John Hwa MD, PhD

Associate Professor of Medicine (Cardiology); Director of Cardiovascular Pharmacogenetics

Research Interests

Prostacyclin; Thromboxane; GPCR; Pharmacogenetics; Atherothrombosis

Research Summary

Our goal is to perform multidisciplinary studies in assessing the contribution of genetic differences to protein structure/function, signal transduction and clinical cardiovascular disease.

Extensive Research Description

The goals of the Hwa laboratory are to decipher the roles played by the prostacyclin and thromboxane receptor (both G-protein coupled receptors) in the development of atherothrombosis. This particular area of research has gained recent attention, due to its central involvement in the targeted pathway of selective COX-2 inhibitors, such as VIOXX. The goals are being achieved through the discovery and study of novel dysfunctional genetic variants (pharmacogenetics), which serve as “functional knockouts” in human patients. The spectrum of studies range from structure function analysis and molecular modeling (molecular pharmacology), to bioinformatics, and assessment for clinical disease association. Additionally, human vascular smooth muscle cells and platelets (two major locations for the prostacyclin and thromboxane receptors) are being assessed for important prostacyclin and thromboxane signaling pathways mediating cardiovascular protection and atherothrombosis. Recent accomplishments from the Hwa Laboratory include the recruitment of a total of 3,239 cardiology patients for their pharmacogenetic studies. In collaboration with 10 national and international centers, they now have access to over 22,024 genomic samples. Forty prostacyclin receptor genetic variants have been discovered from sequencing the full coding regions (PTGIR) in 2,430 patients, and 33 genetic variants discovered in the human thromboxane receptor gene from 1000 patients. Functional characterization has thus far demonstrated many of the mutations to be deficient in signaling, with one in particular (R212C) showing a significant association with accelerated clinical disease. Additional studies have identified novel non-canonical signaling pathways. Such studies are important for confirming the importance, and detecting the mechanisms by which eicosanoids modulates atherothrombosis. Prostanoids may emerge as new targets for therapy against atherothrombosis.

Selected Publications

  • Arehart E, Stitham J, Asselbergs F., Douville K, MacKenzie T, Fetalvero K, Gleim S, Kasza Z, Rao Y, Martel L, Segel S, Robb J, Kaplan A, Simons M, Powell R, Moore J, Rimm E.B., Martin K, and Hwa J. (2008) Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation, potential implications for COX-2 inhibition.. Circ Research 102:986-993 (Cover of Issue & Editors Pick)
  • Ogden S.K., Ahmed Y.F., Hwa J., Robbins D.J. (2008) A G-protein functions immediately downstream of Smoothened in Hedgehog signaling. Nature 456, 967-970
  • Martin K.A., Hwa J. Shp shape - FAKs about hypertrophy. (Editorial) Circ Research 103(8):776-8 2008
  • Fetalvero K.M., Shyu M., Zhang P., Young B., Hwa J., Young R.C., Martin K.A.. (2008) A novel role for prostacyclin in human parturtion. J Clin Invest 118(12):3966-79
  • Stitham J., Gleim S.R., Douville K., Arehart E., Hwa J. (2007) Versatility and differential roles of cysteine residues in human prostacyclin receptor structure and function. J Biol Chem 281(48):37227-36 2006
  • Stojanovic A., Stitham J., Hwa J. (2004) Critical role of transmembrane segment zinc binding in the structure and function of rhodopsin J Biol Chem 279(34):35932-41 (Paper of the Week)

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