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ß-2 Adrenergic Receptor Polymorphism and Gene Expression are Associated with Risk of Development of and Disease Severity in Pulmonary Arterial Hypertension Associated with Scleroderma

Stephen Mathai


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 01.04.2013

Presentation Type: Audio & Video Podcasts

This abstract was presented at PHA's 10th International Conference and Scientific Sessions.

Mathai SC*, Gao L, Cheadle C, Rafaels N, Berger AE, Grigoryev DN, Barnes KC, Hassoun PM

Johns Hopkins University Baltimore, Maryland USA
* Presenting the abstract 

BACKGROUND: Little is known about the role of neurohormonal dysfunction in the pathophysiology of pulmonary arterial hypertension (PAH), particularly with respect to PAH-related to scleroderma (SSc-PAH). Single nucleotide polymorphisms (SNPs) in the β-2 adrenergic receptor (ADBR2) gene have been associated with cardiovascular disease and specifically, risk of development of left heart failure. Similarly, expression of related genes in peripheral blood mononuclear cells (PBMC) has been associated with disease severity in left heart failure. Therefore, we sought to 1) determine whether previously validated SNPs in ADBR2 were associated with the risk of development of PAH in SSc and 2) characterize the gene expression of ADBR2 in treatment-naïve SSc-PAH patients.

METHODS: 308 SSc patients without PAH and 140 SSc-PAH patients provided blood for genetic analyses. Several SNPs of the ADBR2 gene (n=13), previously demonstrated to have functional significance in cardiovascular disease, were examined for their association with the risk of development of PAH in SSc at the single locus level using PLINK. Fifteen of the SSc-PAH patients, who were treatment-naïve at enrollment, also provided PBMCs for gene expression analyses using Illumina high-density BeadArrays. Pearson correlations between ADBR2 and clinical variables were calculated along with p-values and false discovery rates (FDR).

RESULTS: Genetic analyses showed a significant association between the ADBR2 SNP Arg16Gly in the promoter region (rs17778257) and development of PAH in SSc (p=0.03). Gene expression profiles showed a strong positive correlation with ADBR2 expression and cardiac output (r=0.81, p<0.0001, FDR<0.01).

CONCLUSIONS: Preliminary results in this cohort suggest that functional SNPs in ADBR2 may be associated with the risk of development of PAH in SSc and that gene expression of ADBR2 is associated with disease severity. Given the known associations between ADBR2 and left heart failure, further study is warranted.