Abstract
Myopia is the most common ocular disease worldwide. We investigated the association of high myopia with the common single nucleotide polymorphisms (SNPs) of five candidate genes – early growth response 1 (EGR1), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), jun oncogene (JUN), vasoactive intestinal peptide (VIP), and vasoactive intestinal peptide receptor 2 (VIPR2). We recruited 1200 unrelated Chinese subjects with 600 cases (spherical equivalent ≤−8.00 diopters) and 600 controls (spherical equivalent within ±1.00 diopter). A discovery sample set was formed from 300 cases and 300 controls, and a replication sample set from the remaining samples. Tag SNPs were genotyped for the discovery sample set, and the most significant haplotypes and their constituent SNPs were followed up with the replication sample set. The allele and haplotype frequencies in cases and controls were compared by logistic regression adjusted for sex and age to give P a values, and multiple comparisons were corrected by permutation test to give P aemp values. Odd ratios (OR) were calculated accordingly. In the discovery phase, EGR1, JUN and VIP did not show any significant association while FOS and VIPR2 demonstrated significant haplotype association with high myopia. In the replication phase, the haplotype association for VIPR2 was successfully replicated, but not FOS. In analysis combining both sample sets, the most significant association signals of VIPR2 were the single marker rs2071625 (P a = 0.0008, P aemp = 0.0046 and OR = 0.75) and the 4-SNP haplotype window rs2071623-rs2071625-rs2730220-rs885863 (omnibus test, P a = 9.10e-10 and P aemp = 0.0001) with one protective haplotype (GGGG: P aemp = 0.0002 and OR = 0.52) and one high-risk haplotype (GAGA: P aemp = 0.0027 and OR = 4.68). This 4-SNP haplotype window was the most significant in all sample sets examined. This is the first study to suggest a role of VIPR2 in the genetic susceptibility to high myopia. EGR1, JUN, FOS and VIP are unlikely to be important in predisposing humans to high myopia.
Highlights
Myopia is the most common eye disorder worldwide and has reached epidemic prevalence in East Asia [1]
This study aims to investigate these primary genes for their potential role in the susceptibility to high myopia
Subject demographics Measurements for all traits were highly correlated between the right and the left eyes, for SE (r = 0.97) and axial length (r = 0.96)
Summary
Myopia is the most common eye disorder worldwide and has reached epidemic prevalence in East Asia [1]. High myopia is defined as a refractive error equal to or worse than 26.00 diopters (D). It is the most concerned type because of its association with irreversible visual impairment such as retinal detachment, glaucoma and, in severe cases, blindness [3]. Both environmental and genetic factors play important roles in the development of myopia [4,5], the principal factor is still under debate. Myopia is a complex disease, and genetic variations can increase the susceptibility to environmental factors and cause an early onset and/or aggressive progression. In order to control the progression of myopia, the underlying pathways leading to this condition must be understood
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