Acta Ophthalmologica 2014
Environmental and genetic risk factors for retinal angiomatous proliferation Albert Caramoy,1 Tina Ristau,1 Yara T. Lechanteur,2 Lebriz Ersoy,1 Sebastian M€ uller,3 3 2 1 2 Faik Gelisken, Carel B. Hoyng, Bernd Kirchhof, Anneke I. den Hollander and Sascha Fauser1 1
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Center for Ophthalmology, University of Tuebingen, Tuebingen, Germany 2
ABSTRACT. Purpose: To identify genetic and environmental risk factors in patients with retinal angiomatous proliferation (RAP), a clinical subtype of age-related macular degeneration (AMD). Methods: In this case–control study, 108 AMD cases with RAP, 258 AMD patients with choroidal neovascularization (CNV) without RAP and 443 healthy controls were evaluated. Single nucleotide polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and various environmental risk factors were analysed. Statistical analysis was performed by univariate and multivariate regression analysis. Results: High age, female sex and genetic variants in CFH and ARMS2 were identified as risk factors for developing any CNV. In RAP patients, arterial hypertension was also identified as a risk factor (OR 2.39; p = 0.0005). Compared with the ‘non-RAP’ CNV group, the association with high age (OR 1.05; p = 0.008) and arterial hypertension (OR 1.82; p = 0.02) was significantly higher in RAP patients, while the association with CFH risk alleles (homozygous OR 0.40; p = 0.003) was significantly lower, which was confirmed in a multivariate analysis (OR 0.41; p = 0.03 for the heterozygous risk allele and OR 0.38; p = 0.03 for the homozygous risk allele). Conclusion: The association with the CFH Y402 risk allele was less pronounced in RAP patients than in ‘non-RAP’ CNV patients, while the association with high age and arterial hypertension appeared to be stronger. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes and their different risk factors and disease mechanisms. Key words: age-related macular degeneration – ARMS2 – CFH – hypertension – retinal angiomatous proliferation – risk factor
Acta Ophthalmol. 2014: 92: 745–748 ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12437
Introduction Age-related macular degeneration (AMD) is a common cause of blindness in industrial countries. Advanced stages are known as geographical atrophy or neovascular AMD. Neovascular AMD
is characterized by choroidal neovascularization (CNV) that originates in the choroid, breaks through Bruch’s membrane and infiltrates the neurosensory retina. Retinal angiomatous proliferation (RAP) is another form of neovascular AMD which originates in
the retina and advances posteriorly into the subretinal space (Yannuzzi et al. 2001). RAP differs from typical CNV in natural course showing a rapid and severe vision loss (Viola et al. 2009) and good response to treatment but high recurrence rates (Stoffelns et al. 2008). Age-related macular degeneration is a complex disease caused by environmental and genetic factors. Two major genetic loci were identified at chromosomes 1q31 and 10q26 which account for more than 50% of cases (Weger et al. 2007). They involve a variant in the complement factor H (CFH) gene, encoding the main regulator of the alternative complement pathway (Hageman et al. 2005), and a polymorphism on chromosome 10q26 encompassing the age-related maculopathy susceptibility 2 (ARMS2) gene (Rivera et al. 2005) and the adjacent high-temperature requirement factor A1 (HTRA1) gene (Dewan et al. 2006) which may alter the integrity of Bruch’s membrane (Vierkotten et al. 2011). While numerous studies have evaluated risk factors for AMD, little data are available for the subgroup of RAP. There is evidence that the CFH risk variant is present less frequently in patients with RAP than in those with other forms of neovascular AMD, while the ARMS2 risk variant showed a stronger association with RAP (Wegscheider et al. 2007; Hayashi et al. 2010). These data suggest that RAP may be a genetically distinct subtype of AMD. In this study, we analysed
745
Acta Ophthalmologica 2014
genetic and environmental risk factors in patients with RAP in comparison to cases with neovascular AMD without RAP and healthy controls.
Methods Study population
From the European Genetic Database (EUGENDA, www.eugenda.org), 443 healthy controls and 366 cases with neovascular AMD were evaluated for this study. The diagnosis of RAP was mainly based on indocyanine green angiography according to characteristics described by Yannuzzi et al. (2001). For comparison, patients with occult or classic CNV were categorized in the CNV ‘non-RAP’ group. We did not enroll patients with retinal scars, if no sufficient medical history of RAP or CNV was present. Individuals were included from the Nijmegen (the Netherlands), Cologne (Germany) and Tuebingen (Germany) areas. Lifestyle factors, including body mass index (BMI), smoking status (never/ever) and arterial hypertension (yes/no), were assessed by a standardized interview-assisted questionnaire. For analysis, BMI was divided into three groups (
Environmental and genetic risk factors for retinal angiomatous proliferation Albert Caramoy,1 Tina Ristau,1 Yara T. Lechanteur,2 Lebriz Ersoy,1 Sebastian M€ uller,3 3 2 1 2 Faik Gelisken, Carel B. Hoyng, Bernd Kirchhof, Anneke I. den Hollander and Sascha Fauser1 1
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Center for Ophthalmology, University of Tuebingen, Tuebingen, Germany 2
ABSTRACT. Purpose: To identify genetic and environmental risk factors in patients with retinal angiomatous proliferation (RAP), a clinical subtype of age-related macular degeneration (AMD). Methods: In this case–control study, 108 AMD cases with RAP, 258 AMD patients with choroidal neovascularization (CNV) without RAP and 443 healthy controls were evaluated. Single nucleotide polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and various environmental risk factors were analysed. Statistical analysis was performed by univariate and multivariate regression analysis. Results: High age, female sex and genetic variants in CFH and ARMS2 were identified as risk factors for developing any CNV. In RAP patients, arterial hypertension was also identified as a risk factor (OR 2.39; p = 0.0005). Compared with the ‘non-RAP’ CNV group, the association with high age (OR 1.05; p = 0.008) and arterial hypertension (OR 1.82; p = 0.02) was significantly higher in RAP patients, while the association with CFH risk alleles (homozygous OR 0.40; p = 0.003) was significantly lower, which was confirmed in a multivariate analysis (OR 0.41; p = 0.03 for the heterozygous risk allele and OR 0.38; p = 0.03 for the homozygous risk allele). Conclusion: The association with the CFH Y402 risk allele was less pronounced in RAP patients than in ‘non-RAP’ CNV patients, while the association with high age and arterial hypertension appeared to be stronger. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes and their different risk factors and disease mechanisms. Key words: age-related macular degeneration – ARMS2 – CFH – hypertension – retinal angiomatous proliferation – risk factor
Acta Ophthalmol. 2014: 92: 745–748 ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12437
Introduction Age-related macular degeneration (AMD) is a common cause of blindness in industrial countries. Advanced stages are known as geographical atrophy or neovascular AMD. Neovascular AMD
is characterized by choroidal neovascularization (CNV) that originates in the choroid, breaks through Bruch’s membrane and infiltrates the neurosensory retina. Retinal angiomatous proliferation (RAP) is another form of neovascular AMD which originates in
the retina and advances posteriorly into the subretinal space (Yannuzzi et al. 2001). RAP differs from typical CNV in natural course showing a rapid and severe vision loss (Viola et al. 2009) and good response to treatment but high recurrence rates (Stoffelns et al. 2008). Age-related macular degeneration is a complex disease caused by environmental and genetic factors. Two major genetic loci were identified at chromosomes 1q31 and 10q26 which account for more than 50% of cases (Weger et al. 2007). They involve a variant in the complement factor H (CFH) gene, encoding the main regulator of the alternative complement pathway (Hageman et al. 2005), and a polymorphism on chromosome 10q26 encompassing the age-related maculopathy susceptibility 2 (ARMS2) gene (Rivera et al. 2005) and the adjacent high-temperature requirement factor A1 (HTRA1) gene (Dewan et al. 2006) which may alter the integrity of Bruch’s membrane (Vierkotten et al. 2011). While numerous studies have evaluated risk factors for AMD, little data are available for the subgroup of RAP. There is evidence that the CFH risk variant is present less frequently in patients with RAP than in those with other forms of neovascular AMD, while the ARMS2 risk variant showed a stronger association with RAP (Wegscheider et al. 2007; Hayashi et al. 2010). These data suggest that RAP may be a genetically distinct subtype of AMD. In this study, we analysed
745
Acta Ophthalmologica 2014
genetic and environmental risk factors in patients with RAP in comparison to cases with neovascular AMD without RAP and healthy controls.
Methods Study population
From the European Genetic Database (EUGENDA, www.eugenda.org), 443 healthy controls and 366 cases with neovascular AMD were evaluated for this study. The diagnosis of RAP was mainly based on indocyanine green angiography according to characteristics described by Yannuzzi et al. (2001). For comparison, patients with occult or classic CNV were categorized in the CNV ‘non-RAP’ group. We did not enroll patients with retinal scars, if no sufficient medical history of RAP or CNV was present. Individuals were included from the Nijmegen (the Netherlands), Cologne (Germany) and Tuebingen (Germany) areas. Lifestyle factors, including body mass index (BMI), smoking status (never/ever) and arterial hypertension (yes/no), were assessed by a standardized interview-assisted questionnaire. For analysis, BMI was divided into three groups (
