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Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian
Xiao Hu1,2, Peng Zhang2,3, Yuan Gao4
1Department of Health Promotion and Behavioral Sciences, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, China.
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.
Insights
This study found that inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) may reduce rheumatoid arthritis (RA) risk. HMGCR shows potential as a drug target for RA treatment and prevention.
Area of Science:
- Genetics and Immunology
- Pharmacology and Therapeutics
Background:
- Lipid metabolism and immune regulation are increasingly recognized as interconnected.
- Causality between lipids and autoimmune diseases (ADs) remains underexplored, limiting therapeutic target identification.
Purpose of the Study:
- To investigate causal associations between lipid traits and ADs.
- To evaluate the therapeutic potential of lipid-lowering drug targets for ADs.
Main Methods:
- Utilized Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses.
- Employed genetic variants from the Global Lipid Genetics Consortium (GLGC) and AD data from MER-IEU and FinnGen.
- Performed enrichment analysis and protein interaction networks for functional insights.
Main Results:
- No causal effects were found for 5 lipid traits or 9 lipid-lowering targets on ADs.
- Genetically proxied inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) significantly reduced rheumatoid arthritis (RA) risk (OR=0.45, P=6.79×10⁻⁶).
- HMGCR inhibition demonstrated causal effects on RA in whole blood and skeletal muscle, independent of BMI, blood pressure, and alcohol/smoking status.
Conclusions:
- Genetically proxied HMGCR inhibition is causally linked to decreased RA risk.
- HMGCR represents a promising candidate drug target for RA prevention and treatment.
