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The Causal Relationship Between Choline Metabolites and Acute Acalculous Cholecystitis: Identifying ABCG8 as
Yuntong Gao1, Kun Mao1, Congying Yang1
1Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
Insights
This study reveals a protective causal link between choline metabolites, including total choline, phosphatidylcholine, and sphingomyelin, and acute acalculous cholecystitis (AAC). These findings suggest potential therapeutic targets for managing this complex condition.
Area of Science:
- Biochemistry
- Genetics
- Gastroenterology
Background:
- Acute acalculous cholecystitis (AAC) presents a significant mortality risk with complex, poorly understood pathogenesis.
- Choline, an essential nutrient, is implicated in various disease processes.
- Understanding the role of choline metabolites in AAC is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the causal relationship between choline metabolites and AAC.
- To explore the potential mechanisms underlying this relationship, including the role of lipids and genetic factors.
- To identify potential therapeutic targets for AAC.
Main Methods:
- Two-sample Mendelian randomization was employed to assess causality between choline metabolites and AAC.
- Multivariable and mediated Mendelian randomization analyses were conducted to evaluate confounding effects from lipids (LDL, HDL, TGs) and coronary artery disease (CAD).
- Linkage disequilibrium score regression, co-localization, and enrichment analyses were used to elucidate molecular mechanisms.
Main Results:
- A significant negative causal relationship was observed between total choline, phosphatidylcholine, and sphingomyelin, and AAC.
- Low-density lipoprotein (LDL) mediated a protective effect of these choline metabolites on AAC.
- The gene ABCG8, associated with SNP rs75331444, was identified as a potential player in the development of AAC.
Conclusions:
- Choline metabolites exert a protective causal effect on AAC, partly mediated by LDL.
- The gene ABCG8 may play a role in the pathogenesis of non-calculous cholecystitis.
- These findings open avenues for novel therapeutic strategies targeting choline metabolism in AAC.
Background:
Acute acalculous cholecystitis (AAC) is a type of cholecystitis with high mortality rate while its pathogenesis remains complex. Choline is one of the essential nutrients and is related to several diseases. This study aimed to explore the causal relationship between choline metabolites and AAC and its potential mechanisms.
Methods:
This research utilized the two-sample Mendelian randomization method to investigate the causal relationship between choline metabolites and AAC. Additionally, multivariable Mendelian randomization and mediated Mendelian randomization were used to explore potential confounding effects from low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), and coronary artery disease (CAD). Linkage disequilibrium score regression (LDSC), co-localization analysis, and enrichment analysis were used to investigate relevant molecular mechanisms.
Results:
There is a negative causal relationship between total choline (OR [95%CI] = 0.9982 [0.9974, 0.9990], p = 0.0023), phosphatidylcholine (OR [95%CI] = 0.9983 [0.9976-0.9991], p = 0.0040), sphingomyelin (OR [95%CI] = 0.9980 [0.9971-0.9988], p = 0.0001), and AAC. The mediating effects of LDL were -0.0006 for total choline, -0.0006 for phosphatidylcholine, and -0.0008 for sphingomyelin, indicating a protective effect of total choline, phosphatidylcholine, and sphingomyelin on AAC. Colocalized SNP rs75331444, which is mapped to gene ABCG8, was identified for total choline (PPH4 = 0.8778) and sphingomyelin (PPH4 = 0.9344).
Conclusions:
There is a causal relationship between choline metabolites and cholecystitis, mediated through the protective action of LDL. Our results suggest that ABCG8 may play a role in the development of non-calculous cholecystitis.
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