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Original Investigation |

Rare Genetic Variants Associated With Development of Age-Related Macular Degeneration

Nicole T. M. Saksens, MD1; Maartje J. Geerlings, MSc1; Bjorn Bakker, BaSc1; Tina Schick, MD2; Mohamed R. Daha, PhD3; Sascha Fauser, PhD2; Camiel J. F. Boon, PhD1,4; Eiko K. de Jong, PhD1; Carel B. Hoyng, PhD1; Anneke I. den Hollander, PhD1,5
[+] Author Affiliations
1Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands
2Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
3Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
4Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
5Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
JAMA Ophthalmol. 2016;134(3):287-293. doi:10.1001/jamaophthalmol.2015.5592.
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Importance  Rare variants in the complement genes CFH, CFI, C9, and C3 have been found to be highly associated with age-related macular degeneration (AMD); however, the effect on clinical characteristics and familial segregation by these variants is lacking.

Objectives  To determine the contribution of rare CFH Arg1210Cys, CFI Gly119Arg, C9 Pro167Ser, and C3 Lys155Gln variants in the development of AMD in 22 multiplex families and to describe clinical differences in carriers vs noncarriers in these families and a large case-control cohort.

Design, Setting, and Participants  This retrospective case-control study included 114 affected and 60 unaffected members of 22 multiplex families with AMD as well as 1589 unrelated patients with AMD and 1386 unrelated control individuals enrolled in the European Genetic Database (EUGENDA). Patients were recruited from March 29, 2006, to April 26, 2013, and data were collected from April 20, 2012, to May 7, 2014. All participants underwent an extensive ophthalmic examination and completed a questionnaire. Venous blood samples were obtained from all participants for genetic analysis, including whole-exome sequencing and measurements of complement activation. Data were analyzed from September 23, 2014, to November 4, 2015.

Main Outcomes and Measures  Differences between carriers and noncarriers of rare variants in age at onset of symptoms, the family history of AMD, complement activation levels (C3d:C3 ratio), the presence of reticular pseudodrusen, and AMD phenotype.

Results  Among the 114 affected and 60 unaffected members of 22 multiplex families with AMD and the 1598 unrelated patients with AMD and 1386 controls in the EUGENDA cohort who underwent analysis, the presence of the CFI Gly119Arg, C9 Pro167Ser, or C3 Lys155Gln variant was confirmed in 18 individuals in 5 families but did not completely segregate with the disease. In the case-control cohort, the 91 affected carriers of these variants were younger at symptom onset (mean [SD] age, 67.4 [8.5] vs 71.3 [8.9] years; P = .01) and more often reported a positive family history (35 of 79 [44.3%] vs 367 of 1201 [30.6%]; P = .008) compared with the 1498 noncarriers. Patients with advanced atrophic AMD carried these rare variants more frequently than patients with neovascular AMD (11 of 93 [11.8%] vs 40 of 835 [4.8%]; P = .04).

Conclusions and Relevance  Previously reported rare variants do not completely segregate within families with AMD. However, patients carrying these rare variants differ clinically from noncarriers by an earlier age at symptom onset, higher prevalence of a positive family history, and AMD phenotype. These results suggest that genetic tests for AMD might be designed to detect common and rare genetic variants, especially in families, because rare variants contribute to the age at onset and progression of the disease.

Figures in this Article


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Figure 1.
Pedigrees of 5 Families With Age-Related Macular Degeneration

Pedigrees depict results of segregation analysis of rare and common CFH Tyr402His and ARMS2 Ala69Ser variants in patients with the rare CFI Gly119Arg, C9 Pro167Ser, or C3 Lys155Gln variants of complement factor genes. Risk alleles are indicated in red. Affected individuals are assigned grades representing AMD stage (1 indicates early; 2, intermediate; 3, advanced with subfoveal geographic atrophy; and 4, advanced with choroidal neovascularization). Outer circles mark the individuals who underwent whole-exome sequencing.

Graphic Jump Location
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Figure 2.
Age at Onset and Complement Activation in Carriers vs Noncarriers of Rare Genetic Variants

Analysis was performed in the members of 5 families with age-related macular degeneration (AMD) and in AMD cases and controls from the European Genetic Database (EUGENDA) cohort. The difference in age at onset between carriers and noncarriers was not significant in the families (mean [SD] age, 63.9 [10.3] vs 69.4 [7.1] years) but was significant in the EUGENDA cohort (67.4 [8.5] vs 71.3 [8.9] years). The complement activation ratio between carriers and noncarriers in the families (1.427 vs 1.180) and EUGENDA cohort (1.463 vs 1.455) was not significant. Lines indicate mean values. Ln indicates natural logarithm.

Graphic Jump Location




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