Can Lipid-Lowering Drugs Reduce the Risk of Cholelithiasis? A Mendelian Randomization Study

Figures & data

Figure 1 Two-Sample MR study design for the association between lipid-lowering drugs and cholelithiasis.

Abbreviations: GWAS, genome-wide association study; eQTLs, expression quantitative trait loci; LDL, low-density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; IVW, multiplicative random effects inverse variance weighted method; SMR, summary-data-based mendelian randomization; HEIDI, heterogeneity in dependent instruments; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; MAF, minor allele frequency.

Table 1 Associations Between LDL Cholesterol Mediated by Gene HMGCR, PCSK9, or NPC1L1 and Cholelithiasis Risk

Exposure	Outcome	Number of SNPs	Beta	se	p value	p value for Cochran Q Test	p value for MR-Egger Intercept	p value for MR-PRESSO Global Test
HMGCR	CHOLELITHIASIS	7	0.767665425	0.158026504	0.000	0.895	0.840	0.904
PCSK9	CHOLELITHIASIS	14	−0.321904803	0.132366007	0.015	0.629	0.583	0.6116667
NPC1L1	CHOLELITHIASIS	6	−0.193596005	0.174642397	0.268	0.626	0.681	0.7016667

Abbreviations: LDL, low-density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; SNP, single nucleotide polymorphisms; OR, odds ratio; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier.

Figure 2 Associations between low-density lipoprotein (LDL) cholesterol mediated by gene HMGCR, PCSK9, or NPC1L1 and cholelithiasis risk.

Abbreviations: HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; SNP, single nucleotide polymorphisms; OR, odds ratio; IVW, inverse variance weighted.

Table 2 SMR Association Between Expression of Gene HMGCR, PCSK9, or NPC1L1 and Cholelithiasis Risk

Gene	Top eQTL SNP	SMR Association			HEIDI Test
		Beta	se	p-value	p-value	Number of SNPs
HMGCR	rs6453133	0.174722	0.071195	1.41E-02	9.11E-03	20
PCSK9	rs472495	−0.10082	0.047746	3.47E-02	2.71E-01	8
NPC1L1	rs41279633	−0.00316	0.022075	8.86E-01	8.75E-01	5

Abbreviations: HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; SNP, single nucleotide polymorphisms; SMR, summary-data-based mendelian randomization; HEIDI, heterogeneity in dependent instruments.

Figure 3 Summary-data-based Mendelian randomization (SMR) association between expression of gene HMGCR, PCSK9, or NPC1L1 and cholelithiasis risk.

Abbreviations: HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; OR, odds ratio; SMR, summary-data-based mendelian randomization.

Table 3 Associations Between LDL Cholesterol Mediated by Gene HMGCR, PCSK9, or NPC1L1 and Coronary Heart Disease

Exposure	OR	95% CI	p value
HMGCR	2.07	1.34–3.20	0.0011
PCSK9	2.57	1.75–3.76	1.41E-06
NPC1L1	5.25	3.02–9.11	0.000000003

Abbreviations: LDL, low-density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; OR, odds ratio.

Table 4 SMR Association Between Expression of Gene HMGCR, PCSK9, or NPC1L1 and LDL Cholesterol Level

Exposure	OR	95% CI	p value	Tissue
HMGCR	1.46	1.37–1.55	3.00E-34	Blood
PCSK9	1.26	1.18–1.34	3.24E-12	Blood
NPC1L1	1.08	1.06–1.10	7.51E-13	Adipose Subcutaneous

Abbreviations: HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; SNP, single nucleotide polymorphisms; SMR, summary-data-based Mendelian randomization.