Genetic mutations and associated phenotypes in familial hypercholesterolemia: A biobank study

Abstract

Background/Synopsis

Familial hypercholesterolemia (FH) is the most common monogenic disease, affecting 1:250-300 people in the general population. Despite the high prevalence of FH, it is often under-recognized and under-treated, which can lead to premature cardiovascular morbidity and mortality in affected individuals. This study explores the relationship between genetic mutations and phenotypic manifestations in familial hypercholesterolemia.

Objective/Purpose

To investigate the phenotypic characteristics associated with genetic mutations in familial hypercholesterolemia, focusing on lipid levels, coronary atherosclerosis, and use of pharmacotherapy. The study aims to provide insights into how genetic variants contribute to clinical outcomes in FH.

Methods

The University of Colorado's Center for Personalized Medicine maintains a genetic biobank of over 235,000 patients, from which a total of 27 participants with mutations consistent with familial hypercholesterolemia were examined. A retrospective analysis was conducted to evaluate the phenotypes including clinical diagnosis, lipid levels, medication usage of these individuals using chart review.

Results

The mean age of participants was 64 years. 96% (26/27) of participants had mutations of the LDL receptor gene (LDL-R). 66% (18/27) had chart identification of heterozygous FH. The most recent mean LDL level was 117 mg/dL (SD = 56 mg/dL), with the average highest recorded LDL-C in the chart of 183 mg/dL. 40% (11/27) of participants had documented coronary atherosclerosis. 70% (19/27) of participants were on statin therapy, and 44% (12/27) were using additional lipid-lowering treatments.

Conclusions

This study highlights the clinical diversity in familial hypercholesterolemia patients based on their genetic mutations and associated phenotypes. Identifying genetic variants in this cohort reveals that while elevated LDL levels and coronary atherosclerosis are common, there is significant variability in clinical presentation, including medication use and clinical identification of heterozygous FH. This approach of identifying genetic mutations first, rather than focusing on phenotypic presentation, offers a unique perspective on FH and its management.