Genetic Determinants of LDL-C Inversely Linked to Type 2 Diabetes Risk

Genetic predispositions impacting low-density lipoprotein cholesterol (LDL-C) levels, including both monogenic and polygenic mechanisms, were inversely linked to the likelihood of type 2 diabetes (T2D), according to a new analysis.1

This cohort study, evaluating a population of more than 361,000 adults in the United Kingdom Biobank, across a follow-up of approximately 14 years, revealed the index of T2D risk was robustly associated with the level of genetic disturbances in LDL-C levels.

“In a large, prospective cohort assessment, we found that monogenic and polygenic mechanisms influencing LDL-C polygenic risk scores (PRS) and incident T2D risk are inversely associated,” wrote the investigative team, led by Pradeep Natarajan, MD, Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital. “The magnitude of T2D risk is strongly correlated with the extent of genetic perturbation in LDL-C levels.”

Evidence has affirmed a strong relationship between LDL-C and coronary artery disease (CAD), but linked CAD treatment with statin therapy to a modestly elevated risk of incident T2D.2 Genetic data have informed the connection between LDL-C and T2D, with some common genetic variants linked to high LDL-C levels thought to correspond with lower T2D risk.3

However, Natarajan and colleagues noted a comprehensive review across the monogenic and polygenic LDL-C spectra has not been established in a single cohort, leading to the aim of the current analysis.1 The team also measured T2D-related risks for familial hypercholesterolemia (FH) and monogenic hypercholesterolemia, based on the predicted loss of function (pLOF) in APOB or PCSK9 variants.

The investigation included UK Biobank participants who underwent whole-exome sequencing, genome-wide genotyping, and baseline lipid level measurement. The population was separated into 7 groups, based on FH, pLOF in APOB or PCSK9 variants, and LDL-C polygenic risk scores (PRS) quintiles. Data were collected between 2006 and 2010 and analyzed from March to November 2024.

For the analysis, an adjusted Cox proportional hazards regression model was used to test the association of the LDL-C genetic factors with incident T2D and CAD risks. Adjustments were performed for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components.

A total of 361,082 participants (mean, 56.8 years) were enrolled in the study, including 194,751 (53.9%) females, with a mean baseline LDL-C level of 138.0 mg/dL. Across the nearly 14-year follow-up, 22,619 (6.3%) individuals developed incident T2D, and 17,966 (5.0%) developed incident CAD.

Upon analysis, the lowest hazard ratio (HR) for incident T2D was identified in the FH group (HR, 0.65; 95% CI, 0.54–0.77), while the highest risks were in the low LDL-C PRS (HR, 1.13; 95% CI, 1.09–1.17), very low LDL-C PRS (HR, 1.26; 95% CI, 1.15–1.38), and pLOF (HR, 1.48; 95% CI, 1.18–1.86) groups. The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66–0.79) for very high LDL-C PRS and 0.87 (95% CI, 0.84–0.90) for high LDL-C PRS.

Further analysis revealed the association of genetic predisposition to hypercholesterolemia, with decreases in incident T2D and increases in incident CAD, was proportional to LDL-C levels. Opposite to T2D, those with FH (HR, 1.43; 95% CI, 1.21–1.68), very high LDL-C PRS (HR, 1.18; 95% CI, 1.08–1.30), and high LDL-C PRS (HR, 1.08; 95% CI, 1.05–1.12) demonstrated a higher risk of CAD.

Meanwhile, low LDL-C PRS (HR, 0.86; 95% CI, 0.83–0.90), very low LDL-C PRS (HR, 0.75; 95% CI, 0.66–0.85), and pLOF (HR, 0.74; 95% CI, 0.53–1.02) were linked to reduced CAD risk, compared with the median LDL-C PRS. Overall, Natarajan and colleagues suggested these data portray a potential metabolic link between genetically determined LDL-C concentration and T2D risk, as well as highlight an emerging connection between 2 metabolic nodes that influence CAD risk.

“Since our PRS does not target specific LDL-C–related pathways, further focused research is warranted to assess T2D risk associated with individual nonstatin cholesterol-lowering medications from a genetic standpoint,” investigators added.

References

1. 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
2. Abdullah SM, Defina LF, Leonard D, et al. Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease. Circulation. 2018;138(21):2315-2325. doi:10.1161/CIRCULATIONAHA.118.034273
3. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313(10):1029-1036. doi:10.1001/jama.2015.1206