Triglycerides and gestational diabetes mellitus: integrated clinical and genetic evidence linking LPL-related lipid metabolism

Abstract Background Gestational diabetes mellitus (GDM) is associated with adverse maternal and offspring outcomes, and disturbances in lipid metabolism may contribute to its metabolic pathophysiology. Elevated triglyceride (TG) levels have been consistently associated with GDM; however, it remains unclear whether this association is independent of correlated lipid traits and which genetic pathways may link TG metabolism to GDM. Methods We conducted a retrospective cross-sectional analysis in 2,735 Chinese pregnant women, including 380 with GDM. Lipid traits were measured at 24–28 gestational weeks, when GDM was diagnosed by 75-g oral glucose tolerance testing. Multivariable logistic regression and restricted cubic splines assessed clinical associations. Two-sample and multivariable Mendelian randomization (MR) using female-specific genome-wide association data, expression quantitative trait locus analyses, summary-data-based MR, and colocalization were used to examine genetically predicted TG, LPL expression, and GDM. Cross-ancestry analyses were performed in East Asian populations. Results TG showed the most consistent positive association with GDM; each 1 mmol/L increase was associated with 24% higher odds of GDM (odds ratio 1.24, 95% confidence interval 1.16–1.33). Genetic analyses supported an association between genetically predicted TG and GDM. This association persisted in the primary multivariable MR models but was attenuated in the exploratory fully adjusted lipid model. Higher genetically proxied LPL expression was associated with lower GDM risk. Colocalization showed moderate evidence of a shared TG-GDM signal at the LPL locus (PP.H4 = 0.688), with consistent results across genomic windows, whereas blood-derived LPL cis-eQTL signals did not clearly colocalize with GDM. East Asian analyses were not statistically significant, although ancestry-specific estimates did not differ significantly. Conclusions TG-related lipid dysregulation was consistently associated with GDM, and complementary genetic analyses support LPL-related metabolism as a biologically plausible candidate pathway. However, the available data do not confirm that this association is mediated through genetically regulated LPL expression in blood. Larger prospective and ancestry-specific pregnancy studies integrating pregnancy-relevant molecular data are warranted to clarify temporality and tissue-specific mechanisms.