A recent study has uncovered intriguing genetic associations linking high LDL cholesterol (LDL-C) levels with both a reduced risk of developing type 2 diabetes and an increased risk of coronary artery disease (CAD). Researchers found that individuals with a genetically predicted high LDL level were less likely to develop type 2 diabetes, while those with the same genetic predisposition faced a heightened risk of CAD.
The study, led by Akshaya Ravi and colleagues at the Broad Institute of MIT and Harvard, aimed to better understand how genetic variations in LDL-C could influence these two major health conditions. Previous studies have hinted at a connection between higher LDL-C levels and a lower risk of type 2 diabetes, but no comprehensive analysis had examined the correlation between genetic LDL-C predictions and the development of diabetes in a large cohort.
To explore this, the researchers analyzed data from 361,082 participants in the U.K. Biobank, tracking their health over a median period of 13.7 years. The participants were categorized based on genetic risk scores for LDL-C, with groups including familial hypercholesterolemia (FH) and individuals with predicted genetic mutations in APOB or PCSK9 genes.
At the start of the study, participants had an average LDL level of 138 mg/dL. Over the follow-up period, 6.3% of participants developed type 2 diabetes, while 5% developed CAD. The study revealed that individuals with FH had the lowest risk of developing diabetes (hazard ratio [HR] = 0.65), while those with genetic mutations in the APOB or PCSK9 genes had the highest risk (HR = 1.48). Interestingly, those with very high genetically predicted LDL levels had a 28% lower risk of diabetes (HR = 0.72), while those with low genetically predicted LDL had a 26% higher risk (HR = 1.26).
In contrast, the researchers found the opposite trend for CAD risk. Individuals with high genetic predispositions for LDL-C, including those with FH or very high LDL polygenic risk scores, had an increased risk of CAD. The risk was 43% higher in those with FH (HR = 1.43) and 18% higher in those with very high LDL polygenic risk scores (HR = 1.18).
These findings suggest that genetically elevated LDL-C levels might influence metabolic pathways differently, potentially lowering the risk of type 2 diabetes while increasing the likelihood of CAD. The researchers point to the growing body of evidence linking statin use with an increased risk of diabetes, which aligns with the study’s results. They emphasize the need for further research into how individual cholesterol-lowering medications, beyond statins, might impact type 2 diabetes risk, particularly from a genetic perspective.
Despite the findings, the study also highlighted that high LDL-C levels are known to provide clear cardiovascular benefits for those at risk for CAD. Thus, while statin therapy is effective in reducing CAD risk, its modest association with type 2 diabetes risk requires additional investigation to understand the full scope of genetic influences.
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