- Design
- Drug-target Mendelian randomisation and genetic association analyses
- Population
- 457,242 UK Biobank participants; 7,058 Singapore Epidemiology of Eye Diseases participants
- Primary outcome
- Risk of early, advanced and exudative AMD and polypoidal choroidal vasculopathy
- Effect
- Advanced AMD OR 1.45 (95% CI 1.25 to 1.67) in Europeans; exudative AMD OR 3.14 (2.16 to 4.57) in East Asians
A drug-target Mendelian randomisation study in Ophthalmology (published 29 September) used genetic variants that mimic the effect of cholesteryl ester transfer protein (CETP) inhibitors, a drug class being developed to lower LDL and raise HDL cholesterol. It examined 457,242 UK Biobank participants of European ancestry and 7,058 participants of a Singapore eye study of East Asian ancestry.
Greater genetically proxied CETP inhibition was associated with higher risk of advanced AMD (OR 1.45, 95% CI 1.25 to 1.67) and early AMD (OR 1.29) in Europeans. In East Asians, the associations were stronger for exudative AMD (OR 3.14), typical neovascular AMD (OR 2.84) and polypoidal choroidal vasculopathy (OR 3.18). A genetic score also predicted slightly higher incident AMD in UK Biobank (HR 1.03 per standard deviation).
Genetic proxies are not the same as taking a drug, and no trial has shown CETP inhibitors cause AMD. But the signal is consistent across ancestries and outcomes, and it gives ophthalmologists a reason to ask about this drug class and to support retinal monitoring in its trials. Patients of East Asian ancestry, in whom polypoidal disease is common, may be most relevant.
- Ask patients with AMD about new lipid-modifying drugs, including CETP inhibitors if they reach practice.
- Report any new or worsening AMD in patients on a CETP inhibitor through pharmacovigilance.
- Advise patients not to stop a prescribed lipid drug on the basis of this genetic study.
- Note that the signal was strongest for exudative disease and polypoidal choroidal vasculopathy in East Asians.
Why it matters
A drug class heading for wide cardiovascular use may carry a retinal risk that trials have not been designed to detect.
Don't overread it
Mendelian randomisation estimates lifelong genetic effects, not the effect of taking a drug for a few years; no trial has shown harm.
The statistics, in plain English
Mendelian randomisation uses inherited gene variants as a natural experiment, which reduces confounding but assumes the variants act only through CETP. Odds ratios around 3 in East Asians are large but come from a much smaller cohort. The hazard ratio of 1.03 per standard deviation in UK Biobank is a small effect at the individual level.
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