Genetic Variations in LDL-C Levels Linked to Type 2 Diabetes Risk: Study Reveals

"Individuals with very low LDL-C polygenic risk scores experienced a 1.26-fold increased risk of T2D, while those with familial hypercholesterolemia, a condition characterized by very high LDL-C levels, showed the lowest risk for T2D (HR 0.65)," the researchers reported.

Treatment aimed at lowering high levels of low-density lipoprotein cholesterol has been shown to reduce the risk of coronary artery disease (CAD). However, it may also modestly increase the risk of developing type 2 diabetes. However, the relationship between genetic factors influencing LDL-C levels and the risk of incident T2D remains unclear. Therefore, Akshaya Ravi, Cardiovascular Disease Initiative, Broad Institute of MIT, and Harvard, Cambridge, Massachusetts, and colleagues aimed to explore how genetic predisposition to higher LDL-C levels may impact the risk of developing T2D.

For this purpose, the researchers analyzed data from the UK Biobank, including participants who underwent whole-exome sequencing and genome-wide genotyping. They categorized individuals into seven groups based on familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data was collected from 2006 to 2010, with a median follow-up of 13.7 years. The study focused on the association between LDL-C levels and the risk of incident T2D and CAD, using statistical models adjusted for key factors.

The following were the key findings of the study:

• The study involved 361,082 participants with an average age of 56.8 years, and 53.9% were female. The mean baseline LDL-C level was 138.0 mg/dL.
• During the follow-up period, 6.3% developed incident type 2 diabetes (T2D), and 5.0% developed incident coronary artery disease (CAD).
• The hazard ratio for T2D was lowest in the familial hypercholesterolemia (FH) group at 0.65, while the highest risk was observed in the predicted loss of function (pLOF) group at 1.48.
• The risk of incident T2D increased with lower LDL-C PRS, with the highest risk in the very low LDL-C PRS group (1.26), and the lowest in the very high LDL-C PRS group (0.72).
• The risk of CAD increased directly with the LDL-C PRS.

"Our cohort study found an inverse relationship between LDL-C levels and T2D risk across various genetic mechanisms influencing LDL-C variation. Further research is needed to better understand the mechanisms linking low LDL-C levels with an increased risk of T2D," the researchers concluded.

Reference:

Ravi A, Koyama S, Cho SMJ, et al. Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes. JAMA Cardiol. Published online January 15, 2025. doi:10.1001/jamacardio.2024.5072