Causal associations between intermediate very-low-density lipoprotein cholesterol-to-total lipids ratio and peptic ulcer: A bidirectional Mendelian randomization study

Abstract

BACKGROUND

Previous epidemiologic investigations have consistently demonstrated a strong association between the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) and the occurrence of peptic ulcers (PU). However, the precise causal relationship between these factors remains ambiguous. Consequently, this study aims to elucidate the potential correlation between the ratio of cholesterol to total lipids in medium VLDL and the incidence of peptic ulcer.

AIM

To investigate the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) association with PU via genetic methods, guiding future clinical research.

METHODS

Genome-wide association study (GWAS) datasets for the ratio of cholesterol to total lipids in intermediate VLDL and peptic ulcer were retrieved from the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk). For the forward Mendelian randomization (MR) analysis, 72 single nucleotide polymorphisms (SNPs) were identified as instrumental variables. These SNPs were selected based on their association with the ratio of cholesterol to total lipids in intermediate VLDL, with peptic ulcer as the outcome variable. Conversely, for the inverse MR analysis, no SNPs were identified with peptic ulcer as the exposure variable and the ratio of cholesterol to total lipids in intermediate VLDL as the outcome. All MR analyses utilized inverse variance weighted (IVW) as the primary analytical method. Additionally, weighted median and MR-Egger methods were employed as supplementary analytical approaches to assess causal effects. Egger regression was used as a supplementary method to evaluate potential directional pleiotropy. Heterogeneity and multiplicity tests were conducted using the leave-one-out method to evaluate result stability and mitigate biases associated with multiple testing.

RESULTS

The genetically predicted ratio of cholesterol to total lipids in medium VLDL was significantly associated with an elevated risk of peptic ulcer (IVW: OR = 2.557, 95%CI = 1.274-5.132, P = 0.008). However, no causal association of peptic ulcer with the ratio of cholesterol to total lipids in medium VLDL was observed in the inverse Mendelian randomization analysis.

CONCLUSION

In conclusion, our study reveals a significant association between the ratio of cholesterol to total lipids in medium VLDL and an elevated risk of peptic ulcers. However, further validation through laboratory investigations and larger-scale studies is warranted to strengthen the evidence and confirm the causal relationship between these factors.

Keywords: Ratio of cholesterol to total lipids in medium VLDL, Peptic ulcer, Mendelian randomization, Casual effect, Single nucleotide polymorphism

Core Tip: Higher ratios of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) levels were causally related to a reduced risk of peptic ulcer (PU) or the main pathways implicated in its development, as suggested by our Mendelian randomization investigation. Further laboratory studies and exploration of molecular mechanisms are required to clarify the role of the ratio of cholesterol to total lipids in medium VLDL in the onset of PU and its main pathways.