{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:53:44Z","timestamp":1787018024167,"version":"build-2736575974"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Severe hypercholesterolemia, defined as LDL (low-density lipoprotein) cholesterol (LDL-C) measurement \u2265190 mg\/dL, is associated with increased risk for coronary artery disease (CAD). Causes of severe hypercholesterolemia include monogenic familial hypercholesterolemia, polygenic hypercholesterolemia, elevated lipoprotein(a) [Lp(a)] hypercholesteremia, polygenic hypercholesterolemia with elevated Lp(a) (two-hit), or nongenetic hypercholesterolemia. The added value of using a genetics approach to stratifying risk of incident CAD among those with severe hypercholesterolemia versus using LDL-C levels alone for risk stratification is not known.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>To determine whether risk stratification by genetic cause provided better 10-year incident CAD risk stratification than LDL-C level, a retrospective cohort study comparing incident CAD risk among severe hypercholesterolemia subtypes (genetic and nongenetic causes) was performed among 130\u2009091 UK Biobank participants. Analyses were limited to unrelated, White British or Irish participants with available exome sequencing data. Participants with cardiovascular disease at baseline were excluded from analyses of incident CAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Of 130\u2009091 individuals, 68\u2009416 (52.6%) were women, and the mean (SD) age was 56.7 (8.0) years. Of the cohort, 9.0% met severe hypercholesterolemia criteria. Participants with LDL-C between 210 and 229 mg\/dL and LDL-C \u2265230 mg\/dL showed modest increases in incident CAD risk relative to those with LDL-C between 190 and 209 mg\/dL (210\u2013229 mg\/dL: hazard ratio [HR], 1.3 [95% CI, 1.1\u20131.7]; \u2265230 mg\/dL: HR, 1.3 [95% CI, 1.0\u20131.7]). In contrast, when risk was stratified by genetic subtype, monogenic familial hypercholesterolemia, elevated Lp(a), and two-hit hypercholesterolemia subtypes had increased rates of incident CAD relative to the nongenetic hypercholesterolemia subtype (monogenic familial hypercholesterolemia: HR, 2.3 [95% CI, 1.4\u20134.0]; elevated Lp(a): HR, 1.5 [95% CI, 1.2\u20132.0]; two-hit: HR, 1.9 [95% CI, 1.4\u20132.6]), while polygenic hypercholesterolemia did not.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Genetics-based subtyping for monogenic familial hypercholesterolemia and Lp(a) in those with severe hypercholesterolemia provided better stratification of 10-year incident CAD risk than LDL-C-based stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.123.319341","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T05:00:42Z","timestamp":1692248442000},"page":"2058-2067","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Subtyping Severe Hypercholesterolemia by Genetic Determinant to Stratify Risk of Coronary Artery Disease"],"prefix":"10.1161","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0353-5521","authenticated-orcid":true,"given":"Alexander S.F.","family":"Berry","sequence":"first","affiliation":[{"name":"Autism and Developmental Medicine Institute Geisinger, Lewisburg, PA (A.S.F.B., M.T.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-5634","authenticated-orcid":true,"given":"Laney K.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger, Danville, PA (L.K.J., S.S.G.)."},{"name":"Heart and Vascular Institute Geisinger, Danville, PA (L.K.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8857-7389","authenticated-orcid":true,"given":"Eric J.","family":"Sijbrands","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (E.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8557-7225","authenticated-orcid":true,"given":"Samuel S.","family":"Gidding","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger, Danville, PA (L.K.J., S.S.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Oetjens","sequence":"additional","affiliation":[{"name":"Autism and Developmental Medicine Institute Geisinger, Lewisburg, PA (A.S.F.B., M.T.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000297"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0325-8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.044795"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.03.057"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.5398"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2019.5954"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04064-3"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2022.01.010"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.03.520"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)62127-8"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.03.065"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000625"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.2687"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0214311"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2853-0"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3679"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2018.1470"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-021-00190-z"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.22241"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.315904"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2018.1717"},{"key":"e_1_3_3_24_2","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2020","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing. 2020. Accessed November 1, 2021. https:\/\/www.R-project.org\/"},{"key":"e_1_3_3_25_2","volume-title":"twoxtwo: Work With Two-by-Two Tables","author":"Nagraj VP","year":"2021","unstructured":"Nagraj, VP. twoxtwo: Work With Two-by-Two Tables. 2021. https:\/\/CRAN.R-project.org\/package=twoxtwo"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2019.08.007"},{"key":"e_1_3_3_29_2","volume-title":"A Package for Survival Analysis in R","author":"Therneau TM","year":"2021","unstructured":"Therneau, TM. A Package for Survival Analysis in R. 2021. Accessed November 2, 2021. https:\/\/CRAN.R-project.org\/package=survival"},{"key":"e_1_3_3_30_2","volume-title":"survminer: Drawing Survival Curves using \u201cggplot2\u201d","author":"Kassambara A","year":"2021","unstructured":"Kassambara, A, Kosinski, M, Biecek, P. survminer: Drawing Survival Curves using \u201cggplot2\u201d. 2021. Accessed November 2, 2021. https:\/\/CRAN.R-project.org\/package=survminer"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2009.03.012"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13697"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0020132"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2022.09.021"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2013.04.011"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(19)30061-1"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2021.01.008"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf7000"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/life10050073"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.018932"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.09.017"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m131"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.120.002919"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2019.04.006"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12869-0"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1113"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17374-3"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.192703"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.115.018585"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.123.319341","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T14:01:09Z","timestamp":1747836069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.123.319341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10]]},"references-count":51,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1161\/ATVBAHA.123.319341"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.123.319341","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10]]},"assertion":[{"value":"2023-03-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}