Premature ovarian insufficiency as a consequence of immunological abnormalities and dyslipidemia: a Mendelian...

Observational studies have suggested associations between premature ovarian insufficiency (POI) and immunological abnormalities or dyslipidemia, but causal evidence remains unestablished.

We conducted a two-sample Mendelian randomization (MR) study to evaluate causal relationships of POI with immune cell traits (CD4+ regulatory T cell [Treg], and its subtype CD39 + CD4+ Treg, CD33 expression) and lipid metabolism markers (low-density lipoprotein [LDL] and intermediate-density lipoprotein [IDL] subfractions). Genetic instruments were derived from three independent sources: immune cell data from 3,757 Sardinians, lipid traits from 21,559 Europeans, and POI cases (N = 655) with population-matched controls (N = 267,780) from FinnGen R12. Primary causal estimates were generated using inverse-variance weighted regression, complemented by sensitivity analyses (MR-Egger, MR-PRESSO).

CD39+ Treg subpopulations showed robust protection against POI in proportional analyses: secreting (%CD4 Treg: OR = 0.889, p = 0.015), activated (%CD4 Treg: OR = 0.881, p = 0.021). CD39+ resting Treg absolute count was significant (OR = 0.861, p = 0.027), while CD39 expression on activated/secreting Treg reduced risk (OR = 0.917-0.904, p < 0.05). Elevated CD33 expression on 9 of 12 myeloid cell subsets (e.g. granulocytic myeloid-derived suppressor Cells, CD33+ monocytes), and plasma CD33 protein (OR = 0.877, p = 0.030) were inversely associated with POI risk. Dyslipidemia traits demonstrated causal associations: total cholesterol (OR = 1.328, p = 0.028), large LDL-free cholesterol (OR = 1.28, p = 0.030), and IDL components-total cholesterol, free cholesterol, phospholipids, particle concentration, and total lipids (OR = 1.287-1.345, all p < 0.05).

Total cholesterol (OR = 1.328, p = 0.028), large LDL-free cholesterol (OR = 1.28, p = 0.030), and IDL components-total cholesterol, free cholesterol, phospholipids, particle concentration, and total lipids (OR = 1.287-1.345, all p < 0.05).

This study establishes POI as an immunometabolic disorder driven by Tregs deficiency, CD33-mediated protection, and lipid dysregulation, advocating targeted therapies for ovarian protection.