Abstract P551: Genetic Variants in the Adenosine Triphosphate-Binding Cassette Transporter A1 and Risk of Age-Related Macular Degeneration

Objective: Genetic variants in the adenosine triphosphate-binding cassette transporter A1( ABCA1 ) is associated with higher concentrations of high-density lipoprotein (HDL) cholesterol. Higher HDL cholesterol concentrations are observationally and genetically associated with higher risk of age-related macular degeneration (AMD). However, whether amino acid changing genetic variants in ABCA1 associated with high HDL cholesterol concentrations confer a higher risk of AMD in the general population is currently unknown. We tested this hypothesis. Methods: We genotyped all amino acid changing ABCA1 variants with a minor allele frequency above 0.002, measured plasma HDL cholesterol and other plasma lipids, and used Cox regression to assess risk of AMD. We created an HDL cholesterol weighted allele score and tested the association with risk of AMD on a continuous scale and in tertiles. Further, we performed mediation analyses. Main outcome measures: 1,554 AMD events. Median follow-up of 10 years. Results: Of 90,344 study participants, 55% were women. Median age was 58 (interquartile range: 47-67) years. On a continuous scale, higher concentrations of genetically determined HDL cholesterol were associated with higher risk of all-cause AMD, dry AMD, and wet AMD both in an age- and sex adjusted model and in a multivariable adjusted model (See Figure). The ABCA1 allele score for the third versus the first tertile was associated with HRs (95% confidence intervals (CIs)) of 1.30 (1.14-1.49) for all-cause AMD, 1.26 (1.06-1.50) for dry AMD, and 1.31 (1.12-1.53) for wet AMD in a multivariable adjusted model. 6-8% of the effect was mediated through HDL cholesterol. There was no interaction between weighted allele score tertiles and confounding factors on risk of AMD. Conclusions: Amino acid changing genetic variants in ABCA1 which were associated with higher HDL cholesterol concentrations, were also associated with higher risk of AMD, both on a weighted allele score continuously and when divided into tertiles.