Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.
Level 3 - non-randomized controlled study
Meta-analysis of observational genetic association studies (Mendelian randomization)
PubMed 27701660 · doi:10.1001/jama.2016.14568
What was done
A meta-analysis of genetic association studies (Mendelian randomization) evaluated whether LDL-C-lowering alleles in or near genes encoding lipid-lowering drug targets (NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDLR) were associated with type 2 diabetes and coronary artery disease. Analyses included 50,775 type 2 diabetes cases and 270,269 controls, alongside 60,801 coronary artery disease cases and 123,504 controls, collected in Europe and the United States between 1991 and 2016.
What was found
Genetically predicted 1-mmol/L (38.7-mg/dL) reduction in LDL-C via NPC1L1 variants was associated with lower risk of coronary artery disease (OR 0.61; 95% CI, 0.42-0.88; P = .008) and higher risk of type 2 diabetes (OR 2.42; 95% CI, 1.70-3.43; P < .001). For PCSK9 variants, a 1-mmol/L genetically predicted reduction in LDL-C was associated with increased type 2 diabetes risk (OR 1.19; 95% CI, 1.02-1.38; P = .03). While coronary artery disease risk reduction was consistent across all evaluated gene variants (heterogeneity I2 = 0%; P = .93), associations with type 2 diabetes showed significant heterogeneity (I2 = 77.2%; P = .002). Specific numerical estimates for HMGCR, ABCG5/G8, and LDLR variants were not reported in the abstract.
Why it matters
These findings suggest that the increased risk of type 2 diabetes seen with statins is not isolated to HMG-CoA reductase inhibition, but extends to other genetic mechanisms of LDL-C lowering, such as NPC1L1 and PCSK9.
Limits
Lifelong genetic exposure does not directly reflect the timing or magnitude of adult-onset pharmacological treatment. Numerical findings were not provided in the abstract for HMGCR, ABCG5/G8, or LDLR variants. Significant heterogeneity across loci implies distinct gene-specific effects on diabetes risk. Datasets were restricted to European and US cohorts.
Cited by
- contradicts Individuals with loss-of-function mutations in PCSK9 and lifelong low LDL-C exhibit no increased incidence of cancer, neurodegenerative disease, or diabetes.