Analysis of functional genetic polymorphisms in prostate cancer and type 2 diabetes : mucin 1 and growth hormone receptor

<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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</p><p>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.</p><h3>List of scientific papers</h3><p>I. Strawbridge RJ, Kärvestedt L, Li C, Efendic S, Ostenson CG, Gu HF, Brismar K (2007). GHR exon 3 polymorphism: association with type 2 diabetes mellitus and metabolic disorder. Growth Horm IGF Res. 17(5): 392-8. Epub 2007 May 29 <br><a href="https://pubmed.ncbi.nlm.nih.gov/17537658">https://pubmed.ncbi.nlm.nih.gov/17537658</a><br><br></p><p>II. Strawbridge RJ, Nister M, Brismar K, Grönberg H, Li C (2008). MUC1 as a putative prognostic marker for prostate cancer. Biomarker Insights. 3: 303-315.</p><p>III. Strawbridge RJ, Nister M, Brismar K, Li C, Lindström S (2008). Influence of MUC1 genetic variation on prostate cancer risk and survival. Eur J Hum Genet. Jul 16: Epub ahead of print <br><a href="https://pubmed.ncbi.nlm.nih.gov/18628787">https://pubmed.ncbi.nlm.nih.gov/18628787</a><br><br></p><p>IV. Strawbridge RJ, Kärvestedt L, Gu HF, Nister M, Li C, Brismar K (2008). A MUC1 SNP (rs4072037) influences risk and metabolic parameters of type 2 diabetes. [Submitted]</p>