Risk alleles in CFH and ARMS2 and the long-term natural history of age-related macular degeneration: the Beaver Dam Eye Study

Abstract

Objective: To describe the relationships of risk alleles in complement factor H (CFH, rs1061170) and age-related maculopathy susceptibility 2 (ARMS2, rs10490924) to the incidence and progression of age-related macular degeneration (AMD) during a 20-year period.

Methods: There were 4282 persons aged 43 to 86 years at the baseline examination in 1988-1990 enrolled in a population-based cohort study who participated in at least 1 examination spaced 5 years apart during a 20-year period and had gradable fundus photographs for AMD and genotype information on CFH and ARMS2. Low, intermediate, and high genetic risk for AMD was defined by the presence of 0 to 1, 2, or 3 to 4 risk alleles for CFH and ARMS2, respectively. Multistate models were used to estimate the progression of AMD throughout the entire age range.

Results: There were 2820 (66%), 1129 (26%), and 333 persons (8%) with low, intermediate, and high genetic risk for AMD, respectively. The 5-year incidences of early and late AMD were 9.1% and 1.6%, respectively, and increased with age but did not differ significantly by sex. Using the multistate model, of persons aged 45 years with no AMD in the low, intermediate, and high AMD genetic risk groups, 33.0%, 39.9%, and 46.5%, respectively, were estimated to develop early AMD, and 1.4%, 5.2%, and 15.3% were estimated to develop late AMD by age 80 years.

Conclusions: These population-based data provide estimates of the long-term risk of the incidence and progression of AMD and its lesions by age and genetic risk alleles for CFH and ARMS2. They also show that when early AMD is present, knowing the phenotype contributes more to risk assessment than knowing the genetic risk based on these 2 AMD genes.

Figures

Figure 1

Estimated cumulative incidence of age related macular degeneration (AMD) by genetic risk and age (assuming no AMD at the starting age) in the Beaver Dam Eye Study, 1988–2010. Rows are ordered by increasing starting age from top to bottom (age 45 and 65 years) and columns are ordered by increasing genetic risk from left to right (low, intermediate, high). For example, Panel A shows the cumulative incidence of AMD in individuals assuming no AMD at age 45 and low genetic risk and Panel E shows the cumulative incidence of AMD in individuals assuming no AMD at age 65 and intermediate genetic risk. Numbers to right of lines indicate AMD severity level on the Beaver Dam AMD Severity Scale.

Figure 2

Estimated cumulative incidence of more severe age related macular degeneration (AMD) in persons at age 45 years by increasing beginning AMD level (rows top [Level 10] to bottom [Level 40]) and increasing genetic risk (columns left [low] to right [high]) in the Beaver Dam Eye Study, 1988–2010. For example, Panel A shows the cumulative incidence of AMD levels 20–50 for an individual whose AMD level is 10 at age 45 and low genetic risk and Panel I shows the cumulative incidence of AMD levels 40 and 50 for an individual who had AMD level 30 age age 45 and high genetic risk. Numbers to right of lines indicate level on the Beaver Dam AMD Severity Scale.

Figure 3

Estimated cumulative incidence by genetic risk level (increasing left [low] to right [high]) of A. intermediate and large size drusen in individuals with no or small drusen at age 45 years; B. hard distinct, soft distinct, and soft indistinct/reticular drusen in individuals with no or hard indistinct drusen at age 45 years; and C. increased retinal pigment, retinal pigment epithelial depigmentation, and pure geographic atrophy in individuals with no pigmentary abnormalities at age 45 years.

Figure 3

Estimated cumulative incidence by genetic risk level (increasing left [low] to right [high]) of A. intermediate and large size drusen in individuals with no or small drusen at age 45 years; B. hard distinct, soft distinct, and soft indistinct/reticular drusen in individuals with no or hard indistinct drusen at age 45 years; and C. increased retinal pigment, retinal pigment epithelial depigmentation, and pure geographic atrophy in individuals with no pigmentary abnormalities at age 45 years.

Figure 3

Estimated cumulative incidence by genetic risk level (increasing left [low] to right [high]) of A. intermediate and large size drusen in individuals with no or small drusen at age 45 years; B. hard distinct, soft distinct, and soft indistinct/reticular drusen in individuals with no or hard indistinct drusen at age 45 years; and C. increased retinal pigment, retinal pigment epithelial depigmentation, and pure geographic atrophy in individuals with no pigmentary abnormalities at age 45 years.

Figure 4

Area under the receiver operating characteristic curves (AUCs) for various models of progression from no or early age-related macular degeneration (AMD) to late AMD over a 5-year interval in the Beaver Dam Eye Study, 1988–2010. ARMS2, age-related maculopathy susceptibility 2; CFH, complement factor H; TR, traditional risk.