Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study

  1. Wuqing Huang
  2. Jun Xiao
  3. Jianguang Ji  Is a corresponding author
  4. Liangwan Chen  Is a corresponding author
  1. Department of Epidemiology and Health Statistics,School of Public Health, Fujian Medical University, China
  2. Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, China
  3. Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, Fujian Province, China
  4. Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Sweden
3 figures, 1 table and 2 additional files

Figures

Summary-data-based Mendelian randomization (SMR) association between expression of gene HMGCR, PCSK9, or NPC1L1 and COVID-19 outcomes.

SMR method was used to assess the association.

Inverse-variance-weighted Mendelian randomization (IVW-MR) association between low-density lipoprotein (LDL) cholesterol mediated by gene HMGCR, PCSK9, or NPC1L1 and COVID-19 outcomes.

IVW-MR method was used to assess the association.

Author response image 1
DAG showing the hypothesized relationships.

Tables

Table 1
Information of genetic instruments.

Abbreviations and acronyms: eQTLs, expression quantitative trait loci; GWAS, genome-wide association study; HEIDI, heterogeneity in dependent instruments; HMGCR, HMG-CoA reductase; IVW-MR, inverse-variance-weighted Mendelian randomization; LDL, low-density lipoprotein; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; MAF, minor allele frequency; NPC1L1, Niemann–Pick C1-Like 1; PCSK9, proprotein convertase subtilisin/kexin type 9; SNP, single-nucleotide polymorphism; SMR, summary-data-based Mendelian randomization.

ExposureGenetic instruments
Genetic variants associated with mRNA expression levels (eQTLs)Genetic variants associated with LDL cholesterol level
HMGCR inhibitorsNine hundred and twenty-one common cis-eQTLs (MAF >1%) in blood for HMGCR gene (p < 5.0 × 10−8), top SNP: rs6453133Seven common SNPs (MAF >1%) in low linkage disequilibrium (r2 < 0.30), associated with LDL cholesterol (p < 5.0 × 10−8), located within ±100 kb windows from HMGCR region
PCSK9 inhibitorsTwenty-four common cis-eQTLs (MAF >1%) in blood for PCSK9 gene (p < 5.0 × 10−8), top SNP: rs472495Twelve common SNPs (MAF >1%) in low linkage disequilibrium (r2 < 0.30), associated with LDL cholesterol (p < 5.0 × 10−8), located within ±100 kb windows from PCSK9 region
NPC1L1 inhibitorsEleven common cis-eQTLs (MAF >1%) in adipose subcutaneous tissue for NPC1L1 gene (p < 5.0 × 10−8), top SNP: rs41279633Three common SNPs (MAF >1%) in low linkage disequilibrium (r2 < 0.30), associated with LDL cholesterol (p < 5.0 × 10−8), located within ±100 kb windows from NPC1L1 region
Statistical analyses
Primary analysisSummary-data-based Mendelian randomizationInverse-variance-weighted Mendelian randomization
Sensitivity analysesF-StatisticPositive control analysis (LDL cholesterol used as outcome)Linkage disequilibrium test: HEIDI testHorizontal pleiotropy test: SMR association between expression of adjacent genes and outcomeF-StatisticPositive control analysis (coronary heart disease used as outcome)Heterogeneity test: Cochran Q testHorizontal pleiotropy test: MR-Egger regression, MR-PRESSO test

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  1. Wuqing Huang
  2. Jun Xiao
  3. Jianguang Ji
  4. Liangwan Chen
(2021)
Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study
eLife 10:e73873.
https://doi.org/10.7554/eLife.73873