Abstract 068: Investigation Of Familial Hypercholesterolemia Subtypes In The UK Biobank

Abstract

Familial hypercholesterolemia (FH) is an inherited disorder characterized by lifelong elevated low density lipoprotein cholesterol (LDL-C) and dramatically increased risk for premature atherosclerotic cardiovascular disease (ASCVD). FH diagnosis currently requires either the presence of a pathogenic variant in an FH gene, or phenotypic characteristics. However, genetic studies now suggest that FH encompasses four discrete subtypes: 1) presence of a monogenic FH variant, 2) a high LDL-C polygenic score, “polygenic FH,” 3) elevated lipoprotein(a), and 4) LDL-C > 190 mg/dl and a positive family history without an identifiable genetic cause, or true “phenotypic FH.” Here, we screened 134,444 unrelated white British individuals with exome sequences available in the UK Biobank for individuals with FH subtypes. We classified 358 individuals (1 in 376; 0.27%) with a pathogenic variant in their exome sequence as monogenic FH, 2,800 had polygenic FH (1 in 48; 2.1%), 2,246 had elevated lipoprotein (a) (1 in 60; 1.7%), and 3,146 had phenotypic FH (1 in 43; 2.3%). The remaining 125,894 samples without an FH subtype were classified as controls. We stratified the cohort into statin treated and untreated individuals. Those with an FH subtype were 2.8 times more likely to be prescribed a lipid lowering medication at the baseline interview compared to controls. In the statin treated group (n=21,875), those with monogenic FH were at the highest risk for 10-year incident ASCVD. We observed a 2.7 (95% confidence interval (95% CI): 1.6-4.3) fold higher ASCVD risk in monogenic FH compared to controls as measured by the hazard ratio (HR). Those with elevated lipoprotein (a) and phenotypic FH were also at increased risk for ASCVD (HR = 1.5 (95% CI: 1.1-2.1) and HR = 1.6 (95% CI: 1.3-2.1), respectively). In contrast, we do not observe elevated rates of incident ASCVD in those with polygenic FH relative to controls among treated individuals. In the untreated group (n=112,569), the risk of ASCVD in FH subtypes was more pronounced relative to controls. Individuals with elevated lipoprotein (a) were at the highest risk of incident ASCVD (HR = 2.9, 95% CI: 2.4-3.7) among the four subgroups. In conclusion, we observed differences in ASCVD risk among subtypes of FH. These findings demonstrate the importance of considering subtypes in ASCVD risk assessment for patients who present with the FH phenotype.