The UGT1A gene complex encodes nine enzymes responsible for converting endogenous molecules such as bilirubin and a range of drugs to soluble glururonides for physiological elimination. Reduced UGT1A1 activity, mainly due to a promoter variant, UGT1A1 *28, underlies mild hereditary hyperbilirubinaemia (a familial jaundice known as Gilbert‟s syndrome) and deficiencies of UGT1A1 and the other UGT1A isoforms may increase risk of adverse drug reactions (ADRs). On the other hand moderately raised bilirubin levels appear to protect against cardiovascular disease in humans, which is purportedly due to the potent antioxidant properties of serum bilirubin. The major aims of this thesis were to: 1) report the prevalence of Gilbert‟s syndrome recorded in GP practices in the UK and identify factors associated with clinical recognition, 2) evaluate the association between bilirubin levels and respiratory diseases, 3) examine the influence of UGT1A1 variants on cardiovascular risk factors, lung function and neonatal jaundice, 4) compare the prevalence of clinically relevant genotypes and haplotypes of the UGT1A gene complex in different human populations. The main findings were: although around 5% of the primary care sample with bilirubin levels recorded had a phenotype consistent with Gilbert‟s syndrome, only 4% of these patients had a medical record of the condition, and factors other than genetics, in particular gender, smoking status, social deprivation and time period can influence clinical diagnosis. In a cohort of over half a million UK primary care patients with bilirubin levels recorded but with no evidence of hepatobiliary disease, each 1.7μmol/L (0.1mg/dL) increase in bilirubin was independently associated with an 8% decrease (95%CI; 5-11%) for males and an 11% decrease (95%CI; 7-14%) for females in the incidence of lung cancer. Each 1.7μmol/L increase in bilirubin was associated with a 6% decrease (95%CI; 5-7%) in COPD and a 3% decrease (95%CI; 2-3%) in mortality for males. The results for COPD and mortality in females were very similar. The UGT1A1*28 allele was not associated with neonatal jaundice, blood pressure or cholesterol levels in a cohort of 2,691 people from the UK followed since birth in 1946. However, there was an association with lung function. Cardiovascular events will be important to study when available. While around 10% of a UK population is homozygous for UGT1A1 *28, the allele frequency was even higher in equatorial African regions. But haplotype diversity was much greater than in Europe where the low activity alleles of the UGT1A gene complex are in most cases present on the same haplotype. These population differences have important implications for pharmacogenetic diagnostics such as those approved for use in the USA.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625707 |
| Date | January 2011 |
| Creators | Horsfall, L. J. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1335831/ |
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