrant are MYP2 (18p11.31) and MYP3 (12q21-q23), both of which exhibit an autosomal-dominant mode of inheritance. Subsequent replication studies of linkage at both MYP2 and MYP3 by independent study groups lend further support to the initial observations.
Despite these encouraging findings, many unanswered questions remain; linkage studies have limited absolute resolution, and the majority of linkage signals only point to broad genomic regions. As such, much effort is required in the search for the actual genes and genetic variants directly responsible for altered susceptibility to myopia within these large
203 Candidate Genes in Myopia Susceptibility
linkage regions. Indeed, a more thorough and finer-scale approach with higher resolution is needed to achieve this aim.
Fortunately, the completion of the human genome project (2003) and the wide availability of human haplotype maps (the international HapMap project, completed in 2005; www.hapmap.org) has enabled finescale mapping using single-nucleotide polymorphisms (SNPs). The rapidly declining cost of genotyping has also rendered this approach economically practical, and in the last decade, candidate gene studies using a high density marker set for analysis were performed widely for a broad selection of complex-trait diseases. In addition to this, the advent of genome-wide association studies have ushered in a new dawn for a more ‘unbiased,’ non-hypothesis-based search for disease genes, with encouraging results. Turning to our focus on myopia susceptibility genes, we discuss some current findings with a selection of candidate genes found to be associated with myopia and its related endo-phenotypes.
Candidate Gene Selection Strategies for Myopia
Candidate genes for myopia susceptibility are genes that encode for a protein product hypothesized to biologically influence individual susceptibility, severity, or progression of myopia. They are normally chosen if existing biological information or observations suggest their involvement in disease pathogenesis. Variants within the selected gene(s) are then identified, genotyped, and analyzed for the presence of association with the myopia phenotype studied (e.g. spherical equivalent, all-cause myopia, severe myopia, axial length, and changes in these phenotypes over time).
The selection of candidate genes will be greatly facilitated if some of the potentially important genes could be first linked to myopia via a genome-wide screen. Thus, the combined ‘positional candidate’ approach offers higher chance of success in identifying disease-causing polymorphisms; a pure candidate gene approach is not without its limitations, as many genes have yet to be identified and researchers employing the candidate gene approach are limited to examining the genes that have been described. More often than not, the candidate gene approach relies on a priori information on the possible pathway for pathogenesis. As our understanding of the molecular mechanisms underlying disease susceptibility and progression of myopia is still limited, novel and crucial genes might well be missed.