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

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.

List of scientific papers

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
https://pubmed.ncbi.nlm.nih.gov/17537658

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.

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
https://pubmed.ncbi.nlm.nih.gov/18628787

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]