Project outline:

The recent swathe of genomewide analyses, which are essentially acephalous scientific experiments testing all available genetic variants for association with common disease traits, has thrown up a series of apparently novel pathways for further analysis. One of these is that of the FTO locus of chromosome 16 which has been shown now to have a association with T2D driven entirely by its robust associaion with fat mass (Zeginni et al Science 2007, Frayling et al Science 2007). As yet, neither the driving force behind this association, nor its biological foundation have been elucidated.

Returning to the work of Remy & Michnick (Molecular and Cellular Biology) and personal experience alongside Pof Jeremy Tavare, Prof Holly recalled that the adjacent locus to FTO, AKTIP (seen below)fundamentally involved in the insulin signalling pathway. This protein has been observed to enhance the PKB mediated recruitment of GLUT4 to the cell surface and hence the action of IGF1, IGF2, and consequent responsiveness to insulin.

Whilst not the actual site of association

Observed by Zeginni and Frayling, the

protein (FT1) encoded by AKTIP

may well lie in the 5' promoter of the

FTO locus, possibly having an impact on

the expression pattern and profile of the

locus concentrated on by these new

reports.

In efforts to verify this, a simple

experiment can be performed which can

enable one to assess the relative

abundance of this protein (FT1) in the

lysate of spent samples (here derived from

the ALSPAC cohort. With genotypes

already collected for this cohort, one simply

requires samples of cell pellets for examination via the use of FT1 antibody which has already been developed and delivered to Bristol (and lab in question here) by Remy and Michnick. This experiment will employ simple western blotting approaches for the examination of FT1 protein levels (measured in a semi-quantitative manner) in individuals organised by their respective FTO genotype. Under the hypothesis that the FTO locus is exerting its observed metabolic association through its interaction with the FT1 locus, one may anticipate a genotype specific difference in the yield of FT1 by this approach.