In the present study, the rs800292 (
CFH gene) was associated with both subtypes of PCV analyzed. We did not examine the Y402H variant in the present study because the minor allele frequency is very low in the Japanese population (0.057%). Furthermore, each subtype was independently associated with
CFH. Therefore, we were not able to rule out the possibility of a susceptibility variant for typical PCV. No subjects in the polypoidal CNV group had the A/A genotype, whereas 7% of typical PCV group patients had this variant. The A/A genotype may be associated with a risk of developing typical PCV. The Y402H variant in the
CFH gene is reportedly associated with ischemic heart disease related to arteriosclerosis.
16 Histopathologic findings of typical PCV suggested arteriosclerosis to likely be the underlying pathology.
7 These reports suggest that the
CFH gene is associated with typical PCV via pathophysiological factors associated with arteriosclerosis. This remains speculative, however. Major limitations of this study are the small sample size and that one of the genotypes (A/A) was not isolated in the CNV group. Further study, with a larger number of subjects, is clearly needed to assess the roles of arteriosclerosis-related pathophysiological factors in PCV.
It has been well established that the
CFH and
ARMS2 genes are associated with AMD, as broadly defined by degenerative maculopathy, and PCV in many cohorts. In particular, A69S in the
ARMS2 gene is strongly associated with AMD and PCV in the Japanese population. Hayashi et al.
12 reported the A69S variant to be associated with all three subtypes of AMD. Their results also indicated a strong association with retinal angiomatous proliferation (RAP), as well as associations with typical AMD (tAMD) and, finally, PCV, which raises the possibility that PCV is not a single disease in terms of its genetic background(s). Recently, Sakurada et al.
17 reported the A69S variant to be associated with subretinal hemorrhage, serous pigment epithelial detachment (PED), and hemorrhagic PED, as well as bilateral lesions and age at PCV onset. Their report also supports a possible correlation of PCV with genetic background.
On the other hand, considering the characteristic IGA and histopathologic findings of PCV, our group reported that PCV could be classified into three groups: typical PCV, which represents choroidal vasculature abnormalities; polypoidal CNV involving deformation of CNV under the retinal pigment epithelium (RPE); and radiation-associated choroidal neovasculopathy.
3 Our research goals, designed to test our hypothesis, include determining which genetic variants are associated with these forms of PCV.
In the present study, there was a significant difference between the typical PCV and polypoidal CNV groups in the distribution of rs10490924. Although rs10490924 was strongly associated with polypoidal CNV, there was no association with typical PCV. In many previous reports, genetic variants in the
ARMS2 gene were found to be associated with PCV. These reports did not estimate associations with the subtypes of PCV described herein and may actually have reflected an association only with polypoidal CNV. Histopathologic features of PCV previously reported by our group support this assumption.
7 One study showed aqueous VEGF levels in eyes with PCV to be higher than those in normal eyes, but significantly lower than levels in eyes with tAMD.
18 This result may also support the existence of distinct varieties of PCV. Although IGA findings of polypoidal CNV appeared to be consistent with CNV, the histopathologic and IGA features of typical PCV showed choroidal vasculature abnormalities. These observations suggest polypoidal CNV to be genetically and histopathologically close to tAMD, a representative form of CNV. Furthermore, typical PCV showed no association with CNV.
In conclusion, the present study is the first to examine the associations between variants in the CFH and ARMS2 genes and PCV subtypes. We found the A/A genotype of rs800292 in the CFH gene to be a potential marker for typical PCV, whereas the T/T genotype of rs10490924 in the ARMS2 gene may be a marker for polypoidal CNV. The rs10490924 variant showed no association with typical PCV. These results suggest that polypoidal CNV has a genetic background different from that of typical PCV. Further studies are needed to examine the effects of various treatments on PCV subtypes.
Supported by the Research Committee on Chorioretinal Degenerations and Optic Atrophy and by The Ministry of Health and Welfare of Japan (MY).
The authors thank all the patients who participated in the study.