MUC1 polymorphism in relation to susceptibility to Helicobacter pylori gastritis
The gene MUC1 encodes a transmembrane mucin glycoprotein that is expressed on the apical surface of most epithelia and is aberrantly expressed in cancer. MUC1 contains an extended domain of tandemly repeated (TR) amino-acid sequence, which acts as the backbone for a large amount of O-linked glycosylation, and which varies in length and sequence in different alleles. Previous studies on MUC1 tandem repeat variation in patients with gastritis (Vinall et al, 2002) and gastric cancer (Carvalho et al, 1997) showed an overrepresentation of short TR alleles in the patient groups when compared with normal controls. The major aim of this thesis is to pursue this observation further. MUC1 allele and three locus haplotype frequencies were compared in 3 populations of different ancestry, from UK, Nigeria and Portugal, which show dramatic differences in gastric disease incidence in patients with gastric disease, patients with other gastrointestinal disease as well as associated controls. There were differences between the Nigerians and unselected European control groups, but there was no significant difference between the groups collected in London and Porto. Analysis of the gastric disease groups showed an over-representation of a particular MUC1 haplotype. A search was made, by sequencing and using a bioinformatics approach, for additional polymorphic markers within and surrounding the MUC1 gene, that might act as convenient markers for future disease association studies. Patterns of Linkage Disequilibrium were established across a 600Kb genomic region containing MUC1 using information in the HapMap resource and this information was used to assist in the selection of the single nucleotide polymorphisms (SNPs) within a 70Kb region to test on disease groups. During the course of this thesis work, a second UK cohort of patients and controls was collected and characterised and a replication study attempted. DNA samples from a total of 154 Northern Europeans classified as H. pylori gastritis (n=33), former H. pylori gastritis (n=44), No H. pylori gastritis (n=18) and normal (n=59). Examination of the MUC1 polymorphisms failed to show over-representation, in the H. pylori gastritis group, of the same haplotype found in the first gastritis cohort. The extended 70Kb haplotypes showed the expected association in the first cohort but no significant differences in the second cohort. However, in the population overall, it was noteworthy that there is a very high frequency haplogroup containing long tandem repeat arrays and this was somewhat lower in frequency in both H. pylori gastritis groups.