Association of serum HDL cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection

Hilser, James R.; Han, Yi; Biswas, Subarna; Gukasyan, Janet; Cai, Zhiheng; Zhu, Ruowei; Tang, W.H. Wilson; Deb, Arjun; Lusis, Aldons J.; Hartiala, Jaana A.; Allayee, Hooman

Individuals with features of metabolic syndrome are particularly susceptible to SARS-CoV-2, a novel coronavirus associated with the severe respiratory disease COVID-19. Despite considerable attention dedicated to COVID-19, the link between metabolic syndrome and SARS-CoV-2 infection remains unclear. Using data from the UK Biobank, we investigated the relationship between severity of COVID-19 and metabolic syndrome-related serum biomarkers measured prior to SARS-CoV-2 infection. Logistic regression analyses were used to test biomarker levels and biomarker-associated genetic variants with SARS-CoV-2-related outcomes. Among SARS-CoV-2-positive cases and negative controls, a 10mg/dL increase in serum high-density lipoprotein (HDL) cholesterol or apolipoprotein A1 (ApoA1) levels was associated with ∼10% reduced risk of SARS-CoV-2 infection, after adjustment for age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. Evaluation of known genetic variants for HDL cholesterol revealed that individuals homozygous for ApoE4 alleles had ∼2-3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared to ApoE3 homozygotes, even after adjustment for HDL cholesterol levels. However, cumulative effects of all evaluated HDL cholesterol-raising alleles and Mendelian randomization analyses did not reveal association of genetically higher HDL cholesterol levels with decreased risk of SARS-CoV-2 infection. These results implicate serum HDL cholesterol and ApoA1 levels measured prior to SAR-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL cholesterol levels are associated with SAR-CoV-2 infection.