Elucidating the role of hepatic enzymes in spontaneous abortion: a Mendelian randomization approach

Abstract

Background: While the hepatic enzymes Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) are crucial for liver function, their role in Spontaneous Abortion (SA) has not been thoroughly explored. Utilizing Mendelian Randomization (MR), this study aims to clarify the putative causal relationship between AST/ALT levels and SA.

Methods: Genome-wide association study (GWAS) summary data for SA (finn-b-O15_ABORT_SPONTAN), AST (ukb-d-30650_raw), and ALT (ukb-d-30620_raw) were acquired from the Integrative Epidemiology Unit OpenGWAS database. Bidirectional MR analysis was conducted using MR-Egger, Weighted Median, Simple Mode, Weighted Mode, and Inverse Variance Weighted (IVW) algorithms, and the robustness of MR results was assessed through sensitivity analyses including Heterogeneity, Horizontal Pleiotropy, and Leave-One-Out (LOO) tests. The causal role of AST and ALT's coaction in SA was explored via multivariable MR (MVMR) analysis.

Results: The MR results via the IVW algorithm revealed a causal relation between both AST and ALT and SA (AST: P = 0.013; ALT: P = 0.017), identifying them as risk factors for SA (AST: odd ratio (OR) = 1.019; ALT: OR = 1.012). Sensitivity analysis substantiated the reliability of these results. Moreover, not notably causality was found between SA and AST/ALT (P > 0.05). Through MVMR analysis, AST and ALT demonstrated functional complementarity in the occurrence of SA, attributable to counterbalanced causalities (AST: P = 0.128; ALT: P = 0.899).

Conclusion: The study substantiates a causal linkage between transaminase levels and SA, enhancing our understanding of their biological interaction and the regulatory mechanisms at play. These insights could have implications for identifying novel biomarkers and therapeutic targets for SA.

Keywords: Mendelian randomization (MR); alanine aminotransferase (ALT); aspartate aminotransferase (AST); hepatic enzymes; spontaneous abortion (SA).

FIGURE 1

Flow chart of this study.

FIGURE 2

Causal effect of Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) on Spontaneous Abortion (SA) in forward Mendelian randomization (MR) analysis. (A) Scatter plot of genetic associations between exposure and outcome. Left: AST and SA. Right: ALT and SA. (B) Left: AST-SA funnel plot. Right: ALT-SA funnel plot. It is found that based on inverse variance weighted (IVW) method, almost left-right symmetry. (C) Left: The forest plot for the single nucleotide polymorphism (SNP) analysis of AST increasing on SA risk. Right: The forest plot for the SNP analysis of ALT increasing on SA risk. The x-axis shows the MR effect size for AST and ALT increasing on SA, while the y-axis illustrates the analysis for each of the SNPs. The dot and bar indicate the causal estimate and 95% confidence intervals (CI) of the association between AST and ALT increasing on SA risk.

FIGURE 3

Sensitivity analysis. (A) Presentation of the leave-one-out sensitivity analysis for the effect of AST increasing SNPs on SA risk in the context of MR. (B) Presentation of the leave-one-out sensitivity analysis for the effect of ALT increasing SNPs on SA risk in the context of MR. The dot and bar indicate the estimate and 95% CI when a specific SNP is removed. OR, odds ratios; IV, instrumental variant; SE, standard error.