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. 2025 Dec 1;11(6):00330-2025.
doi: 10.1183/23120541.00330-2025. eCollection 2025 Nov.

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

Katherine A Fawcett  1 , Robert J Hall  2 , Richard Packer  1   3 , Kayesha Coley  1 , Nick Shrine  1 , Louise V Wain  1   3 , Martin D Tobin  1   3 , Ian P Hall  2
Affiliations

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

Katherine A Fawcett et al. ERJ Open Res. .

Abstract

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.

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Conflict of interest statement

Conflict of interest: I.P. Hall reports previous funding from Boehringer Ingelheim, outside the submitted work. L.V. Wain, M.D. Tobin and R. Packer report collaborative research funding from GSK and Orion Pharma, outside of the submitted work. L.V. Wain reports consultancy for GSK, Boehringer Ingelheim and Galapagos and has funding from Roche outside the submitted work. K.A. Fawcett, N. Shrine, R.J. Hall and K. Coley report no competing interests.

Figures

FIGURE 1
FIGURE 1
Phenome-wide association of 1746 UK Biobank traits with the β2-adrenergic receptor gene (ADRB2) Thr164Ile variant. Each triangle is a trait generated by DeepPheWAS software v0.2.0 and colour-coded according to phenotypic category. The −log10 of the false discovery rate (FDR) is generated from association testing: linear regression (for quantitative traits) or logistic regression (for binary traits), adjusting for age, sex, genotyping array and the first 10 ancestry-based principal components. The red line indicates the FDR threshold of 1%. The directions of effects are aligned with the minor T allele. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; DFP: data field phenotype; cDFP: combined DFP; CP: composite phenotype; VLDL: very low-density lipoprotein; L-VLDL: large VLDL; S-VLDL: small VLDL; VL-VLDL: very large VLDL; GOLD: Global Initiative for Chronic Obstructive Lung Disease.
FIGURE 2
FIGURE 2
Bubble plots of enriched pathways and upstream regulators among proteins associated with the Thr164Ile variant, generated using Ingenuity Pathway Analysis. The colour of the circles indicates whether or not the pathway is predicted to be activated or inhibited (or whether no direction can be determined), and the size of the circles indicates the percentages of proteins in the full pathway that are among the Thr164Ile-associated proteins. TNF: tumour necrosis factor; TNFR: tumour necrosis factor receptor; IL: interleukin; HAVCR: hepatitis A virus cellular receptor.
FIGURE 3
FIGURE 3
Phenome-wide association of UK Biobank traits with a gene-based model of rare (minor allele frequency <0.0001), nonsynonymous β2-adrenergic receptor gene (ADRB2) variants. Each triangle is a trait generated by DeepPheWAS software v0.2.0 and colour-coded according to phenotypic category. The −log10 of the false discovery rate (FDR) is generated from association testing: linear regression (for quantitative traits) or logistic regression (for binary traits), adjusting for age, sex, genotyping array and the first 10 ancestry-based principal components. The red line indicates the FDR threshold of 1%.
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