{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T14:00:50Z","timestamp":1768572050310,"version":"3.49.0"},"posted":{"date-parts":[[2025,11,15]]},"group-title":"Cardiovascular Medicine","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T00:00:00Z","timestamp":1763164800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Measures of genetic predisposition can improve prediction of risk of cardiometabolic diseases but more data is needed in groups under-represented in genomics research. In this study, we investigated the impact of genetic risk factors for coronary heart disease (CHD) - polygenic risk, monogenic risk [in the form of familial hypercholesterolemia (FH)], and family history (FamHx) - on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults - eMERGE IV (eIV) and\n                    <jats:italic>All of Us<\/jats:italic>\n                    (AoU).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race\/ethnicity (SIRE) was used as a population descriptor. We calculated a polygenic risk score for CHD (PRS\n                    <jats:sub>CHD<\/jats:sub>\n                    , PGS004698), ascertained FH as presence of pathogenic\/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in a first-degree family member. We employed Pooled Cohort Equations (PCE) to estimate the 10-year risk of CHD for adults \u226540 y and modeled the association of conventional risk factors with CHD in adults &lt;40 y. We analyzed the impact of PRS\n                    <jats:sub>CHD<\/jats:sub>\n                    and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We analyzed data for 19,348 participants from eIV (age 50.6\u00b115.0, 68% female, 40.5% non-White) and 239,645 participants from AoU (age 55.4\u00b117.0, 60.6% female, 48% non-White). The effects of PRS\n                    <jats:sub>CHD<\/jats:sub>\n                    and FamHx on CHD were independent and additive in the two cohorts and incorporating both into PCE for eIV participants significantly improved discrimination (C-statistic increased from 0.719 to 0.753;\n                    <jats:italic>P<\/jats:italic>\n                    -diff=9.1\u00d710\n                    <jats:sup>\u22123<\/jats:sup>\n                    ) and reclassified risk in 18.7% and 20.2% of participants at the 7.5% and 10% 10-y CHD risk thresholds, respectively. Between the 7.5% and 10% 10-y CHD risk thresholds, incorporating PRS\n                    <jats:sub>CHD<\/jats:sub>\n                    and FamHx into the PCE improved the net benefit of the risk prediction models across all SIRE groups.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    PRS\n                    <jats:sub>CHD<\/jats:sub>\n                    and FamHx were independently and additively associated with CHD across major SIRE groups in two diverse cohorts in the US. Incorporating PRS\n                    <jats:sub>CHD<\/jats:sub>\n                    and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants at actionable 10-y CHD risk thresholds, and improved net benefit of the PCE, motivating the addition of these factors to clinical risk algorithms.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.10.25339939","type":"posted-content","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T23:15:11Z","timestamp":1763248511000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of Genetic Risk Factors on Coronary Heart Disease Risk Across the Age Spectrum in Three Major Race\/Ethnicity Groups in the United States"],"prefix":"10.64898","author":[{"given":"Mohammadreza","family":"Naderian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5861-0413","authenticated-orcid":false,"given":"Johanna L.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwan E.","family":"Hamed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ozan","family":"Dikilitas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josh B.","family":"Cortopassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth M.","family":"McNally","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6213-793X","authenticated-orcid":false,"given":"Qiping","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Irvin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail P.","family":"Jarvik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-2220","authenticated-orcid":false,"given":"Leah C.","family":"Kottyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nita A.","family":"Limdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bahram","family":"Namjou-Khales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Roy-Puckelwartz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robb","family":"Rowley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah C.","family":"Hanks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eimear E.","family":"Kenny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noura S.","family":"Abul-Husn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemant K.","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Qi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atlas","family":"Khan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.","family":"Connolly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgia","family":"Wiesner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teri A.","family":"Manolio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard R.","family":"Sharp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iftikhar J.","family":"Kullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025111802055686000_2025.11.10.25339939v1.1","doi-asserted-by":"crossref","first-page":":2204","DOI":"10.1016\/S0140-6736(24)00685-8","article-title":"Burden of disease scenarios for 204 countries and territories, 2022&#x2013;2050: a forecasting analysis for the Global Burden of Disease Study 2021","volume":"403","year":"2024","journal-title":"The Lancet"},{"key":"2025111802055686000_2025.11.10.25339939v1.2","doi-asserted-by":"crossref","unstructured":"Kullo IJ . 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