Cholesteryl Ester Transfer Protein Inhibition and Risk of Age-Related Macular Degeneration.

<h4>Purpose</h4>Cholesteryl ester transfer protein (CETP) inhibitors have shown cardiovascular benefits, but genetically proxied CETP inhibition may increase age-related macular degeneration (AMD) risk. We evaluated this association in European- and East Asian-ancestry populations.<h4>Design</h4>Drug-target Mendelian randomization (MR) and observational genetic association analyses in the UK Biobank and the Singapore Epidemiology of Eye Diseases (SEED) study.<h4>Participants</h4>457,242 UK Biobank participants without AMD at baseline and 7,058 SEED participants.<h4>Methods</h4>In drug-target MR, CETP inhibition was instrumented using a CETP protein quantitative trait locus (pQTL) instrument in Europeans and a high-density lipoprotein (HDL)-weighted CETP-region instrument in East Asians. Outcomes included advanced and early AMD in Europeans and exudative AMD, typical neovascular AMD (nAMD), and polypoidal choroidal vasculopathy (PCV) in East Asians. In observational analyses, a CETP pQTL score was evaluated against incident AMD in the UK Biobank, and an HDL-weighted CETP genetic score against prevalent AMD in SEED.<h4>Main outcome measures</h4>Risk of AMD RESULTS: In drug-target MR, greater genetically proxied CETP inhibition was associated with higher risks of advanced AMD (OR, 1.45; 95% CI, 1.25, 1.67) and early AMD (OR, 1.29; 95% CI, 1.19, 1.41) in Europeans, and exudative AMD (OR, 3.14; 95% CI, 2.16, 4.57), typical nAMD (OR, 2.84; 95% CI, 1.69, 4.79), and PCV (OR, 3.18; 95% CI, 2.05, 4.93) in East Asians (all P<0.001). In UK Biobank, each 1-SD decrease in the CETP pQTL score, representing greater genetically proxied CETP inhibition, was associated with higher incident AMD risk (HR,1.03; 95% CI, 1.01, 1.06; P=0.008). In SEED, the HDL-weighted CETP genetic score showed a U-shaped association with prevalent early AMD. Compared with the midrange group, higher odds were observed in the highest decile, representing greater genetically proxied CETP inhibition (OR, 1.74; 95% CI, 1.07, 2.72; P=0.019), and the lowest tertile, representing weaker inhibition (OR, 1.50; 95% CI, 1.13, 1.99; P=0.005).<h4>Conclusions</h4>Greater genetically proxied CETP inhibition was associated with higher AMD risk across genetic analyses in European- and East Asian-ancestry populations. These findings raise a potential retinal safety signal requiring validation in clinical trials and longitudinal observational studies in clinical practice.