Unraveling the causal pathway between phosphatidylinositol, metabolites, and metabolic syndrome: a Mendelian randomization study

YueGuang Yang; YanLing Ma; Ming Li; YuBo Han; Li Liu

doi:10.1186/s13098-025-01731-7

Unraveling the causal pathway between phosphatidylinositol, metabolites, and metabolic syndrome: a Mendelian randomization study

Diabetol Metab Syndr. 2025 May 20;17(1):162. doi: 10.1186/s13098-025-01731-7.

Authors

YueGuang Yang¹, YanLing Ma¹, Ming Li¹, YuBo Han², Li Liu³

Affiliations

¹ Heilongjiang University of Chinese Medicine;, Heilongjiang, P.R. China.
² The First Department of Cardiovascular, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 26 Heping Road, Xiangfang, Harbin, Heilongjiang, 150040, P.R. China. hanyb1989@163.com.
³ The First Department of Cardiovascular, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 26 Heping Road, Xiangfang, Harbin, Heilongjiang, 150040, P.R. China. liliu429@163.com.

Abstract

Introduction: Observational studies have increasingly acknowledged the influence of Phosphatidylinositol (PI) on metabolic syndrome (MetS). Nevertheless, the causal association between PI and MetS remains unclear due to the presence of confounding factors and the potential for reverse causation in observational settings. This study seeks to clarify the causal link between PI and MetS while investigating the role of mediating metabolites.

Methods: A two-sample Mendelian randomization (MR) analysis was performed to examine the association between PI and MetS, utilizing aggregated data from genome-wide association studies (GWAS). Additionally, a two-step MR approach was applied to quantify the mediation effect of metabolites on the PI-MetS relationship. The inverse variance weighted (IVW) method served as the primary analytical approach, complemented by various sensitivity analyses employing alternative techniques.

Results: A significant positive association was found between genetically predicted PI and a 17% increased risk of MetS. Genetically predicted metabolites, including 4-cholesten-3-one (IVW: OR 1.264, 95% CI 1.076-1.483, p = 0.004), N-acetylalliin (IVW: OR 1.189, 95% CI 1.008-1.402, p = 0.040), and the Adenosine 5'-diphosphate to 5-oxoproline ratio (IVW: OR 1.191, 95% CI 1.045-1.357, p = 0.009), were each significantly associated with an increased risks of MetS, accounting for 14.50, 11.41%, 11.87% and % of the total effect, respectively. Notably, the Retinol to oleoyl-linoleoyl-glycerol ratio (IVW: OR 0.643, 95% CI 0.466-0.887, p = 0.007) mediated 62.6% of the effect, highlighting its pivotal role in the causal pathway linking PI to MetS. Moreover, 1-palmitoyl-2-dihomo-linolenoyl-GPC (IVW: OR 0.865, 95% CI 0.752-0.995, p = 0.042) and the Creatine to carnitine ratio (IVW: OR 0.853, 95% CI 0.740-0.983, p = 0.028) were associated with a reduced risk of MetS, demonstrating inhibitory effects within their respective pathways that accounted to 35.03% and 8.45% reductions in risk, respectively.

Conclusions: Our MR analysis demonstrated a positive association between PI and an increased risk of MetS. Furthermore, the metabolite-mediated PI significantly influenced MetS risk. These findings may offer valuable insights into the pathogenesis of MetS and inform future clinical research.

Keywords: Mendelian randomization; Metabolic syndrome; Metabolite; Phosphatidylinositol.

Abstract

Grants and funding