|Title||Familial Hypercholesterolemia in the Electronic Medical Records and Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, and Outcomes After Return of Results.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Dikilitas, 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|
|Journal||Circ Genom Precis Med|
|Date Published||2023 Apr|
|Keywords||Adult, 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|
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.
|Alternate Journal||Circ Genom Precis Med|
|PubMed Central ID||PMC10113961|
|Grant List||K24 HL137010 / HL / NHLBI NIH HHS / United States |
R01 HL135879 / HL / NHLBI NIH HHS / United States
U01 HG006379 / HG / NHGRI NIH HHS / United States
U01 HG008679 / HG / NHGRI NIH HHS / United States