Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results.

TitleFamilial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results.
Publication TypeJournal Article
Year of Publication2023
AuthorsDikilitas, O, Sherafati, A, Saadatagah, S, Satterfield, BA, Kochan, DC, Anderson, KC, Chung, WK, Hebbring, SJ, Salvati, ZM, Sharp, RR, Sturm, AC, Gibbs, RA, Rowley, R, Venner, E, Linder, JE, Jones, LK, Perez, EF, Peterson, JF, Jarvik, GP, Rehm, HL, Zouk, H, Roden, DM, Williams, MS, Manolio, TA, Kullo, IJ
JournalCirc Genom Precis Med
Volume16
Issue2
Paginatione003816
Date Published2023 Apr
ISSN2574-8300
KeywordsAdult, Cardiovascular Diseases, Coronary Artery Disease, Electronic Health Records, Genomics, Heart Disease Risk Factors, Humans, Hyperlipoproteinemia Type II, Penetrance, Prevalence, Proprotein Convertase 9, Prospective Studies, Risk Factors
Abstract

BACKGROUND: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network.

METHODS: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including , , and . FH variant prevalence and penetrance (defined as low-density lipoprotein cholesterol >155 mg/dL) were estimated after excluding participants enrolled on the basis of hypercholesterolemia. Multivariable logistic regression was used to estimate the odds of CHD compared to age- and sex-matched controls without FH-associated variants. Process (eg, referral to a specialist or ordering new tests), intermediate (eg, new diagnosis of FH), and clinical (eg, treatment modification) outcomes within 1 year after return of results were ascertained by electronic health record review.

RESULTS: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00-4.53]) and premature CHD (odds ratio, 3.68 [2.34-5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results.

CONCLUSIONS: In a multisite cohort of electronic health record-linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record-linked biobanks to detect FH.

DOI10.1161/CIRCGEN.122.003816
Alternate JournalCirc Genom Precis Med
PubMed ID37071725
PubMed Central IDPMC10113961
Grant ListR01 HL135879 / HL / NHLBI NIH HHS / United States
U01 HG008664 / HG / NHGRI NIH HHS / United States
U01 HG008679 / HG / NHGRI NIH HHS / United States
U01 HG008666 / HG / NHGRI NIH HHS / United States
U01 HG008684 / HG / NHGRI NIH HHS / United States
U01 HG008672 / HG / NHGRI NIH HHS / United States
U01 HG008676 / HG / NHGRI NIH HHS / United States
U01 HG008685 / HG / NHGRI NIH HHS / United States
K24 HL137010 / HL / NHLBI NIH HHS / United States
U01 HG008673 / HG / NHGRI NIH HHS / United States
U54 MD007593 / MD / NIMHD NIH HHS / United States
U01 HG008657 / HG / NHGRI NIH HHS / United States
U01 HG008680 / HG / NHGRI NIH HHS / United States
U01 HG008701 / HG / NHGRI NIH HHS / United States
U01 HG006379 / HG / NHGRI NIH HHS / United States
U01 HG011166 / HG / NHGRI NIH HHS / United States

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