High genetically predicted LDL level tied to lower type 2 diabetes risk, elevated CAD risk
Click Here to Manage Email Alerts
Key takeaways:
- High genetic predisposition to elevated LDL was linked to lower risk for developing type 2 diabetes.
- High genetically predicted LDL was linked to elevated risk for coronary artery disease.
High genetically predicted LDL was inversely associated with risk for incident diabetes, whereas the opposite trend was observed for CAD risk, researchers reported.
“Individual genetic studies have yielded informative observations between LDL-C and type 2 diabetes,” Akshaya Ravi, an undergraduate researcher at the Broad Institute of MIT and Harvard, and colleagues wrote. “Although common genetic variants associated with higher LDL-C levels have been shown to correlate with lower type 2 diabetes risk, the association between participant-level genetic LDL-C predicted by a genome-wide polygenic risk score and incident type 2 diabetes risk has not, to our knowledge, been assessed, nor has a comprehensive comparison of the magnitude of type 2 diabetes risk across the monogenic and polygenic LDL-C spectra within a single cohort.”
Ravi and colleagues evaluated risk for diabetes in a prospective cohort of 361,082 participants in the U.K. and estimated the associations between genome-wide LDL polygenic risk score and incident diabetes (mean age 57, years; 54% women)
Participants were classified into one of seven groups: familial hypercholesterolemia, predicted loss of function in APOB or PCSK9 variants or a quintile based on LDL polygenic risk score.
The average LDL at baseline was 138 mg/dL, and during a median follow-up of 13.7 years, 6.3% of participants developed incident diabetes and 5% developed incident CAD.
Ravi and colleagues reported that risk for incident diabetes was lowest among people with FH (HR = 0.65; 95% CI, 0.54-0.77), and risk was highest among those with predicted loss of function in APOB or PCSK9 variants (HR = 1.48; 95% CI, 1.18-1.86) compared with individuals with median LDL polygenic risk score.
The researchers observed an inverse association between LDL polygenic risk score and risk for incident diabetes, with lower risk for diabetes among those with very high LDL polygenic risk (HR = 0.72; 95% CI, 0.66-0.79) and higher risk in those with very low LDL polygenic risk (HR = 1.26; 95% CI, 1.15-1.38).
Moreover, the researchers reported the opposite trend for CAD risk, with risk increasing among those with FH (HR = 1.43; 95% CI, 1.21-1.68), very high LDL polygenic risk (HR = 1.18; 95% CI, 1.08-1.3) and high LDL polygenic risk (HR = 1.08; 95% CI, 1.05-1.12) compared with those with median LDL polygenic risk.
“These findings suggest a potential metabolic link between genetically determined LDL-C concentration and type 2 diabetes risk, supported by the association between statin use and type 2 diabetes risk described in clinical trials,” the researchers wrote. “Since our polygenic risk score does not target specific LDL-C–related pathways, further focused research is warranted to assess type 2 diabetes risk associated with individual nonstatin cholesterol-lowering medications from a genetic standpoint. For individuals with high CAD risk, clinical trials have overwhelmingly demonstrated the benefit of statins relative to modest type 2 diabetes risk.”
Collapse
Click Here to Manage Email Alerts