Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization

Abstract

Backgrounds: A growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs.

Objectives: This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.

Methods: Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.

Results: There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10^{- 06}) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10^{- 05}). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10^{- 03}) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10^{- 02}). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).

Conclusions: Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

Keywords: Autoimmune diseases; Lipid-lowering drugs; Mendelian randomization; Rheumatoid arthritis.

Fig. 1

Overview of the study design (a) Identification of genetic associations using Mendelian randomization. (b) Constructions of gene enrichment and network analysis. ADs: Autoimmune diseases; Apo-A1: apolipoprotein A1; Apo-B: apolipoprotein B; BMI: body mass index; CHD: coronary heart disease; DBP: diastolic blood pressure; MR: Mendelian randomization; eQTL: Expression quantitative trait loci; IVs: instrumental variables; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: Protein-protein interaction; SMR: summary data-based MR; TSMR: two-sample MR; MVMR: multivariable MR; LDL-C: low-density lipoprotein cholesterol; TG: triglyceride (TG); HDL-C: high-density lipoprotein cholesterol; HEIDI: heterogeneity in dependent instruments

Fig. 2

Forest plot of association of lipid traits with risk of ADs. ADs: Autoimmune diseases; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; MS: Multiple sclerosis; UC: ulcerative colitis; CD: Crohn’s disease; Apo-A1: apolipoprotein A1; Apo-B: apolipoprotein B; LDL-C: low-density lipoprotein cholesterol; TG: triglyceride (TG); HDL-C: high-density lipoprotein cholesterol; N.SNPs: number of single-nucleotide polymorphisms; OR: odds ratio

Fig. 3

Forest plot of associations of genetically proxied drug targets with risk of ADs. HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; PCSK9: proprotein convertase subtilisin/kexin type 9; NPC1L1: Niemann-Pick C1-like intracellular cholesterol transporter 1; ABCG5/ABCG8: ATP binding cassette subfamily G member 5/8; LDLR: low-density lipoprotein receptor; APOB: apolipoprotein B; LPL: lipoprotein receptor; ANGPTL3: angiopoietin-like 3; APOC3: apolipoprotein C3; ADs: Autoimmune diseases; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; MS: Multiple sclerosis; UC: ulcerative colitis; CD: Crohn’s disease; N.SNPs: number of single-nucleotide polymorphisms; OR: odds ratio

Fig. 4

Functional interactions between HMGCR gene and the approved RA drug targets. (a) The combination diagram of Sankey and bubbles depicts the action mechanism of HMGCR; (b) GO enrichment results for three terms. HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; MF: molecular function; CC: cellular components; BP: biological processes

Fig. 5

PPI network between HMGCR and the approved drug targets of RA. HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; PPI: Protein–protein interaction; RA: rheumatoid arthritis

Fig. 6

The immunoregulatory effects of statins. STAT4: signal transducer and activator of transcription 4; GATA3: GATA binding protein 3; STAT6: signal transducer and activator of transcription 6; STAT1: signal transducer and activator of transcription 1; STAT3: signal transducer and activator of transcription 3; IRF4: interferon regulatory factor 4; SOCS1: suppressor of cytokine signaling 1; SOCS3: suppressor of cytokine signaling 3; SOCS7: suppressor of cytokine signaling 7; Smad6: Smad Family Member 6; Smad7: Smad Family Member 7; MMPs: matrix metalloproteinases; PPARs: peroxisome proliferator-activated receptors; NF-κB: nuclear transcription factor-kappa B; LFA-1: lymphocyte function-associated antigen 1; VLA-4: very late appearing antigen-4; CD11b: CD11 antigen-like family member b; CD18: integrin β2 subunit; VCAM1: vascular cell adhesion molecule 1