Age at menarche, type 2 diabetes, and heart failure: A Mendelian randomization study

Area of Science:

• Reproductive health
• Metabolic diseases
• Cardiovascular diseases

Background:

• Observational studies suggest a link between early menarche and increased risk of type 2 diabetes mellitus (T2DM) and heart failure (HF).
• The causal nature of these associations has remained uncertain.
• Age at menarche (AAM) is a potential early life marker for later health outcomes.

Purpose of the Study:

• To investigate the causal relationships between age at menarche (AAM) and T2DM, HbA1c levels, and HF.
• To utilize Mendelian randomization (MR) to assess these genetic causal links.

Main Methods:

• A 2-sample Mendelian randomization (MR) analysis was performed using large-scale genome-wide association study (GWAS) summary statistics.
• Instrumental variables (IVs) were derived from genome-wide significant single nucleotide polymorphisms (SNPs) associated with AAM.
• Inverse variance weighted (IVW) method was the primary analytical approach, with sensitivity analyses conducted to ensure robustness.

Main Results:

• Genetically predicted later AAM was associated with a reduced risk of T2DM (OR, 0.881; P=6.92×10⁻⁷).
• Later AAM was also linked to lower HbA1c levels (OR, 0.964; P=2.06×10⁻⁵) and decreased risk of HF (OR, 0.907; P=7.98×10⁻⁶).
• These causal associations persisted even after excluding SNPs associated with body mass index (BMI).

Conclusions:

• This MR study provides robust evidence for a causal effect of AAM on T2DM, HbA1c, and HF.
• Assessing AAM routinely may aid in clinical risk stratification for these conditions.
• Findings support the development of targeted prevention strategies based on AAM.