The role of the ADRB2 Thr164Ile variant in lung function determination, plasma proteome variability and other phenotypes in UK Biobank.

INTRODUCTION

The effect of coding polymorphisms of the β2-adrenergic receptor gene (ADRB2) on functional properties of the receptor is well established. We recently reported a genome-wide significant association between Thr164Ile and lung function, but the contribution of this variant to other traits remains unclear.

METHODS

To identify pleiotropic effects of ADRB2 Thr164Ile and other coding variants, we performed respiratory-focused and phenome-wide association studies in UK Biobank. In addition, we used available Olink proteomic data to characterise enriched pathways and upstream regulators of proteins associated with ADRB2 polymorphisms.

RESULTS

The minor T allele of Thr164Ile was associated with reduced lung function, but not COPD or asthma or risk of exacerbations on long-acting β-agonist treatment. It was also associated with nonrespiratory traits including increased eosinophil counts and blood lipid measurements, including increased cholesterol, reduced triglycerides and reduced apolipoprotein A. Proteins associated with Thr164Ile (p≤0.01) were enriched for various pathways, with the eosinophil-raising allele associated with reduced neutrophil degranulation, immunoregulatory interactions between lymphoid and nonlymphoid cells, tumour necrosis factor binding and DAP12 interactions, as well as activation of lipid metabolism pathways, including FXR/RXR activation and LXR/RXR activation. A gene-based analysis of rare, nonsynonymous ADRB2 variants, identified a novel association with nonrheumatic pulmonary valve disorders, but no association with lung function.

DISCUSSION: In conclusion, the lung function-lowering allele of Thr164Ile is associated with traits and proteins indicative of a role in immune and lipid metabolism pathways, suggesting potential targets for therapeutic intervention.