{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:51:07Z","timestamp":1793127067460,"version":"4.5.0"},"reference-count":15,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:sec id=\"ab-hbr240021-4\"><jats:title>Importance<\/jats:title><jats:p>Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hbr240021-5\"><jats:title>Objective<\/jats:title><jats:p>To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hbr240021-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in <jats:italic>APOB<\/jats:italic> or <jats:italic>PCSK9<\/jats:italic> variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hbr240021-7\"><jats:title>Exposures<\/jats:title><jats:p>LDL-C level, LDL-C PRS, FH, or pLOF variant status.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hbr240021-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hbr240021-9\"><jats:title>Results<\/jats:title><jats:p>Among the 361\u202f082 participants, mean (SD) age was 56.8 (8.0) years, 194\u202f751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg\/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hbr240021-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamacardio.2024.5072","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T16:00:59Z","timestamp":1736956859000},"page":"379","source":"Crossref","is-referenced-by-count":13,"title":["Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes"],"prefix":"10.1001","volume":"10","author":[{"given":"Akshaya","family":"Ravi","sequence":"first","affiliation":[{"name":"Program of Medical and Population Genetics, Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard, Cambridge, Massachusetts"},{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston"},{"name":"Center for Genomic Medicine, Massachusetts General 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