| Title: | Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes |
| Journal: | JAMA Cardiology |
| Published: | 1 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39813027/ |
| DOI: | https://doi.org/10.1001/jamacardio.2024.5072 |
Publication 14842
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Abstract
Importance: 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.</p>
Objective: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk.</p>
Design, Setting, and Participants: 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 APOB or PCSK9 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.</p>
Exposures: LDL-C level, LDL-C PRS, FH, or pLOF variant status.</p>
Main Outcomes and Measures: 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.</p>
Results: Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (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.</p>
Conclusions and Relevance: 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.</p>
16 Keywords
- Adult
- Aged
- Apolipoprotein B-100
- Cholesterol, LDL
- Diabetes Mellitus, Type 2
- Female
- Genetic Predisposition to Disease
- Humans
- Hyperlipoproteinemia Type II
- Incidence
- Male
- Middle Aged
- Proprotein Convertase 9
- Prospective Studies
- Risk Factors
- United Kingdom
7 Authors
- Akshaya Ravi
- Satoshi Koyama
- So Mi Jemma Cho
- Sara Haidermota
- Whitney Hornsby
- Patrick T. Ellinor
- Pradeep Natarajan
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
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