Abstract
Prostate cancer and type 2 diabetes are complex diseases, the genetic and
environmental basis of which are not well established. Epidimiology
suggests a link between the two diseases, with type 2 diabetes redusing
the risk of prostate cancer, and faily history of prostate cancer
reducing the risk of type 2 diabetes. Common genetic variations are
believed to influence risk of both diseases, with very little overlap
between the genes implicated.
Metabolism may be a link between the two diseases: diabetes is
characterised by abberant utilization and storage of dietary energy,
where as prostate cancer has a high demand for energy input. It is
plausible that genes and thier variants which alter metabolic homeostasis
influence risk of both diseases in the opposite directions.
In order to investigate whether this hypothesis is correct, we
investigated common genetic variation of two genes, GHR and MUC1, in
prostate cancer and type 2 diabetes. Bothe genes have previously been
implicated in prostate cancer, with some evidence suggesting a role for
MUC1 as a biomarker for prostate cancer. The GH-IGF-I-Insulin axis is
key to metabolism, thus is likely ot be important in diabetes. The
suggestion of a role for MUC1 in type 2 diabetes is a novel.
A number of MUC1 isoforms, some of which have been implicated in various
cancers, are determined by a SNP in exon 2. Functional differences
between the variants are as yet unknown. A polymorphism in the GHR where
by exon 3 is excluded is believed to have increased bioactivity compared
to the full length form, although this is much debated.
In this thesis we demonstrated that the GHR exon 3 polyorphism reduces
risk of type 2 diabetes, and is associated with increased BMI, CRP and
IGF-I levels in diabetic subjects.
The variant allele of MUC1 was associated with an increased risk of type
2 diabetes and lower IGF-I levels. Subjects homozygous for the variant
allele had increased LDL and CRP levels
In conclusion, these genetic variations of GHR and MUC1 have potential as
biomarkers for type 2 diabetes, and its complications. Genetic variation
of MUC1 in blood DNA samples does not influence prostate cancer risk or
survival, however tumour-specific genetic alterations may be important.
Sequence analysis indicates that MUC1 isoforms may have distinct
differences.
