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Clinical Rheumatology

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10-01-2024 | Rheumatoid Arthritis | ORIGINAL ARTICLE

Genetically proxied therapeutic inhibition of lipid-lowering drug targets and risk of rheumatoid arthritis disease: a Mendelian randomization study

Authors: Liang Qiao, Shun Lv, Kai Meng, Jianmei Yang

Published in: Clinical Rheumatology | Issue 3/2024

Abstract

Objective

To evaluate the potential impact of consistent use of similar treatments over a long period; it is essential to investigate the potential correlation between genetic variations that influence the expression or function of pharmacological targets for reducing lipid levels and the risk of developing rheumatoid arthritis.

Methods

We used variants in the following genes to conduct Mendelian randomization analyses: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, such as evolocumab and alirocumab), and NPC1L1 (encoding the target for ezetimibe). Data from lipid genetics consortia (173,082 sample size) were used to weight variations according to their correlations with low-density lipoprotein cholesterol (LDL-C). In two large datasets (total n = 19,562 cases, 501,655 controls). We conducted a meta-analysis of Mendelian randomization estimates, weighted by LDL-C levels, on the regional differences in the risk of rheumatoid arthritis using data from two large databases.

Results

We approached SMR and IVW-MR analyses to examine the relationship between target gene expression (including HMGCR, PCSK9, and NPC1L1) and LDL-C levels mediated by these genes with RA. The IVW-MR analysis revealed no significant association between genetically predicted LDL-C concentration and the risk of RA (OR = 0.88, 95% CI = 0.59–1.29; OR = 0.91, 95% CI = 0.67–1.23; OR = 0.81, 95% CI = 0.49–1.36; all p > 0.05). Similarly, our findings from the SMR approach provided no evidence to suggest that gene expression of HMGCR, PCSK9, and NPC1L1 was associated with the risk of RA (OR = 0.91, 95% CI = 0.79–1.05, p = 0.207; OR = 0.96, 95% CI = 0.85–1.09, p = 0.493).

Conclusions

Our results do not provide evidence to support the hypothesis that reducing LDL-C levels with statins, alirocumab, or ezetimibe effectively prevents the risk of developing RA. However, our study provides valuable insights into the assessment of lipid-lowering agents in RA, which can enhance our understanding of the condition and assist in clinical practice by aiding in the determination and monitoring of RA status to clinical response.

Key Points

• Common lipid-lowering drugs such as statins, alirocumab, or evolocumab may not effectively prevent the development of rheumatoid arthritis.

• This study provides clues for further exploration of the role of lipid-lowering therapy in other high-risk diseases, contributing to a deeper understanding of the potential effects of lipid-lowering treatment.

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Title: Genetically proxied therapeutic inhibition of lipid-lowering drug targets and risk of rheumatoid arthritis disease: a Mendelian randomization study
Authors: Liang Qiao
Shun Lv
Kai Meng
Jianmei Yang
Publication date: 10-01-2024
Publisher: Springer International Publishing
Keywords: Rheumatoid Arthritis
Alirocumab
Statins
PCSK9 Inhibitor
Published in: Clinical Rheumatology / Issue 3/2024
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-023-06837-9

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Abstract

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