Mendelian randomization analysis reveals causal effects of blood lipidome on gestational diabetes mellitus

Abstract

Background: Observational studies have revealed associations between maternal lipid metabolites and gestational diabetes mellitus (GDM). However, whether these associations are causal remain uncertain.

Objective: To evaluate the causal relationship between lipid metabolites and GDM.

Methods: A two-sample Mendelian randomization (MR) analysis was performed based on summary statistics. Sensitivity analyses, validation analyses and reverse MR analyses were conducted to assess the robustness of the MR results. Additionally, a phenome-wide MR (Phe-MR) analysis was performed to evaluate potential side effects of the targeted lipid metabolites.

Results: A total of 295 lipid metabolites were included in this study, 29 of them had three or more instrumental variables (IVs) suitable for sensitivity analyses. The ratio of triglycerides to phosphoglycerides (TG_by_PG) was identified as a potential causal biomarker for GDM (inverse variance weighted (IVW) estimate: odds ratio (OR) = 2.147, 95% confidential interval (95% CI) 1.415-3.257, P = 3.26e-4), which was confirmed by validation and reverse MR results. Two other lipid metabolites, palmitoyl sphingomyelin (d18:1/16:0) (PSM(d18:1/16:0)) (IVW estimate: OR = 0.747, 95% CI 0.583-0.956, P = 0.021) and triglycerides in very small very low-density lipoprotein (XS_VLDL_TG) (IVW estimate: OR = 2.948, 95% CI 1.197-5.215, P = 0.015), were identified as suggestive potential biomarkers for GDM using a conventional cut-off P-value of 0.05. Phe-MR results indicated that lowering TG_by_PG had detrimental effects on two diseases but advantageous effects on the other 13 diseases.

Conclusion: Genetically predicted elevated TG_by_PG are causally associated with an increased risk of GDM. Side-effect profiles indicate that TG_by_PG might be a target for GDM prevention, though caution is advised due to potential adverse effects on other conditions.

Keywords: Gestational diabetes mellitus; Lipid metabolites; Phenome-wide Mendelian randomization; Two-sample Mendelian randomization.

Fig. 1

Conceptual framework of Mendelian randomization study. The study consists of two parts. a Part 1, we assessed the causality for the association between 295 lipid metabolites and the risk of GDM. b Part 2, we investigated a broad spectrum of side effects associated with targeting identified lipid metabolites in 1210 non-GDM diseases. GWAS = genome-wide association study, MR = Mendelian randomization, N in a = number of lipid metabolites, N in b = number of phenotypes

Fig. 2

The flow chart of instrumental variables selection. GWAS genome-wide association study, IVW inverse variance weighted, MR Mendelian randomization; SNP = single nucleotide polymorphism

Fig. 3

Circular Manhattan plot displaying the associations between lipid metabolites and the risk of GDM in the Mendelian randomization analysis. The dashed red line represents the Bonferroni-corrected significance threshold (P < 1.92e−3), while the inner line indicates the suggestive significance threshold (P < 0.05). (Suggestive) Significant lipid metabolites are labeled accordingly. Blue bars denote tier 1 lipid metabolites while grey bars denote tier 2 lipid metabolites. The 295 blood lipid metabolites are categorized and color-coded by lipid classes as shown in Fig. 1 and Table S5. Detailed results for the associations between blood metabolites and GDM by Mendelian randomization analysis are presented in Table S6. GDM gestational diabetes mellitus, TG_by_PG ratio of triglycerides to phosphoglycerides, PSM (d18:1/16:0) palmitoyl sphingomyelin (d18:1/16:0), XS_VLDL_TG triglycerides in very small VLDL

Fig. 4

Potential on-target side effects associated with TG_by_PG, TG and PG intervention revealed by phenome–wide Mendelian randomization analysis. Odds ratios with their 95% confidence intervals represent the effect estimates on the risk of various non-GDM diseases of per 10% reduction in GDM risk by targeting a TG_by_PG, b triglycerides and c phosphoglycerides, respectively. Associations that are above the horizontal line with a black dash indicate deleterious side effects, while those below represent beneficial side effects. The upper red dashed horizontal line (odds ratio = 1.10) represents the point at which decreased GDM risk is counterbalanced by an equal increase in disease risk. CI   confidence interval, OR  odds ratio, TG_by_PG ratio of triglycerides to phosphoglycerides