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Age at menarche is increasingly recognized as an important reproductive factor associated with long-term metabolic and gastrointestinal health outcomes.
Earlier age at menarche increases the risk of gallstone disease, with liver function, lipid metabolism, and body fat acting as key mediators.
Age at menarche is increasingly recognized as an important reproductive factor associated with long-term metabolic and gastrointestinal health outcomes. Understanding the genetic relationship between pubertal timing and cholelithiasis may improve risk stratification and preventive strategies. Researchers determined the causal connection between age at menarche and cholelithiasis and evaluated key metabolic mediators underlying this relationship.
A genome-wide association study (GWAS) dataset was used to assess the link between age at pubertal menstrual onset and cholelithiasis. Genetic variants strongly linked with age at menarche were chosen as instrumental variables. The inverse-variance weighted method acted as the key analytical model.
A two-step Mendelian randomization (MR) framework was subsequently applied to identify potential mediators involved in the association. For checking pleiotropy and heterogeneity, sensitivity assessments, including MR-Egger regression, Cochran’s Q test, and MR-PRESSO, were carried out.
Earlier age at menarche was significantly related to an increased likelihood of cholelithiasis (Odds ratio 0.90; 95% confidence interval 0.82–0.99; P=0.0369). The findings supported a potential causal relationship between pubertal timing and gallstone development.
Two-step MR analysis further recognized alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and body fat percentage (BFP) as significant mediators contributing to this link. Sensitivity analyses verified the stability and reliability of the genetic estimates, with no major evidence of directional pleiotropy.
This bidirectional two-sample MR analysis provided genetic evidence that earlier menarche was causally associated with a higher risk of cholelithiasis. Metabolic and hepatic factors, including LDL-C, ALT, and BFP, appeared to partially mediate this relationship. These findings highlighted the importance of reproductive timing in gallstone pathogenesis and supported future strategies targeting metabolic health in women at increased risk.
BMC Women's Health
Genetic association and potential mediators between age at menarche and cholelithiasis: a two-sample two-step bidirectional mendelian randomization study
Ziquan Yuan et al.
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