Objective: To investigate the association of high myopia with common single-nucleotide polymorphisms (SNPs) in the IGF1, IGFBP3, and IGFBP4 genes in a Chinese population. Methods: For our case-control study, we recruited 600 unrelated participants: 300 case participants with high myopia (−8.00 diopters or less) and 300 emmetropic controls (within ±1.00 diopter). Twenty-one tag SNPs were selected from these candidate genes and were genotyped. Genotype data were analyzed by logistic regression. Multiple comparisons were corrected by running 15 000 permutations of case-control status. Results: Although we did not find any significant association for IGF1 SNPs using single-marker analysis, we identified many windows with haplotype frequencies significantly different between case participants and control participants using a variable-sized sliding-window strategy. In particular, the most significant association was shown by a 3-SNP window consisting of rs12423791, rs7956547, and rs5742632 (omnibus test: asymptotic P asym =3.70ϫ10 −9 and empirical P emp =6.67ϫ10 −5). There were 3 high-risk haplotypes: CAC (P asym =2.35ϫ10 −6 ; odds ratio [OR], 5.06), GAT (P asym =3.56ϫ10 −4 ; OR, 3.18), and GGC (P asym =2.25ϫ 10 −3 ; OR, 25.10). There was 1 protective haplotype: GAC (P asym =8.43ϫ10 −4 ; OR, 0.63). On the other hand, our single-marker and haplotype analyses did not show any significant association for IGFBP3 and IGFBP4. Conclusions: IGF1 haplotypes are associated with genetic susceptibility to high myopia in Chinese adults, whereas IGFBP3 and IGFBP4 are unlikely to be important in the genetic predisposition to high myopia. Clinical Relevance: IGF1 is associated with high myopia, and identifying the causal variants is important for understanding the underlying mechanisms.

Objective: To investigate the genetic association between transforming growth factor ␤1 (TGFB1) gene polymorphisms and high myopia in a Chinese population. Methods: Six hundred adults were recruited for this casecontrol study, including 300 subjects with high myopia (−8.0 diopters or worse) and 300 control subjects (within ±1.0 diopters). Seven tag single-nucleotide polymorphisms (SNPs) and 1 coding SNP were genotyped. Their frequencies were compared between cases and controls by statistical tests. Results: Four SNPs in the 5Ј half of the gene showed significant differences in allele and genotype frequencies between cases and controls. The results remained significant after correction for multiple comparisons. The previously reported association of the coding SNP rs1800470 with high myopia was successfully replicated. The tag SNP rs4803455 in intron 2 was found to account for the positive results of the other 3 SNPs by stepwise logistic regression. The minor allele T of rs4803455 was protective against high myopia with an odds ratio of 0.67 (95% confidence interval, 0.53-0.86; P=.001). Conclusion: TGFB1 is a myopia susceptibility gene. Clinical Relevance: TGFB1 is the first myopia susceptibility gene successfully replicated. The functional significance of rs4803455 or the genuine causative SNPs in linkage disequilibrium with it remains to be determined.

This study demonstrates the association of PAX6 variants with susceptibility to high myopia. The PAX6 locus may contain polymorphisms playing a role in high myopia in southern Han Chinese.

MMP2, TIPM2, and TIMP3 genes were not associated with high myopia in this Chinese sample and hence are unlikely to play a major role in the genetic susceptibility to high myopia.

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.