I have studied the GNB3 gene as a candidate gene for hypertension and left ventricular mass in a systematic and comprehensive manner. I have carried out association studies in three independent populations - A case-control study with well characterised hypertensive and their matched controls; a twin study looking at echocardiographic LV mass; and a large family based study analysing blood pressure and ECG LV mass. In addition I have also looked at three additional candidate genes including ACE, aldosterone synthase and beta-1 adrenoceptor. Though these studies concluded that there was no association between the C825T polymorphism and blood pressure or LV mass, I have demonstrated a significant heritability of various electrocardiographic measures of LV mass and an interaction between GNB3, ACE and SF1 explaining the variability of continuous measures of LV mass in this population. I studied the functional aspects of the GNB3 polymorphism by measuring platelet aggregation in normal human volunteers, using it as a marker of G-protein related signal transduction. However, there was also no association between epinephrine or platelet activating factor induced platelet aggregation and the GNB3 genotype. Finally, I performed molecular studies using cells transfected with b3 (wild-type) and b3-s (splice-variant) of GNB3 along with a fusion construct of a2AGi, and measuring of GTPase activity and calcium signalling. There was no significant difference between b3 or b3-s transfected cells, in terms of epinephrine stimulated GTPase activity, onset-delay of calcium release and time-to-peak of calcium signal. However, cells expressing b3-s showed a significantly lower rate of calcium release compared to cells expressing b3. These results indicate that the G protein b3-s subunit has no functional difference or possible slightly reduced effect compared to the wild type.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:415256 |
| Date | January 2004 |
| Creators | Padmanabhan, Sandosh |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/3784/ |
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