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

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

doi:10.1016/j.jlr.2021.100061

Abstract

Individuals with features of metabolic syndrome are particularly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus associated with the severe respiratory disease, coronavirus disease 2019 (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 10 mg/dl increase in serum HDL-cholesterol or apolipoprotein A1 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 apolipoprotein E4 alleles had ∼2- to 3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared with apolipoprotein E3 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 apolipoprotein A1 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.

Highlights

Based on information related to SARSCoV-2 infection status and other available data on demographics, clinical characteristics, serum biomarkers, and genetic variants, we defined a group of hospitalbased cases and controls as well as a matched casecontrol data set using a subset of these subjects (Fig. 1)
We sought to identify circulating metabolic biomarkers that were associated with risk of severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV-2) infection and its adverse outcomes using measurements obtained at the time of enrollment into the UK Biobank but in the context of the current COVID-19 pandemic
Protective associations were observed between SARSCoV-2 infection and high levels of HDL-cholesterol or apolipoprotein A1 (ApoA1), among individuals with the highest levels that were one interquartile range (∼20 mg/dl) above the median in whom risk was reduced by ∼20%

Summary

Introduction

Association of the 155 HDL-cholesterol SNPs with risk of SARS-CoV-2 infection among cases and unmatched hospitalbased controls was tested by logistic regression with adjustment for age, sex, PC1–10, and genotyping array. The per-unit associations of the UK Biobankbased unweighted and weighted GRSs with HDL-cholesterol levels among both case-control data sets were validated by linear regression, with adjustment for age, sex, self-reported ethnicity, genotyping array, BMI, education, smoking, systolic blood pressure, type 2 diabetes, and CAD status.

Results

Conclusion