Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Historical Cholesterol Exposure

Abstract

AimsFamilial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease (CAD) even after adjusting for low-density lipoprotein cholesterol (LDL-C) levels, using a single measurement. This study evaluated whether multiple historical measures of LDL-C observed in the electronic health record (EHR) can account for the risk associated with FH variants.Methods and ResultsWe analyzed 418,790 participants in the Million Veteran Program with EHR data spanning up to 15 years prior to and 7 years after enrollment, including ∼6.3 million LDL-C measurements. FH variants in LDLR, APOB, and PCSK9 were identified using a custom genotype array. We implemented a nested case-control design, using incidence density sampling to match etiologic exposure windows and measure CAD risk while adjusting for LDL-C exposure. In a cohort of 23,091 primarily prevalent cases and 230,910 matched controls, FH variants conferred increased risk for CAD (odds ratio: 1.53; 95% confidence interval: 1.24 to 1.89; p: 7.8×10−5). Adjusting for mean LDL-C exposure prior to the index date attenuated this risk more than adjusting for a single measurement, but significant risk remained (odds ratio: 1.33; 95% confidence interval: 1.08 to 1.64; p = 8.4×10−3). The pattern was also apparent in stratified analyses by sex and ancestry, and we found evidence of an interaction between sex and FH carrier status.ConclusionThe risk associated with FH variants cannot be fully captured by the LDL-C data available in the EHR, even when considering multiple LDL-C measurements spanning more than a decade.