Low LDL cholesterol and risk of bacterial and viral infections: observational and Mendelian randomization studies

Low levels of LDL cholesterol may be associated with risk of infectious disease. We tested the hypothesis that low LDL cholesterol due to genetic variation in the LDLR, PCSK9, and HMGCR genes and a polygenic LDL cholesterol score is associated with risk of infectious diseases in the general population.

Using observational and Mendelian randomization designs, we examined associations of low plasma LDL cholesterol with risk of bacterial and viral infections in 119 805 individuals from the Copenhagen General Population Study/Copenhagen City Heart Study, 468 701 from the UK Biobank, and up to 376 773 from the FinnGen Research Project. Observationally, low LDL cholesterol concentrations were associated with risk of hospitalization for both bacterial and viral infections. In genetic analyses, a 1 mmol/L lower LDL cholesterol was associated with lower plasma PCSK9 {-0.55 nmol/L [95% confidence interval (CI): -1.06 to -0.05]; P = 0.03}, leucocyte count [-0.42 × 10⁹/L (-0.61 to -0.24); P < 0.001], and high-sensitivity C-reactive protein [-0.44 mg/L (-0.79 to -0.09); P = 0.014]. Using an LDLR, HMGCR, and PCSK9 score, a 1 mmol/L lower LDL cholesterol was associated with risk ratios of 0.91 (95% CI: 0.86-0.97; P = 0.002) for unspecified bacterial infection, of 0.92 (0.87-0.97; P = 0.004) for diarrhoeal disease, and of 1.15 (1.03-1.29; P = 0.012) for unspecified viral infections and 1.64 (1.13-2.39; P = 0.009) for HIV/AIDS. Using a polygenic LDL cholesterol score largely showed similar results and in addition a lower risk of 0.85 (0.76-0.96; P = 0.006) for bacterial pneumonia and 0.91 (0.82-0.99; P = 0.035) for sepsis.

Genetically low LDL cholesterol concentrations were associated with lower concentration of markers of inflammation; lower risk of hospitalization for unspecified bacterial infections, infectious diarrhoeal diseases, bacterial pneumonia, and sepsis; and higher risk of viral infections and HIV/AIDS.