The inflammatory bowel diseases (IBD) are chronic conditions of the intestinal tract, divided into two main subtypes Crohn's disease (CD) and ulcerative colitis (UC). The exact pathogenesis is unclear but the current paradigm is thought to be an aberrant immune response in a genetically susceptible individual. The incidence and prevalence of IBD has traditionally been higher in North America, Europe, Australia and Israel compared to other regions of the world including China, Japan, India and Korea. More recently there is evidence of an increase in immigrant populations. Studies have also suggested that the clinical characteristics differ across ethnic groups. This has been mirrored by genetic studies that suggest different genetic susceptibilities between groups. A systematic review was performed to define the relevance of gene variants to IBD in a South Asian population. This found that few studies (n=6) have genotyped susceptibility variants in the South Asian population. The majority of these studies examined three common polymorphisms (R702W, G908R, 1007fs) in NOD2/CARD15 in Caucasians and have determined that these are absent in South Asians.The first hypothesis of this study was that clinical characteristics and mucosal distribution differed in South Asians compared with White British in the North of England. A total of 1318 individuals (314 South Asians) with a diagnosis of IBD were recruited. In the South Asian cohort 59% had a diagnosis of UC, 41% CD. In contrast the Caucasian cohort 56% had CD and 44% had UC. South Asians had twice the rate of extensive colitis compared to White British cohort (46% SA vs. 24% White British) and a younger age of diagnosis (30 years vs. 40 years). In the CD cohort South Asians were twice as likely to have colonic disease than White British (54% vs. 20%). Also they had a younger age of onset and were less likely to need surgery for CD.The second hypothesis was that common variants in the same genes described in Caucasian IBD were relevant in South Asians. 13 known SNPs from GWA Studies robustly associated with IBD in Caucasian cohorts were sequenced in South Asians IBD cohort (n=255) and unrelated ethnically matched controls (n=275) to determine if they were relevant to IBD in South Asians. These were genotyped by Sequenom MassArray and no significant associations were discovered.The final hypothesis was that rare highly penetrant variants underlie a group of IBD in consanguineous families in South Asian IBD. A consanguineous family in which the proband had inflammatory colitis diagnosed at 18 months of age was recruited. No disease causing mutations were present in IL10RA, IL10RB and ADAM17. DNA from other family members was used to perform autozygosity mapping of the proband and family. Exome sequence analysis identified 6099 variants in autozygous regions. Further analysis focused on three novel variants. One variant (PPP1R3G) was considered a likely candidate and Sanger sequencing was performed which confirmed it was homozygous in the proband, but it did not segregate in the family and so unlikely to underlie IBD in this individual.In summary this thesis has shown that few genetic studies have been done in South Asian IBD. Also there are significant differences in the clinical characteristics and mucosal distribution between groups and that 13 SNPs associated with IBD in Caucasians were not replicated in the South Asian IBD cohort. Finally autozygosity mapping and exome sequencing has not been successful in identifying a rare novel variant responsible for IBD in the consanguineous family but work is continuing.
|Date of Award||1 Aug 2015|
- The University of Manchester
|Supervisor||William Newman (Supervisor)|
- Inflammatory bowel disease
- South Asians