| Title: | Polygenic Risk, Rare Variants, and Family History Independent and Additive Effects on Coronary Heart Disease |
| Journal: | JACC Advances |
| Published: | 1 Sep 2023 |
| DOI: | https://doi.org/10.1016/j.jacadv.2023.100567 |
Publication 9665
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Abstract
Background Genetic factors are not included in prediction models for coronary heart disease (CHD). Objectives The authors assessed the predictive utility of a polygenic risk score (PRS) for CHD (defined as myocardial infarction, coronary revascularization, or cardiovascular death) and whether the risks due to monogenic familial hypercholesterolemia (FH) and family history (FamHx) are independent of and additive to the PRS. Methods In UK-biobank participants, PRSCHD was calculated using metaGRS, and 10-year risk for incident CHD was estimated using the pooled cohort equations (PCE). The area under the curve (AUC) of the receiver operator curve and net reclassification improvement (NRI) were assessed. FH was defined as the presence of a pathogenic or likely pathogenic variant in LDLR, APOB, or PCSK9. FamHx was defined as a diagnosis of CHD in first-degree relatives. Independent and additive effects of PRSCHD, FH, and FamHx were evaluated in stratified analyses. Results In 323,373 participants with genotype data, the addition of PRSCHD to PCE increased the AUC from 0.759 (95% CI: 0.755-0.763) to 0.773 (95% CI: 0.769-0.777). The AUC and NRIEvent for PRSCHD were higher before the age of 55 years. Of 199,997 participants with exome sequence data, 10,000 had a PRSCHD ≥95th percentile (PRSP95), 673 had FH, and 46,163 had FamHx. The CHD risk associated with PRSP95 was independent of FH and FamHx. The risks associated with combinations of PRSCHD, FH, and FamHx were additive and comprehensive estimates could be obtained by multiplying the risk from each genetic factor. Conclusions Incorporating PRSCHD into the PCE improves risk prediction for CHD, especially at younger ages. The associations of PRSCHD, FH, and FamHx with CHD were independent and additive.</p>
6 Authors
- Seyedmohammad Saadatagah
- Mohammadreza Naderian
- Ozan Dikilitas
- Marwan E. Hamed
- Hana Bangash
- Iftikhar J. Kullo
1 Application
| Application ID | Title |
|---|---|
| 79990 | Development and validation of polygenic risk scores for coronary heart disease and related risk factors in diverse racial/ethnic groups |
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