Age at first birth and lung cancer: a two-sample Mendelian randomization study

Area of Science:

• Reproductive Health
• Oncology
• Genetics

Background:

• Female reproductive factors, specifically age at first birth (AFB), are increasingly implicated in lung cancer (LC) progression.
• Previous research on AFB and LC risk is limited by confounding factors, insufficient histological analysis, and potential reverse causality.
• The causal relationship between AFB and LC risk remains incompletely understood.

Purpose of the Study:

• To investigate the potential causal association between age at first birth (AFB) and the risk of developing lung cancer (LC).
• To explore this association across different histological subtypes of lung cancer.
• To leverage large-scale genome-wide association study (GWAS) data and Mendelian randomization (MR) methods for robust causal inference.

Main Methods:

• Utilized aggregated genetic data from large genome-wide association studies (GWAS) for AFB (n=251,151) and lung cancer data from the International Lung and Cancer Consortium (ILCCO, n=11,348 cases, 15,861 controls).
• Employed 10 AFB-associated single nucleotide polymorphisms (SNPs) as instrumental variables in a two-sample Mendelian randomization (MR) framework.
• Conducted secondary analyses stratified by lung cancer histotypes and performed sensitivity analyses to assess pleiotropy.

Main Results:

• A genetic predisposition for each one-year increase in AFB was associated with an 18% reduction in overall lung cancer risk (OR=0.82, P=0.029).
• This inverse association was significant for lung adenocarcinoma (OR=0.75, P=0.017) but not for squamous cell lung cancer (OR=0.77, P=0.103).
• Sensitivity analyses, including MR-Egger and MR-PRESSO, did not indicate significant pleiotropy (P=0.412). Older AFB was also associated with increased years of schooling, lower BMI, and reduced alcohol consumption.

Conclusions:

• The study provides evidence that an older age at first birth (AFB) acts as a causal protective factor against lung cancer (LC) development.
• The protective effect appears more pronounced in lung adenocarcinoma compared to squamous cell lung cancer.
• Further research is warranted to elucidate the specific biological mechanisms underlying this protective association.