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Maureen Neitz, Jay Neitz; Insight from OPN1LW gene haplotypes into the cause and prevention of myopia. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4842.
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© ARVO (1962-2015); The Authors (2016-present)
Human long (L) and middle (M) wavelength cone photoreceptors play a critical role in myopia. That is, specific haplotypes of the human L and M cone photopigment genes (OPN1LW and OPN1MW, respectively) that cause a messenger RNA (mRNA) splicing defect are associated with high myopia. The splicing defect excludes exon 3 from the mature mRNA. OPN1LW shows extreme haplotype diversity, with 8 single nucleotide polymorphisms (SNPs) in exon 3. The purpose of this study is to investigate the potential role of OPN1LW exon 3 haplotypes in axial myopia.
Subjects were males of European ancestry with normal color vision, a single OPN1LW gene sequence and no eye injury or surgery. They were unselected for refractive error. Exons 2, 3 and 4 of the OPN1LW and OPN1MW genes were sequenced and the relative number of OPN1LW and OPN1MW genes estimated. Spherical equivalent refraction (SER) was calculated from measurements of the corneal curvature and axial length taken with the Zeiss IOL Master. Statistical analyses were performed using the GraphPad InStat3.
There were twelve haplotypes shared by at least three people representing 395 of the 409 subjects. The variation among the median SERs for the twelve haplotypes was greater than expected by chance (p = 0.0076, Kruskal Wallis nonparametric ANOVA). Although there were too many haplotypes to allow specific haplotypes to be associated with SER through multiple comparisons, it is notable that 83% of the males with the haplotype associated with the most myopia had an SER of -1.0 D or lower (more myopic). Previously we reported the SNP rs145009674 had the largest effect on exon 3 exclusion from OPN1LW mRNA. The Mann-Whitney U non-parametric test was used to compare median SERs for subjects with A vs G at SNP rs145009674 (p = 0.0363). The median SER was -0.9975 D for males with haplotypes that had A at rs145009674, and -2.920 D for those with G. Thus, the effect size of A vs G at rs145009674 is about 2 D. The mean SER for the two groups differed by ~1 D (-1.1486 vs -2.504). In this sample, all haplotypes that had G at rs145009674 excluded exon 3 from mRNA ≥18% compared to ≤15% for haplotypes with A.
Common OPN1LW exon 3 haplotypes are associated with common axial myopia. OPN1LW exon 3 SNP rs145009674 has a minor allele frequency of 4% (dbSNP150). Thus, the probability of a male having 2 diopters of refractive error from this SNP alone is ~4%.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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