Population Genomic Screening Improves Lipid Management in Familial Hypercholesterolemia

Population genomic screening shows significant potential for supporting optimal lipid management and low-density lipoprotein cholesterol (LDL-C) reductions in patients with familial hypercholesterolemia (FH), according to new data published by investigators in Circulation: Genomic and Precision Medicine.¹

What is Familial Hypercholesterolemia?

FH, a genetic disorder, is characterized by lifelong, abnormally high LDL-C levels, which contribute to an increased risk of early-onset cardiovascular events. Pathogenic variants in genes crucial to the lipid metabolism, such as LDLR, APOB, and PCKS9, cause the disorder. There is a significant risk for both untreated males and females, who harbor 50% and 30% risks of experiencing a coronary event by age 50 and age 50 years, respectively.^2,3

Despite its recognition as a serious contributor to early cardiovascular disease and atherosclerosis, FH remains underdiagnosed and undertreated. Because genetic testing is often not possible in many centers, FH can often be overlooked or at least be difficult to distinguish from other causes of high cholesterol.⁴

Large-scale integration of genomics could assist in identifying individuals with FH. Past studies of population genomic screening programs have evaluated the prevalence and risk associated with FH, but there remains limited data on the impact of these programs on clinical outcomes. Pharmacists would benefit immensely from greater clarity on a patient’s FH status, as, based on their diagnosis, LDL-C goals can be adjusted to achieve greater reductions.¹

How Can We Identify FH More Effectively?

Using the Helix Research Network program, a large multicenter population genomics initiative that screens adult patients for CDC-determined genomic conditions, the current authors sought to analyze changes in the clinical management of LDL-C levels among patients with FH. The authors utilized the population screening program to identify patients with an FH-associated pathogenic variant. These results were integrated into a patient’s electronic health records (EHRs) within each health system partner.¹

In their analysis, the investigators evaluated multiple EHR-based clinical outcomes within up to 3 years postscreening for patients identified to have an FH-associated genetic variant. Patients were assessed for new or modified prescriptions for LDL-lowering therapies, including statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Next, changes in serum LDL-C concentrations were computed, with the authors comparing each follow-up LDL-C result to the most recent LDL-C result prescreening. These differences, in addition to the proportions of patients achieving targets of less than 70 mg/dL and over 50% reductions, were calculated.¹

Across the Helix Research Network, 228,602 adults underwent screening for FH between January 2017 and February 2025. A total of 1155 individuals were found to carry a variant linked to FH. EHR data were available for 94.1% of this cohort; these patients had higher mean serum concentrations of LDL-C based on their most recent prescreening measurement and their highest historical measurement. These patients were also more likely than those without FH to have been previously treated with an LDL-lowering agent (57.2% versus 26.7%) and have a prior coronary artery disease diagnosis (17.2% versus 7.4%).¹

Most patients with an FH-associated variant (84.2%) did not have a prior diagnosis of FH documented in the HER. Since genetic screening was employed, 46.0% of patients without a prior diagnosis had a new FH diagnosis subsequently documented in the EHR after a median of 4.7 months. For patients with a new clinical FH diagnosis documented in the EHR within the first year postscreening, 56.9% received new or modified lipid-lowering therapy within the same period, compared with 17.0% of those without documentation.¹

Among patients with at least 1 or more LDL-C measurements postscreening, the overall mean maximum reduction in LDL-C was 34 mg/dL, a 20.6% reduction from baseline. For patients with new or modified therapies within 1-year postscreening, there was a mean LDL-C reduction of 52 mg/dL, compared with 20 mg/dL in individuals with no new or modified therapy. Furthermore, patients with a prior CAD diagnosis were more likely to achieve either a 50% or more reduction in LDL-C or LDL-C levels of less than 70 mg/dL compared with those without a diagnosis.¹

The data suggests that population screening has potential for improving lipid management in patients with FH-associated pathogenic variants. The investigators wrote that their results highlight the significant underdiagnosis of FH in standard clinical practice. Population-level genomic screening could serve to not only identify more patients with the disorder but also direct them to appropriate lipid-lowering therapies to prevent adverse cardiovascular outcomes.¹

“Future efforts should focus on optimizing result documentation, enhancing long-term lipid management, and evaluating cardiovascular outcomes to maximize the benefits of genomic screening,” the study authors concluded.¹

REFERENCES

1. Levy M, Barrett KMS, Betts MN, et al. Population genomic screening and improved lipid management in patients with familial hypercholesterolemia. Circulation: Genomic and Precision Medicine. Published Online November 5, 2025. Accessed November 5, 2025. doi:10.1161/CIRCGEN.125.005206

2. McGowan MP, Dehkordi SHH, Moriarty PM, Duell PB. Diagnosis and treatment of heterozygous familial hypercholesterolemia. J Am Heart Assoc. 2019;8(24):e013225. doi:10.1161/JAHA.119.013225

3. Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. J Am Coll Cardiol. 2018;72(6):662-680. doi:10.1016/j.jacc.2018.05.044

4. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490. doi:10.1093/eurheartj/eht273