Citations 2
Abstract 10822: Familial Hypercholesterolemia in the EMERGE Network: 1-Year Outcomes After Return of Results
Kochan, David C., Perez, Emma , Anderson, Katherine , Salvati, Zachary , Hebbring, Scott J. , Gibbs, Richard A. , Linder, Jodell E. , Roden, Dan M. , Manolio, Teri A. , Sherafati, Alborz , Dikilitas, Ozan , Saadatagah, Seyedmohammad , Satterfield, Benjamin A. , Jones, Laney K , Sharp, Richard R. , Sturm, Amy C. , Zouk, Hana , Venner, Eric , Chung, Wendy K. , Peterson, Josh F. , Jarvik, Gail P. , Rehm, Heidi L. , Roden, Dan M. , Williams, Marc S , Kullo, Iftikhar J.
Circulation | June 15, 2023 | Volume: 146 | Issue: Suppl_1 | Pages: No page available
10.1161/circ.146.suppl_1.10822
Introduction: Relatively little is known about outcomes following return of secondary findings detected in large scale sequencing projects. We assessed 1-year outcomes following return of pathogenic/likely pathogenic (P/LP) variants associated with familial hypercholesterolemia (FH) in phase III of the eMERGE network (2015-2019). Methods: Adult participants (n=18,544) at 7 sites were enrolled in a prospective cohort study to study the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . Process, intermediate, and/or clinical outcomes within 1-year after return of results (RoR) were ascertained by electronic health record (EHR) review. A process outcome was defined as referral to a specialist or ordering new tests, including lipid profile and screening tests for coronary heart disease. An intermediate outcome was defined as new diagnosis of FH or atherosclerotic cardiovascular disease. A clinical outcome was defined as initiation or change in lipid-lowering medication. The primary outcomes were a new diagnosis of FH and modification of lipid lowering therapy. Results: Results were returned to 134 individuals, and data for 119 participants were available for the outcomes analysis. Process (86%), intermediate (49%), and/or clinical (26%) outcomes occurred in 92% of participants. Process outcomes included 72% with new tests ordered and 61% referred to a specialist. Before RoR, 86.5% of individuals with FH associated P/LP variants had a diagnosis of hypercholesterolemia but only 17.6% had a diagnosis of FH; 89% were on a statin but only 58% were on a high intensity statin. Following RoR, 44% (52/119) received a new diagnosis of FH. Lipid lowering treatment was modified in 26% (31/119), including initiation of a statin in 5%, increasing statin dose in 13%, and adding ezetimibe or a PCSK9 inhibitor in 12.6%. Conclusions: In a multisite cohort of EHR-linked biobanks, monogenic FH was underdiagnosed (only 17.6% had a specific diagnosis) and undertreated (only 58% were on a high intensity statin); 44% of participants received a new diagnosis of FH and 26% had lipid lowering treatment modified after RoR. These results highlight the clinical utility of returning FH variants in EHR-linked biobanks.
Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results
Dikilitas, Ozan , Sherafati, Alborz , Saadatagah, Seyedmohammad , Kochan, David C., Anderson, Katherine , Chung, Wendy K. , Hebbring, Scott J. , Salvati, Zachary , Sharp, Richard R. , Sturm, Amy C. , Gibbs, Richard A. , Rowley, Robb , Linder, Jodell E. , Perez, Emma , Peterson, Josh F. , Jarvik, Gail P. , Roden, Dan M. , Manolio, Teri A. , Satterfield, Benjamin A , Anderson, Katherine C , Chung, Wendy K. , Salvati, Zachary M , Sharp, Richard R , Sturm, Amy C , Rowley, Robb , Venner, Eric , Linder, Jodell E , Jones, Laney K , Peterson, Josh F , Jarvik, Gail P , Rehm, Heidi L , Zouk, Hana , Roden, Dan M. , Williams, Marc S , Manolio, Teri A , Kullo, Iftikhar J , Dikilitas, Ozan , Satterfield, Benjamin A. , Venner, Eric , Rehm, Heidi L. , Kullo, Iftikhar J.
Circulation: Genomic and Precision Medicine | February 22, 2023 | Volume: 16 | Issue: 2 | Pages: No page available
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.