Register now to R3i !
Your login
Your password
Confirm your password
Your email
I agree to receive the R3i newsletter

Focus on...

26 April 2021
Low HDL cholesterol and risk for severe COVID-19 infection
Using data from the UK Biobank Study, this report implicates pre-existing low plasma concentration of high-density lipoprotein cholesterol (HDL-C), a feature of the metabolic syndrome, as a risk factor for severe COVID-19 infection.
Hilser JR, Han Y, Biswas S et al. Association of serum HDL cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection. J Lipid Res 2021; doi: 10.1016/j.jlr.2021.100061.


Objective: To investigate the relationship between severity of COVID-19 disease and metabolic syndrome-related serum biomarkers measured before SARS-CoV-2 infection.
Study design: This was a case-control cohort analysis based on data from the UK Biobank, a large-scale biomedical database containing in-depth genetic and health information from half a million UK participants. Mendelian randomization analyses were used to estimate the causal effect of genetically increased HDL-C on SARS-CoV-2 infection in about 400,000 UK Biobank subjects of self-reported white European ancestry.
Study population: The unmatched case-control dataset comprised 1117 COVID-19 cases and 3544 hospital-based controls and the matched case-control dataset comprised 719 cases and 1438 hospital-based controls. SARS-CoV-2-positive cases were more likely to be male, obese, and to have type 2 diabetes, elevated diastolic blood pressure, and higher body mass index (BMI) than controls.
Primary variable: • SARS-CoV-2 infection
• HDL-C plasma concentration before infection
Methods: The association between 19 biomarkers, including HDL-C, apolipoprotein A1 (apoA1), and triglyceride levels and risk for SAR-CoV-2 infection was investigated using Spearman's correlation and logistic regression, with age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease, BMI, education, and smoking among the variables included in the models.
Main results:

The case-control analysis (unmatched subset) demonstrated a significant association between SARS-CoV-2 infection and higher levels of HDL-C or apoA1. A 10 mg/dL increase in plasma HDL-C concentration was associated with ~10% reduced risk of SARS-CoV-2 infection (Table 1); for individuals with the highest HDL-C levels (~20 mg/dL above the median), the risk was reduced by ~20%. There was no association between baseline triglycerides and risk for severe SARS-CoV-2 infection. Similar findings were reported for the matched subset. Mendelian randomization analyses did not show any association between genetically higher HDL-C levels with decreased risk of SARS-CoV-2 infection.


Table 1. Association of higher HDL-C and apoAI levels (before infection) with risk for severe SARS-CoV-2 infection (unmatched cohort)


Adjusted odds ratio (95% CI) for 10 mg/dL higher levels


0.90 (0.85-0.95)


0.94 (0.92-0.97) 0.82

Authors’ conclusion: These results implicate plasma HDL-C and apoA1 levels measured before SARS-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL-C levels are associated with SARS-CoV-2 infection.


Observational studies show that individuals with obesity and cardiometabolic co-morbidities, including type 2 diabetes, are more susceptible to developing severe COVID-19 (1-3). Interest has focused on features of the metabolic syndrome, notably low HDL-C, which is characteristic of patients with SARS-CoV-2 infections (4). As infection per se can alter levels of lipids and acute phase inflammatory proteins (5), the current study investigated whether this and other biomarkers play a causal role in influencing COVID-19 outcomes, based on plasma levels preceding infection.

The results identify a protective association between HDL-C concentration and risk for severe COVID-19. Given that the magnitude of this association was similar in unmatched and matched case-control cohorts suggests lack of confounding due to other characteristics known to increase susceptibility to COVID-19. Mendelian analyses, however, did not demonstrate causality between raised HDL-C plasma concentration and reduced risk for COVID-19. The findings of the study are strengthened by the size of the cohorts and associated genetic analyses, the strict definition of cases (i.e., symptomatic severe COVID-19 symptoms and positive for SARS-CoV-2 in a hospital setting) and matching of controls in a subset of the analysis.

The study raises questions about the underlying role of low HDL-C in the pathophysiology of SARS-CoV-2 infection and adverse COVID-19 outcome. Indeed, HDL is known to be a key player in both innate and adaptive immunity, with immuno-inflammatory functionality dependent on the cargo of proteins and lipids carried by these lipoprotein particles (6,7). These findings provide a rationale for further study of metabolic risk factors in the pathophysiology and progression of COVID-19.

References 1. Bornstein SR, Dalan R, Hopkins D, et al. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrinol 2020;16: 297-8.
2. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584: 430-6.
3. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
4. Scalsky RJ, Desai K, Chen YJ, et al. Baseline cardiometabolic profiles and SARS-CoV-2 risk in the UK Biobank. medRxiv 2020; doi: 10.1101/2020.07.25.20161091
5. Marin-Palma D, Sirois CM, Urcuqui-Inchima S, et al. Inflammatory status and severity of disease in dengue patients are associated with lipoprotein alterations. PLoS One 2019;14: e0214245
6. Catapano AL, Pirillo A, Bonacina F, et al. HDL in innate and adaptive immunity. Cardiovascular Res 2014;103: 372–83.
7. Creasy KT, Kane JP, Malloy MJ. 2018. Emerging roles of HDL in immune function. Curr Opin Lipidol 2018;29:486-7
Key words COVID-19; HDL cholesterol; infection; association