Research questions: Does Polycystic Ovary Syndrome (PCOS) affect asthma through metabolic dysfunction?
Objectives
1. Measure the prevalence of asthma in patients with PCOS in the UK Biobank
2. To use Mendelian randomisation (MR) to investigate the causal association between PCOS and asthma.
3. To understand the underlying mechanism by stratifying by asthma phenotypes (e.g., Type 2 high/low) and metabolic phenotypes (e.g., type-2 diabetes, overweight or obesity).
Rationale
PCOS affects ~10% of women, causing obesity, type 2 diabetes and infertility. Observational studies report women with PCOS are twice as likely to develop asthma. Shared mechanisms may explain a causal link, including metabolic dysfunction, chronic inflammation and hormonal imbalance. Notably, we have shown that metformin, a common PCOS treatment, reduces asthma exacerbations by nearly 50%. Understanding the relationship between PCOS and asthma could provide mechanistic insights into both conditions and metformin’s therapeutic effects. Traditional observational studies are prone to bias. In our study of 2 million asthma patients, nearly all women with PCOS had type 2 diabetes or overweight/obesity, risking residual confounding. Furthermore, many women remain undiagnosed with PCOS.
We will use Mendelian randomisation to investigate the causal relationship. It applies genetic variants as proxies for PCOS to test causal effects on asthma, reducing risks of reverse causation, misdiagnosis, and time-related confounding. Genetic variants for PCOS are already known, expediting analyses, and large resources exist (UK Biobank, Trans-National Asthma Genetic Consortium). This approach was used in my group to show that asthma does not cause cardiovascular disease, disproving an incorrect association held for over 30 years.
Additionally, data from UK Biobank allow exploration of mechanistic pathways: is causation through metabolic dysfunction or inflammation?
