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Pharmacogenomics in PAH: Roles of Downstream Polymorphisms of the ET-1 Pathway

N. C. Olave

Raymond Benza


P. E. Wolkowicz

H. E. Grenett

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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Olave N.C., Benza R.L., Wolkowicz P.E., Grenett H.E.

Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA

BACKGROUNDPulmonary arterial hypertension (PAH) is characterized by vasoconstriction of the pulmonary bed leading to a progressive increase in pulmonary vascular resistance, right ventricular afterload, and cardiac failure. It is well known that patients with PAH vary in their clinical response to therapy. A growing body of evidence suggests that genetic variation can alter gene expression at the molecular or cellular level and this may correlate with variations in the organism's drug response. Thus, variability in PAH patient responsiveness may be related to inherited characteristics in individual patients and may associate with particular polymorphisms in certain genes. These studies were carried out to examine whether polymorphisms in the G protein β3 subunit gene (GNB3) and the endothelial nitro oxide synthase (eNOS) of PAH patient-derived lung tissue affect the expression of key regulators of vascular remodeling such as, the mitogen-activated protein kinase (MAPK), the vasodilator-stimulated phosphoprotein (VASP), and the serine/threonine Akt kinase (AKT).

METHODSLungs from patients with PAH were supplied from the Tissue Collection and Banking

Facility at UAB and from the Pulmonary Hypertension Breakthrough Initiative (PHBI, AHA), including two IPAH lungs (lungs #1 and 4) and two associated PH lungs (lung #2 and 3 thromboembolic PH and scleroderma PH, respectively). The associated PH lungs are designated as APH lungs. Lungs were genotypes for the Gβ-3 C825T, Gβ-3 G5177A, and eNOS G894T polymorphisms. ET-1 mRNA levels were analyzed by real-time PCR. Western analysis evaluated MAPKs, AKT-Thr308, and VASP-Ser157.

RESULTSIdiopathic PAH (IPAH) lungs showed increased mRNA for ET-1 compared with APH

lungs. All IPAH have diminished phospho p38 compared to the APH lungs. Interestingly IPAH lung #1 had a substantial increase in phospho-ERK1/2 and -JNK compared with IPAH lung #4 and both APH lungs. In contrast both APH lungs had elevated AKT-T308 and VASP-S157 compared with the IPAH lungs. The phosphorylation of AKT-T473 showed no difference between these two groups of lungs.

COMMENTS AND CONCLUSIONS: Taken together these data, suggest that the two polymorphisms in the GNB3 gene, C825T and G5177A, and the eNOS G894T polymorphism, may be associated with specific alterations in relevant downstream signaling pathway.

Expanding these analyses may provide new insight and understanding into how polymorphisms in certain genes may affect patient response to PAH-specific pharmacotherapy. This knowledge could lead to tailored pharmacologic therapies for PAH and better clinical responses.