Rare and Common Genetic Variants, Smoking and Higher Body Mass Index Are Associated with Earlier Age of Progression to Geographic Atrophy and Neovascular Advanced Stages of Macular Degeneration in a Prospective Analysis

ABSTRACT IMPORTANCE Genes and lifestyle factors influence progression to advanced age-related macular degeneration (AAMD). However, the impact of genetic and behavioral factors on age when this transition occurs has not been evaluated prospectively. OBJECTIVE To determine whether genetic and environmental factors are associated with age of progression to AAMD and to quantify the effect on age. DESIGN, SETTING, AND PARTICIPANTS Longitudinal progression to AAMD was based on the severity scale in the Age-Related Eye Disease Study database. Progression was defined as an eye that transitioned from non-advanced dry AMD without any evidence of geographic atrophy (GA) (levels 1-8) to any GA or evidence of neovascularization (NV) or both (levels ≥9) during 13 years follow up. Genotypes were determined from DNA samples. MAIN OUTCOME AND MEASURES A stepwise selection of genetic variants with the eye as the unit of analysis, using age as the time scale, yielded 11 genetic variants associated with overall progression, adjusting for sex, education, smoking history, BMI, baseline severity scale, and AREDS treatment. Multivariate analysis was also performed to calculate the effect of genetic and behavioral factors on age of progression. RESULTS Among 5421 eyes, 1206 progressed. Genetic variants associated with progression to AAMD were in the complement, immune, inflammatory, lipid, extracellular matrix, DNA repair and protein binding pathways. Three of these variants were significantly associated with earlier age of progression, adjusting for other covariates: CFH R1210C (P=0.019) with 4.7 years earlier age at progression among carriers of this mutation, C3 K155Q (P=0.011) with 2.44 years earlier for carriers, and ARMS2/HTRA1 A69S (P=0.012) with 0.67 years earlier per allele. Subjects who were smokers (P CONCLUSIONS Carriers of rare variants in the complement pathway and a common risk allele in ARMS2/HTRA1 develop advanced AMD at an earlier age, and unhealthy behaviors including smoking and higher body mass index lead to earlier age of progression to AAMD. KEY POINTS Question Are genetic and modifiable factors associated with earlier age of developing advanced AMD? Findings In this prospective analysis of 5421 eyes with non-advanced AMD at baseline, 1206 developed advanced stages of AMD. Smoking together with a higher BMI led to 5.5 years earlier progression to advanced disease, and genetic burden, determined by rare and common variants, lowered age of progression by up to an additional 6.0 years, adjusting for all covariates. Meaning Modifiable factors alter age when advanced AMD and associated visual loss occurs, and genetic susceptibility impacts age of this transition. Results underscore the importance of both nature and nurture on earlier progression to advanced disease leading to a longer duration of disease and treatment burden. Submitted as ARVO abstract December, 2019: abstract citation: Widjajahakim R, Rosner B, Seddon J; Rare and Common Genetic Variants and Behavioral Modifiable Factors Are Associated with Earlier Age of Progression to Advanced AMD. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2436).