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. 2023 Dec 1:14:1301163.
doi: 10.3389/fendo.2023.1301163. eCollection 2023.

Causal effects of circulating lipids and lipid-lowering drugs on the risk of urinary stones: a Mendelian randomization study

Zilong Tan  1 , Jing Hong  2 , Aochuan Sun  3 , Mengdi Ding  1 , Jianwu Shen  1
Affiliations

Causal effects of circulating lipids and lipid-lowering drugs on the risk of urinary stones: a Mendelian randomization study

Zilong Tan et al. Front Endocrinol (Lausanne). .

Abstract

Background: Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal relationship between the two remains inconclusive.

Objective: This study aimed to assess the causal relationship between circulating lipids (Triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein A [APOA], apolipoprotein B [APOB] and Pure hypercholesterolaemia), lipid-lowering drugs (HMGCR [HMG-CoA reductase] inhibitors and PCSK9[Proprotein Convertase Subtilisin/Kexin Type 9] inhibitors) and the risk of urinary stones, using genetic data.

Methods: Genetic instrumental variables (GIVs) for circulating lipids and lipid-lowering drugs were obtained from the UK Biobank and existing literature. Outcome data were extracted from a genetic association database with 3,625 urinary stone cases and 459,308 controls. Two-sample MR analysis, employing the TwoSampleMR software package in R 4.2.3, was conducted to assess the associations between multiple exposures. The primary outcome was determined using the inverse variance weighted (IVW) method for the causal relationship between exposure and outcome, while additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were utilized as supplementary analyses. Robustness of the Mendelian Randomization (MR) analysis results was assessed through leave-one-out analysis and funnel plots.

Results: The MR analysis revealed a significant association between elevated TG levels per 1 standard deviation and the occurrence of urinary stones (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.000-1.003, P = 0.010). However, no significant association was observed between factors other than TG exposure and the risk of urinary stone occurrence across all methods(LDL-C: [OR], 1.001; 95% [CI], 1.000-1.003, P=0.132;HDL-C: [OR], 0.999; 95% [CI], 0.998-1.000, P=0.151;APOA:[OR] being 1.000 (95% [CI], 0.999-1.001, P=0.721;APOB: [OR] of 1.001 (95% [CI], 1.000-1.002, P=0.058;Pure hypercholesterolaemia: [OR] of 1.015 (95% [CI], 0.976-1.055, P=0.455) and lipid-lowering drugs (HMGCR inhibitors: [OR], 0.997; 95% [CI], 0.990-1.003, P=0.301 and PCSK9 inhibitors:[OR], 1.002; 95% [CI], 1.000-1.005, P=0.099).

Conclusion: Our findings provide conclusive evidence supporting a causal relationship between an increased risk of urinary stones and elevated serum TG levels. However, we did not find a significant association between urinary stone occurrence and the levels of LDL-C, HDL-C, APOA, APOB, Pure hypercholesterolaemia and lipid-lowering drugs.

Keywords: Mendelian randomization; causality; circulating lipids; genetics; lipid-lowering drugs; urinary stones.

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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
Schematic representation of the three assumptions and study design. (1) The employed genetic IVs are firmly linked to the exposure; (2) The chosen IVs exhibit no associations with potential confounding factors; (3) The IVs can solely influence the outcome risk through the exposure in a dependent manner.
Figure 2
Figure 2
Genetic instrument selection of single-variable Mendelian randomization study. TG, Triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; APOA, apolipoprotein; APOB, apolipoprotein; IVW, inverse-variance weighting; MR, Mendelian randomization; SNP, single nucleotide polymorphisms.
Figure 3
Figure 3
The impact of circulating lipids and lipid-lowering drugs on the risk of urinary stones was assessed through MR analysis utilizing the IVW model.
See this image and copyright information in PMC

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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Beijing Municipal Health Commission, Capital Health Development Scientific Research Special Project; (No. Capital Health Development 2022-3-4176), China Academy of Traditional Chinese Medicine, Science and Technology Innovation Project Major Research Project; (No. C12021A02206). Those funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.