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.
| Exposure | Genetic instruments | |
|---|---|---|
| Genetic variants associated with mRNA expression levels (eQTLs) | Genetic variants associated with LDL cholesterol level | |
| HMGCR inhibitors | Nine hundred and twenty-one common cis-eQTLs (MAF >1%) in blood for HMGCR gene (p < 5.0 × 10−8), top SNP: rs6453133 | Seven 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 inhibitors | Twenty-four common cis-eQTLs (MAF >1%) in blood for PCSK9 gene (p < 5.0 × 10−8), top SNP: rs472495 | Twelve 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 inhibitors | Eleven common cis-eQTLs (MAF >1%) in adipose subcutaneous tissue for NPC1L1 gene (p < 5.0 × 10−8), top SNP: rs41279633 | Three 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 analysis | Summary-data-based Mendelian randomization | Inverse-variance-weighted Mendelian randomization |
| Sensitivity analyses | F-StatisticPositive control analysis (LDL cholesterol used as outcome)Linkage disequilibrium test: HEIDI testHorizontal pleiotropy test: SMR association between expression of adjacent genes and outcome | F-StatisticPositive control analysis (coronary heart disease used as outcome)Heterogeneity test: Cochran Q testHorizontal pleiotropy test: MR-Egger regression, MR-PRESSO test |