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. 2023 Nov 17:14:1272167.
doi: 10.3389/fendo.2023.1272167. eCollection 2023.

Association of HMGCR inhibition with rheumatoid arthritis: a Mendelian randomization and colocalization study

Li Ma #  1   2 , Yufei Du #  1 , Chao Ma  3 , Ming Liu  1
Affiliations

Association of HMGCR inhibition with rheumatoid arthritis: a Mendelian randomization and colocalization study

Li Ma et al. Front Endocrinol (Lausanne). .

Abstract

Objective: The objective of this study was to investigate the association between hydroxymethylglutaryl coenzyme A reductase (HMGCR) inhibition and rheumatoid arthritis (RA) using drug-target Mendelian randomization (MR) and genetic colocalization analyses.

Methods: Two sets of genetic instruments were employed to proxy HMGCR inhibitors: expression quantitative trait loci (eQTLs) of target genes from the eQTLGen Consortium and genetic variants associated with low-density lipoprotein cholesterol (LDL-C) levels with HMGCR locus from open genome-wide association studies (GWAS). Positive control analyses were conducted on type 2 diabetes and coronary heart disease, and multiple sensitivity analyses were performed.

Results: Genetically proxied expression of eQTL was associated with a lower risk of RA (OR=0.996, 95% CI =0.992-0.999, p= 0.032). Similarly, hydroxymethylglutaryl coenzyme A reductase (HMGCR)-mediated low-density lipoprotein cholesterol was negatively associated with risk of RA (OR=0.995, 95% CI =0.991-0.998, p= 0.007) in the inverse variance weighted (IVW) method. Colocalization analysis suggested a 74.6% posterior probability of sharing a causal variant within the SNPs locus (PH4 = 74.6%). A causal relationship also existed between HMGCR-mediated LDL and RA risk factors. The results were also confirmed by multiple sensitivity analyses. The results in positive control were consistent with the previous study.

Conclusion: Our study suggested that HMGCR inhibition was associated with an increased risk of RA while also highlighting an increased risk of current smoking and obesity. These findings contribute to a growing body of evidence regarding the adverse effects of HMGCR inhibition on RA risk, calling for further research on alternative approaches using HMGCR inhibitors in RA management.

Keywords: HMG-CoA reductase; Mendelian randomization; genetic colocalization; rheumatoid arthritis; statin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study flame of the drug target Mendelian randomization and colocalization study. RA, rheumatoid arthritis.
Figure 2
Figure 2
Causal effect of HMGCR mediated LDL on RA risk factors in the IVW method. Forest plots showing the range of OR values for different serological indicators. The vertical lines on either side of the point represent the 95% confidence interval. current: current tobacco smoking; past: past tobacco smoking; alcohol: current alcohol drinking; OR, odds ratio; 95%CI, 95% confidence interval.
Figure 3
Figure 3
Leave-one-out analysis of the HMGCR mediated LDL cholesterol and RA.
See this image and copyright information in PMC

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