Heritability and Risk Factors of Incident Small and Large Drusen in the Copenhagen Twin Cohort Eye Study: A 20-Year Follow-Up

Abstract

Introduction: The transition from a normal fundus to one with early drusen (≥ 20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥ 63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursors lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. Methods: Single-center, 20-year follow-up of 138 twins, including biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) 1) < 20 small hard drusen, 2) ≥ 20 small hard drusen, 3) drusen ≥ 63 µm, or 4) ≥ 20 small hard drusen combined with drusen ≥ 63 µm. Additive and dominant genetic effects as well as shared and non-shared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. Results: Median participant age was 59 (range 41 - 66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥ 20 small hard drusen, and 18 had drusen ≥ 63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥ 20 small hard drusen (p = 0.04) and incident drusen ≥ 63 µm (p = 0.003). Having ≥ 20 small hard drusen at baseline was associated with incident drusen ≥ 63 µm at follow-up (p = 0.02). Development of drusen ≥ 63 µm was attributable to 49% genetic effects and 51% environmental effects. Conclusion: The risk of progressing from 0-19 small hard macular drusen per eye to having ≥ 20 small hard drusen or drusen ≥ 63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥ 20 small hard drusen in the absence of drusen ≥ 63 µm at baseline was associated with incident drusen ≥ 63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

Histology, Dimensions, and Fluorescein Staining Characteristics of Nodular and Cuticular Drusen in Age-Related Macular Degeneration

“…25,26 In 138 twins of 69 pairs, the 20-year incidence of developing $20 small hard drusen and drusen $63 mm was 5.6% and 13.1%, respectively. 5 This study also reported that unshared environmental effects (smoking, diet, lifestyle, and physical activity) explained one-half of incident larger drusen (that will enlarge over time), with aging and smoking equal in impact to genetics. 5 Numerous complement genes are strongly expressed in cells of the choroid, 27,28 and drusen themselves are notably immunoreactive for complement proteins.…”

“…5 This study also reported that unshared environmental effects (smoking, diet, lifestyle, and physical activity) explained one-half of incident larger drusen (that will enlarge over time), with aging and smoking equal in impact to genetics. 5 Numerous complement genes are strongly expressed in cells of the choroid, 27,28 and drusen themselves are notably immunoreactive for complement proteins. These genes may regulate outflow in the successive barrier model (above) and respond by resident and transient immune cells of the choroid.…”

“…It has been proposed that noninvasive in vivo multimodal imaging, anchored on optical coherence tomography (OCT), is the best way to learn whether high-risk drusen form as a direct transformation of small hard drusen. 5 We suggest that dye angiography provides important information in this quest.…”

Small hard drusen and associated factors in early seniority

“…We identified three participants where large drusen had developed in a place previously occupied by small hard drusen. Also, having ≥ 20 small hard drusen at baseline increased the 20-year risk of developing larger drusen [ 4 ].…”

“…They typically have a diameter smaller than 63 μm [ 1 – 3 ]. Our study group showed in a recently published 20-year follow-up twin study that ≥ 20 small hard drusen is significantly associated with drusen ≥ 63 μm [ 4 ], which is the conventional threshold for diagnosing age-related macular degeneration (AMD). In the Watermen Study, the presence of numerous (≥ 5) small hard drusen was associated with a higher incidence of soft drusen ≥ 63 μm [ 5 ].…”