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

• Published in: Gynecological endocrinology Vol. 41; no. 1; p. 2541647
• Main Authors: Shao, Fengping, Li, Yinguang
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis Group 01.12.2025
• Subjects: Case-Control Studies; CD4-Positive T-Lymphocytes - metabolism; Dyslipidemias - blood; Dyslipidemias - genetics; Dyslipidemias - immunology; Female; Humans; immune cell traits; lipid metabolism; Lipid Metabolism - genetics; Lipid Metabolism - immunology; Lipoproteins, IDL - blood; Lipoproteins, IDL - genetics; Lipoproteins, IDL - immunology; Lipoproteins, LDL - blood; Lipoproteins, LDL - genetics; Lipoproteins, LDL - immunology; mendelian randomization; Mendelian Randomization Analysis; premature ovarian insufficiency; Primary Ovarian Insufficiency - blood; Primary Ovarian Insufficiency - genetics; Primary Ovarian Insufficiency - immunology; Proportional Hazards Models; Sialic Acid Binding Ig-like Lectin 3 - blood; Sialic Acid Binding Ig-like Lectin 3 - genetics; Sialic Acid Binding Ig-like Lectin 3 - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; immune cell traits; premature ovarian insufficiency; mendelian randomization; lipid metabolism
• ISSN: 0951-3590; 1473-0766; 1473-0766
• DOI: 10.1080/09513590.2025.2541647

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 (  = 655) with population-matched controls (  = 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,  = 0.015), activated (%CD4 Treg: OR = 0.881,  = 0.021). CD39+ resting Treg absolute count was significant (OR = 0.861,  = 0.027), while CD39 expression on activated/secreting Treg reduced risk (OR = 0.917-0.904,  < 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,  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,  = 0.028), large LDL-free cholesterol (OR = 1.28,  0.030), and IDL components-total cholesterol, free cholesterol, phospholipids, particle concentration, and total lipids (OR = 1.287-1.345, all  < 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.