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Maartje Geerlings, Nicole T.M. Saksens, Bjorn Bakker, Tina Schick, Sascha Fauser, Camiel J F Boon, Eiko de Jong, Carel C B Hoyng, Anneke I Den Hollander; Rare variants in complement genes associated with age-related macular degeneration result in a lower age at onset and higher familial occurrence. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3988.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, rare variants in the CFH (Arg1210Cys), CFI (Gly119Arg), C3 (Lys155Gln) and C9 (Pro167Ser) genes were found to be highly associated with age-related macular degeneration (AMD). The aim of the current study was to determine the contribution of these rare variants in the development of AMD in 22 multiplex families. In addition, we aimed to describe differences in clinical characteristics in carriers versus non-carriers of rare genetic variants, in these multiplex families and in a retrospective case-control cohort.
We included 707 AMD patients and 518 control individuals (>50 years) from the European Genetic Database (EUGENDA) database, including 114 affected and 60 unaffected members of 22 multiplex AMD families. All individuals underwent an ophthalmic examination including grading according to the standard protocol of the Cologne Image Reading Center and Laboratory, and completed a questionnaire on non-genetic risk factors, family history for AMD and age at onset of first symptoms. Venous blood was obtained for genetic analysis and measurement of complement activation levels.
Rare variants CFI Gly119Arg, C9 Pro167Ser and C3 Lys155Gln were identified in five out of 22 multiplex families, but did not completely segregate with the disease phenotype. AMD patients who carried rare variant CFI Gly119Arg, C9 Pro167Ser or C3 Lys155Gln had a significantly lower age at first symptoms (65.7 vs 71.8 years; p = 0.011), and more often had a positive family history for AMD (52.5% vs 19.8%; p < 0.001) than patients who did not carry these rare variants. Advanced AMD patients with geographic atrophy carried these rare variants more frequently than patients with neovascular AMD (p = 0.03).
Rare genetic variants CFI Gly119Arg, C9 Pro167Ser and C3 Lys155Gln are more prevalent in patients with a positive family history for AMD, but do not completely segregate within families. Patients who carry one of these rare variants differ clinically from patients without this rare variant, as they have a lower age at first symptoms and more often progress to geographic atrophy.
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