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

Abstract

IntroductionThe effect of coding polymorphisms of the beta-2 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. MethodsTo 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. ResultsThe minor allele of Thr164Ile was associated with reduced lung function, but not COPD or asthma defined using self-report and diagnostic codes in healthcare records. It was also associated with non-respiratory traits including increased eosinophil counts and blood lipid measurements, including increased cholesterol, reduced triglycerides and reduced apolipoprotein A. Proteins associated with Thr164Ile (P-value[≤]0.01) were enriched for various pathways, with the eosinophil-raising allele associated with reduced neutrophil degranulation, immunoregulatory interactions between a Lymphoid and a non-Lymphoid cells, TNF 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, non-synonymous ADRB2 variants, identified a novel association with non-rheumatic pulmonary valve disorders, but no association with lung function. DiscussionIn conclusion, the lung function-lowering allele of Thr164Ile is associated with traits and proteins indicative of a role in immune and lipid metabolism pathways, but not COPD or asthma. In contrast, ADRB2 rare coding variants are not associated with lung function.