👤 Whitney Hornsby

Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers. This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD. Show less

Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood. To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024. LDL-C level, LDL-C PRS, FH, or pLOF variant status. Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks. Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS. In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted. Show less

Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for coronary artery disease (CAD). Data on long-term outcomes following invasive coronary angiography (ICA) in those with elevated Lp(a) are limited. This study examined the association of Lp(a) levels with clinical outcomes after index ICA, accounting for baseline atherosclerotic plaque burden. Data were from participants with Lp(a) measurement who underwent index ICA between 2000 and 2023. Lp(a) levels were categorized as normal (<75 nmol/L), intermediate (75- < 125 nmol/L), high (125- < 175 nmol/L), and very high (≥175 nmol/L). Angiographic characteristics (severity, burden), CAD presentation (stable, acute), and subsequent clinical outcomes [acute myocardial infarction (AMI), revascularization, in-stent restenosis (ISR), and all-cause mortality] were assessed. Among 5118 participants, 973 (19.0%) had very high Lp(a). Compared with normal Lp(a), very high Lp(a) was associated with severe obstructive CAD {adjusted odds ratio (aOR), 1.51 [95% confidence interval (CI), 1.17-1.96]}, left main disease [aOR, 1.67 (95% CI, 1.22-2.29)], and a 14.04-point higher Gensini score (95% CI, 9.57-18.52). During a median (interquartile range) follow-up of 16.87 (6.38-18.99) years, participants with very high vs. normal Lp(a) had higher risk of AMI [adjusted hazard ratio (aHR), 1.20 (95% CI, 1.05-1.37)], revascularization [aHR, 1.32 (95% CI, 1.13-1.56)], ISR [aHR, 1.28 (95% CI, 1.04-1.56)], and mortality [aHR, 1.19 (95% CI, 1.05-1.34)]. Among 798 individuals undergoing coronary artery bypass grafting surgery after index ICA, those with very high vs. other Lp(a) were more likely to require subsequent percutaneous coronary intervention [aHR, 2.20 (95% CI, 1.06-4.58)]. Elevated Lp(a) levels are associated with increased burden of coronary atherosclerosis and significant residual risk for adverse outcomes following ICA, highlighting a need for targeted risk-reduction strategies. Show less