ARMS2/HTRA1 Locus Can Confer Differential Susceptibility to the Advanced Subtypes of Age-Related Macular Degeneration

Abstract

Purpose To determine if genetic variants that have been associated with age-related macular degeneration (AMD) have a differential effect on the risk of choroidal neovascularization (CNV) and geographic atrophy. Design Genetic association study. Methods Setting Multicenter study. Study Population Seven hundred forty-nine participants with geographic atrophy and 3209 participants with CNV were derived from 4 AMD studies with similar procedures from Tufts Medical Center, the Age-Related Eye Disease Study, University of Utah, and Hopital Intercommunal de Creteil. Procedures AMD grade was assigned based on fundus photography and examination using the clinical age-related maculopathy staging system. All samples were genotyped for single nucleotide polymorphisms (SNPs) previously associated with AMD. Allele frequencies were compared between participants with CNV and geographic atrophy using PLINK within each cohort and Mantel-Haenszel meta-analysis was performed to combine odds ratios (OR). Main Outcome Measures Differences in allele frequencies between participants with geographic atrophy and CNV. Results The frequency of the T allele of ARMS2/HTRA1 rs10490924 was significantly higher in participants with CNV than in those with geographic atrophy (OR, 1.37; 95% confidence interval, 1.21–1.54; P value = 4.2 × 10−7). This result remained statistically significant when excluding individuals who had geographic atrophy in 1 eye and CNV in the contralateral eye (P = 2.2 × 10−4). None of the other SNPs showed a significant differential effect for CNV vs geographic atrophy, including CFH, C2/CFB, C3, CFI, LIPC, and TIMP3. Conclusions Genetic variation at the ARMS2/HTRA1 locus confers a differential risk for CNV vs geographic atrophy in a well-powered sample.

Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice

“…This is likely to be the case for CNV pathogenesis as well because PCV and CNV are genetically similar in the 10q26 loci (10). The role of HTRA1 in wet AMD is supported by recent studies showing that genetic variants at HTRA1-ARMS2 loci are significantly associated with lesion sizes in both PCV and CNV patients (49,50), and confer a higher risk of CNV than geographic atrophy in a well-powered sample (51). In contrast, there is no functional evidence to date that ARMS2 plays any angiogenic role related to CNV or PCV.…”

LIPC rs10468017, rs493258 and LPL rs12678919 Role in Patients With Age- Related Macular Degeneration

“…This study included (n=545) patients with advanced AMD and n=275 controls. [23]. Other study done by Zhang goes in agreement with the previous studies-this study group analyzed LIPC in 157 neovascular age-related macular degeneration (nAMD) patients, 250 polypoidal choroidal vasculopathy (PCV) patients and 204 controls without any macular abnormality.…”

“…No association was found with LIPL rs10468017 gene polymorphism and AMD [17]. On the other hand other four studies [16,17,23,24] deny results, and are in conflict with the previuos studies, which proved possible risk-reducing effect on AMD development [11,12,18,19,21,22]. One study revealed rs10468017 in LIPC being associated with a decreased risk of progression from large drusen to NV [25], but it seems that this study can be in agreement with the previous six studies, which found that LIPC rs10468017 can decrease AMD development.…”

“…Among these six studies, two studies analyzed LIPC (rs10468017) gene polymorphism [12,21] and three LIPC (rs493258) [11,18,22], while one study analyzed both gene polymorphisms [19]. Four studies found no association with AMD [16,17,23,24], two studies analyzed only rs10468017 polymorphism association with AMD [16,17] and two other studies analyzed both LIPC gene polymorphisms [23,24]. Interestingly, there was one study [25] which found an association between rs10468017 polymorphism in LIPC and a decreased risk of progression from large drusen to NV (HR=0.57, P=0.04), and from normal to intermediate drusen (HR=0.72, P=0.07) [25].…”

Image and Non-Image Forming Melanopsin Function in Age-Related Macular Degeneration

“…In advanced AMD, a loss of central vision results from disruption and death of the photoreceptors and the underlying layers (retinal pigment epithelium, Bruch's membrane and choriocapillaris) due to central geographic atrophy (GA) or from subretinal choroidal neovascularization (CNV). Pathophysiologically, these two advanced forms of AMD are distinct (Seddon & Chen 2004) and the susceptibility to either GA or CNV might be driven by different gene polymorphisms (Sobrin et al 2011). The progression of AMD occurs in response to deposition of cell debris containing proteins related to inflammation, so-called drusen (Figure 2.1), between the retinal pigment epithelium (RPE) and Bruch's membrane (BM) at early stages of disease (Sarks, Sarks & Killingsworth 1994).…”