Abstract 4370493: Hypercholesterolemia polygenic score modulates response to statin therapy

Background: Studies have shown that individuals with high CAD PGS have greater reduction in cardio outcomes from statin use than do those with low PGS. Here, we quantify the effect of a hypercholesterolemia PGS on response to statin therapy. Methods: A retrospective study of real world EMR data from ~200k Helix Research Network participants, enrolled from the general population during routine medical care from >15 health systems across the country. This study utilizes Exome+(R) sequencing; hypercholesterolemia PGS000889; longitudinal LDL levels; and statin start date. We analyzed a median of 9 LDL measurements spanning 8 years and studied percent change in LDL after beginning statins. Results: We analyzed 12,444 individuals who had baseline LDL above 100 mg/dL and then began statins, dropping their LDL by a median of 31%. We found that highPGS individuals (>90%) had less reduction in their LDL compared to lowPGS (<10%). This effect was most pronounced in those with lower baseline LDL: for those with LDL between 100-130, lowPGS individuals saw a 35% reduction, compared to 20% reduction for highPGS, while for those with LDL >160, both high and low PGS experienced a 34% reduction. In contrast, the effect of statins on reducing subsequent CAD was higher for highPGS: a 1.6x reduction in risk for lowPGS vs. a 4.2x reduction for highPGS with baseline LDL 100-300, and a 4.1x reduction for lowPGS vs. 7.1x for highPGS with baseline LDL >160. This observed difference was mostly due to untreated highPGS individuals having high risk even without clinically elevated LDL. Conclusion: Our data shows an association between hypercholesterolemia PGS and CAD risk reduction following statin use. The observed percent LDL reduction appeared lower in highPGS individuals, with the greatest difference in association observed in individuals with relatively low LDL.