Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results. (22nd February 2023)

• Record Type: Journal Article
• Authors: Dikilitas, Ozan; Sherafati, Alborz; Saadatagah, Seyedmohammad; Satterfield, Benjamin A.; Kochan, David C.; Anderson, Katherine C.; Chung, Wendy K.; Hebbring, Scott J.; Salvati, Zachary M.; Sharp, Richard R.; Sturm, Amy C.; Gibbs, Richard A.; Rowley, Robb; Venner, Eric; Linder, Jodell E.; Jones, Laney K.; Perez, Emma F.; Peterson, Josh F.; Jarvik, Gail P.; Rehm, Heidi L.; Zouk, Hana; Roden, Dan M.; Williams, Marc S.; Manolio, Teri A.; Kullo, Iftikhar J.
• Is Part Of: Circulation. Volume 16:Number 2(2023)
• Page Start: e003816
• Publication Date: 2023-02-22
• Subjects: adult -- genomics -- hypercholesterolemia -- penetrance -- prevalence; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.122.003816
• Languages: English
• ISSNs: 2574-8300

Abstract

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 LDLR, APOB, and PCSK9 . 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.