Causal Inference for Genetically Determined Levels of High-Density Lipoprotein Cholesterol and Risk of Infectious Disease.

HDL (high-density lipoprotein) cholesterol (HDL-C) and LDL (low-density lipoprotein) cholesterol (LDL-C) are inversely associated with infectious hospitalizations. Whether these represent causal relationships is unknown. Approach and Results: Adults of 40 to 69 years of age were recruited from across the United Kingdom between 2006 and 2010 and followed until March 31, 2016, as part of the UK Biobank. We determined HDL-C, LDL-C, and triglyceride polygenic scores for UK Biobank participants of British white ancestry (n=407 558). We examined the association of lipid levels and polygenic scores with infectious hospitalizations, antibiotic usage, and 28-day sepsis survival using Cox proportional hazards or logistic regression models. Measured levels of HDL-C and LDL-C were inversely associated with risk of infectious hospitalizations, while triglycerides displayed a positive association. A 1-mmol/L increase in genetically determined levels of HDL-C associated with a hazard ratio for infectious disease of 0.84 ([95% CI, 0.75-0.95]; Our results provide causal inference for an inverse relationship between HDL-C, but not LDL-C or triglycerides, and risk of an infectious hospitalization.