Genes whose products play a critical role in regulation of the immune response include the human leucocyte
antigen (HLA) and
cytokine families of genes. The HLA genes are the most polymorphic found in the human genome, and the bulk of this polymorphism results in functional differences in expressed HLA molecules, resulting in inter-individual differences in presentation of
peptide antigens to T-cells. In addition, a considerable number of
cytokine-associated gene polymorphisms have been identified, the bulk of which occur in the upstream promoter sequences of these genes, which in many cases results in differential in vitro expression of the respective pro- or anti-inflammatory gene product. Particular HLA polymorphisms result in well-defined associations with a large number of immunologically-mediated diseases, including some diseases with known dietary risk factors. For example, individuals of
HLA-DQA1*0501, DQB1*0201 genotype have a greater than 200-fold increased risk of developing intolerance to dietary wheat
gluten (coeliac disease), and additional HLA-related factors may influence the development of
malignant lymphoma within pre-existing coeliac disease. Similarly,
HLA-DRB1 alleles sharing a common sequence motif constitute the primary known genetic risk factor for
rheumatoid arthritis. The influence of polymorphisms associated with differential
cytokine expression on
disease susceptibility is currently of much interest. Most attention has been focused on associations with susceptibility to benign immunologically-mediated diseases, including a number of gut diseases. However, recent work from our laboratory indicates that
cytokine polymorphisms may influence susceptibility to and prognosis in a number of different
cancers, including
malignant melanoma skin cancer and solid tumours which may be influenced by diet, such as
prostate cancer (collaboration with the CRC/BPG UK
Familial Prostate Cancer study). In addition, preliminary work suggests that dietary modulation of expression levels of certain
cytokines in healthy human subjects may be genotype dependent.