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<.001) or had high BMI (P=0.006) also had an earlier age at progression (4.1 years and 1.4 years, respectively).
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.
Association of Common Genetic Variants with Diabetes and Metabolic Syndrome Related Traits in the Arizona Insulin Resistance Registry: A Focus on Mexican American Families in the Southwest
