Asthma and incident coronary heart disease: an observational and Mendelian randomisation study

Abstract

Observational studies suggest asthma is a risk factor for coronary heart disease (CHD) and sex modifies the risk, but they may suffer from methodological limitations. To overcome these, we applied a ‘triangulation approach’, where different methodologies, with different potential biases, were leveraged to enhance confidence in findings. First, we conducted an observational study using U.K. medical records to match asthma patients, by age, sex and GP practice, 1:1 to the general population. We measured the association between asthma and incident CHD (myocardial infarction: hospitalisation/death) by applying minimal sufficient adjustment: model 1, smoking, body mass index, oral corticosteroids, atopy and deprivation; model 2, additionally adjusting for healthcare behaviour (GP consultation frequency). Second, we conducted a Mendelian Randomisation (MR) study using data from the UK Biobank, Trans-National Asthma Genetic Consortium, and Coronary Artery Disease Genome -wide Replication and Meta-analysis consortium. Using 64 asthma SNPs, the effect of asthma on CHD was estimated with inverse variance-weighted meta-analysis and methods that adjust for pleiotropy. In our observational study (N=1,522,910), we found asthma was associated with 6% increased risk of CHD (model 1: HR=1.06, 95%CI=1.01-1.13), after accounting for healthcare behaviour, we found no association (model 2: HR=0.99, 95% CI=0.94-1.05). Asthma severity did not modify the association, but sex did (females: HR=1.11, 95%CI=1.01-1.21; males: HR=0.91, 95%CI=0.84-0.98). Our MR study (N=589,875) found no association between asthma and CHD (OR=1.01; 95%CI=0.98-1.04) and no modification by sex. Our findings suggest that asthma is not a risk factor for CHD. Previous studies may have suffered from detection bias or residual confounding.