Risk for coronary artery disease among individuals with normal low-density lipoprotein cholesterol (LDL-C) levels

Low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL are generally considered normal. We tested the controversial hypothesis that a subset of individuals with ‘normal’ LDL-C levels may have a non-negligible risk of coronary artery disease (CAD) due to inherited factors, including monogenic variants and polygenic risk scores (PGS). A retrospective analysis of a prospective cohort from the Genomic Health Initiative at Endeavor Health, including 7,880 participants without a prior diagnosis of CAD and not on statins at recruitment. Participants were stratified by baseline LDL-C levels and followed for incident CAD. The association of CAD risk with carrier status for pathogenic/likely pathogenic (P/LP) variants in LDLR , APOB , and PCSK9 , as well as with PGS, was tested using Cox regression models adjusted for relevant covariates at baseline. Among participants, 31.2% had LDL-C <100 mg/dL (normal), 39.5% had LDL-C 100-129 mg/dL, and 29.3% had LDL-C ≥130 mg/dL. Over a median follow-up of 8 years, CAD was diagnosed in 5.3%, 6.9%, and 7.6% of participants in these LDL-C groups, respectively. Among those with normal LDL-C, CAD incidence rose to 9.5% in individuals with high genetic risk (P/LP variants and/or high PGS). Genetic risk was significantly associated with CAD in multivariable models ( P <0.001). These findings were consistent in subjects of European and non-European ancestry. Individuals with ‘normal’ LDL-C levels can have substantial CAD risk if they carry high genetic risk. These findings underscore the importance of incorporating genetic information into CAD risk assessment, even among those with traditionally normal lipid profiles.