In Reply We thank Guijarro and colleagues for their interest in our work.1 We agree that an interesting finding from this study is the lesser effect size of polygenic compared with monogenic hypercholesterolemia on cardiovascular disease risk.1 While the reasons for this are not fully known, it appears likely that hypercholesterolemia may manifest earlier in life in those with a monogenic compared with a polygenic cause, leading to greater cumulative exposure to atherogenic low-density lipoprotein (LDL) cholesterol over an individual’s life span. This is supported by the observation that a greater proportion of individuals with monogenic compared with polygenic hypercholesterolemia in the UK Biobank cohort reported a prior history of high cholesterol levels despite similar lipid levels at the time of study enrollment.1 We also note that although the increased risk of cardiovascular disease observed in the polygenic hypercholesterolemia group was modest, this was in comparison with a group of individuals with nongenetic hypercholesterolemia who were matched for LDL cholesterol levels.
Trinder M, Brunham LR. Genetic Confirmation of Monogenic Familial Hypercholesterolemia Advises a More Intensive Lipid-Lowering Approach—Reply. JAMA Cardiol. 2020;5(12):1453. doi:10.1001/jamacardio.2020.4120
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