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Title: Inflammatory bowel disease in the UK South Asian population : insights into clinical phenotype and pathogenesis
Author: Walker, David Grahame
ISNI:       0000 0004 2706 3546
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are significant causes of gastrointestinal morbidity. Previous research in IBD has predominantly focused on large white European/American populations, which have defined the clinical phenotype and led to important biological insights, including its genetic predisposition, and immunological and metabonomic associations. Recent studies suggest that there may be differences in the clinical phenotype of IBD in different ethnic groups. There is still limited information on the phenotype of South Asian IBD patients originating from India, Pakistan and Bangladesh, but there have been suggestions that it differs from the Northern European white population. Since the 1950s there has been substantial migration from South Asia, and currently 2.08 million South Asians live in the UK: studies of IBD in this population could provide valuable information, and may help to distinguish the degree of influence of genetic and environmental pathogenic factors. This thesis aimed to define the clinical phenotype of IBD in UK South Asians, and then to investigate the genetic, serological and metabonomic associations of IBD in South Asians and to compare the findings with a white Northern European cohort. The phenotypic details of 367 South Asian IBD patients (273 UC: 94 CD), undergoing active follow-up in five North West London hospitals, were compared to those of 403 consecutively collected white Northern European IBD patients (188 UC: 215 CD). The phenotype of IBD differed significantly between the two populations with more extensive disease and less proctitis in the South Asian UC cohort compared to Northern Europeans (P<0.0001 for both). CD behaviour differed significantly between the groups with less penetrating disease compared to Northern Europeans (P=0.01) and a reduced need for surgery (P=0.003). Genotyping, serological testing and urinary nuclear magnetic resonance (NMR) spectroscopy were used to investigate cohorts of South Asian IBD patients and healthy South Asian controls in order to investigate the different aetiological factors in South Asian IBD. Results were compared with a previously collected white Northern European cohort. The genotype frequency of HLA-DRB1*1502 was significantly higher in South Asian patients with UC compared to both controls (P=0.005) and Northern European UC patients (P<0.0001). HLA-DRB1*0103 was not found in the South Asian population and CARD15/NOD2 polymorphisms were rare, significantly different to Northern Europeans with IBD. The sensitivity and specificity of serological tests (ASCA and atypical pANCA) was similar for both populations. Urinary NMR spectroscopy results from the South Asian IBD cohort showed significantly lower levels of hippurate (a co-metabolite related to gut microbial metabolism), compared to healthy South Asian controls (P<0.0001). Differences were also observed between the South Asian and Northern European UC cohorts, with lower levels of 4-cresol sulphate (P<0.0001) and hippurate (P=0.0006) in South Asians. Conclusion: The phenotype and genotype of IBD in South Asians living in North West London is significantly different from that of a white Northern European IBD cohort. The emerging technique of urinary NMR spectroscopy has shown specific urinary metabolites differ between South Asian and European IBD patients which could reflect underlying differences in the gut microbiota.
Supervisor: Orchard, Tim Sponsor: St Mary's Paddington Charitable Trustees ; Broad Medical Research Program; Johnson & Johnson Pharmaceuticals
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral