Circulation. Genomic and precision medicine · 2025
Population Genomic Screening and Improved Lipid Management in Patients With Familial Hypercholesterolemia.
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Levy Matthew E, Schiabor Barrett Kelly M, Betts Megan N, Kann David, Bolze Alexandre, Khuder Basil, Telis Natalie, McEwen Lisa M, Sturm Amy C, Haldeman-Englert Chad, Cauwels Jeremy, Stoller Douglas, Chahal C Anwar A, Chapman Christopher N, Waring Ashley A, Olson Douglas A, Grzymski Joseph J, Washington Nicole L, Lee William, Cirulli Elizabeth T, Hajek Catherine
Аннотация
BACKGROUND: The Helix Research Network program is a large population genomics initiative that screens an all-comers population of patients for Centers for Disease Control and Prevention Tier 1 genetic conditions, including familial hypercholesterolemia (FH). We evaluated changes in clinical management and low-density lipoprotein cholesterol (LDL-C) levels among patients we identified to have FH.
METHODS: Participants across 9 US health systems provided samples that underwent clinical-grade exome sequencing. Individuals with a positive screening result for a Tier 1 condition were offered no-cost genetic counseling through their health system. Using medication and laboratory testing records, we evaluated changes in patients' lipid-lowering therapies and LDL-C levels.
RESULTS: Among 228 602 adults enrolled between 2017 to 2025, 1155 (≈1/198) had a pathogenic FH variant in LDLR (74%), APOB (25%), or PCSK9 (1%). Of the 622 with retrospective and prospective electronic health record data available (mean of 11.8 and 2.1 years, respectively), 84% lacked a prior clinical FH diagnosis. Overall, 33% received new/modified lipid-lowering therapy within the first year, but this proportion was higher in those with a newly documented FH diagnosis code (57% versus 17% for those without documentation; P<0.001). Patients with new/modified therapies had a mean LDL-C reduction of 52 mg/dL, compared with 20 mg/dL in patients with no therapeutic change (difference=32 mg/dL; P<0.001).
CONCLUSIONS: Following genetic screening, many patients with a pathogenic FH variant experienced improvements in clinical management and LDL-C levels. Electronic health record documentation of the diagnosis code was associated with a greater likelihood of therapeutic modifications, which, in turn, were associated with larger LDL-C reductions. Findings underscore the powerful potential of population genomic screening for supporting optimal lipid management in individuals with FH.
METHODS: Participants across 9 US health systems provided samples that underwent clinical-grade exome sequencing. Individuals with a positive screening result for a Tier 1 condition were offered no-cost genetic counseling through their health system. Using medication and laboratory testing records, we evaluated changes in patients' lipid-lowering therapies and LDL-C levels.
RESULTS: Among 228 602 adults enrolled between 2017 to 2025, 1155 (≈1/198) had a pathogenic FH variant in LDLR (74%), APOB (25%), or PCSK9 (1%). Of the 622 with retrospective and prospective electronic health record data available (mean of 11.8 and 2.1 years, respectively), 84% lacked a prior clinical FH diagnosis. Overall, 33% received new/modified lipid-lowering therapy within the first year, but this proportion was higher in those with a newly documented FH diagnosis code (57% versus 17% for those without documentation; P<0.001). Patients with new/modified therapies had a mean LDL-C reduction of 52 mg/dL, compared with 20 mg/dL in patients with no therapeutic change (difference=32 mg/dL; P<0.001).
CONCLUSIONS: Following genetic screening, many patients with a pathogenic FH variant experienced improvements in clinical management and LDL-C levels. Electronic health record documentation of the diagnosis code was associated with a greater likelihood of therapeutic modifications, which, in turn, were associated with larger LDL-C reductions. Findings underscore the powerful potential of population genomic screening for supporting optimal lipid management in individuals with FH.