We thank Lepre and associates for their interest in and comments to our recent article. Our study was a screening study for genes significantly associated with age-related macular degeneration (AMD). In Lepre and associates’ study, they typed 974 Italian subjects including 342 patients with diagnosis of AMD. With this large number, they had good statistical power to evaluate their findings.
AMD is a complex disorder that is genetically associated with many susceptibility loci. Both genetic predisposition and environmental factors play important roles in the pathogenesis of AMD. In Western countries, dry AMD is more common than the exudative type, but exudative AMD is more common in the Japanese. In addition, there are substantial differences in the disease phenotype and different frequencies of single nucleotide polymorphisms (SNPs) between these 2 groups. In multifactorial diseases, such as AMD, the factors that explain why some individuals develop the more aggressive exudative AMD while others have the dry AMD type have not been definitively determined.
The allele frequency of the T variant of LOXL1 SNP, rs1048661, in Lepre and associates’ study was not significantly different from that in our study. However, the 6 out of 22 cases of T/T homozygote in the exudative AMD cases had massive subretinal hemorrhages, that is, the more severe phenotype. Thus, our findings suggest that the LOXL1 locus could be a modifier for the growth of the choroidal neovascularization.
We agree that the small sample size in our study was a limitation, as we stated in our manuscript, and we could not exclude the possibility of false positives. However, the purpose of our study was to investigate the association between the major AMD gene ARMS2 and the modifier gene in Japanese patients with dry AMD, exudative AMD, and polypoidal choroidal vasculopathy. We had hope that this study would shed light on the effect of this modifier locus on the genetics of AMD.