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UGT1A1 polymorphisms and colorectal cancer susceptibility
  1. N T Brockton
  1. Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, UK; n.t.brockton{at}abdn.ac.uk

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UDP-glucuronosyltransferase (UGT) 1A7 polymorphisms may be involved in the aetiology of colorectal cancer

The contribution of the xenobiotic metabolising enzymes (XMEs) to disease susceptibility, particularly cancer, has been a focus for a great deal of research over the last two decades.1 Many of these genes are polymorphic and exhibit significant interindividual variation in their activity. Although these enzymes all have endogenous substrates, they are also involved in the metabolism of exogenous, often mutagenic, substances to which humans are exposed.2

The central hypothesis of these studies has been that genetic changes functionally alter the enzymes and consequently modify an individual's response to a given exposure, putatively associated with the disease. The increased risk for the individual is likely to be small. However, the higher frequency of these alterations, compared with the risks associated with genetic defects implicated in familial syndromes, raises the possibility that the attributable risk, at the population level, may be substantial and therefore of considerable public health importance.3

The involvement of UDP-glucuronosyltransferase (UGT) 1A7 polymorphisms in the aetiology of colorectal cancer (CRC) is presented by Strassburg et al in this issue of Gut4[see page 851] is biologically plausible. The authors have shown that UGT1A7 contributes to the elimination of substances to which humans are commonly exposed and many of these substances are known to be mutagenic.5 The polymorphism is relatively common and has been demonstrated to affect enzyme function. Also, expression of this gene has been detected in the colon.6 However, these factors are true for other gene variants for which only weak and inconsistent associations have been observed.7

Strassburg et al report about a twofold increase in the risk of developing CRC for those possessing the UGT1A7*3/*1 and UGT1A7*3/*2 genotypes (odds ratio (OR) 2.26 (95% confidence interval (CI) 1.09–4.68) and OR 2.39 (95% CI 1.15–4.99), respectively) and an almost threefold increased risk associated with the presence of the UGT1A7*3 allele (OR 2.75 (95% CI 1.6–4.71)). There are a number of factors that should be considered when interpreting studies of this type.

A case control study relies upon the comparison between subjects with a given disease and those unaffected; it is therefore crucially important that the case and control subjects are representative of the population with the disease and at risk of the disease, respectively. The response rates for both case and control groups should be stated and it is important to consider whether cases are newly incident, otherwise there may be a bias associated with survival; if possible, archived records should be consulted to determine if the case group is typical.

The control subjects used by Strassburg et al were “healthy blood donors”; although blood donors are a commonly used source of control subjects, they are not necessarily a representative sample of the population at risk of colorectal cancer. Ideally, control subjects should be recruited from the population from which the cases have been collected so that effects due to ethnic variation and environmental exposures are minimised. Where possible, the age and sex of the controls should match the distribution of the cases, especially for a disease of late onset such as CRC. If a given genotype is related to survival, irrespective of the disease being investigated, then there may be an over/under representation of a given genotype in a more elderly population. This might either obscure an association or lead to spurious associations with the disease being investigated.8

One of the reasons for studying genes such as UGT1A7 is their involvement in the elimination of exogenous mutagens. Failure to assess the exposure of the subjects within the study to such substances may either dilute or exaggerate the magnitude of any potential association.9 The diverse range of substrates for UGT1A7, which include many endogenous substances, makes quantification of these exposures particularly challenging. However, the fact that many therapeutic drugs are substrates for UGT1A7 suggests that a relatively easily quantifiable exposure is available; are users of these drugs at an increased risk of CRC?

UGT1A7 is a phase II enzyme and the risk conferred by the polymorphisms may be influenced by other competing phase 2 enzymes (for example, N-acetlytransferases, glutathione-S-transferases) or by phase I enzymes (for example, cytochrome P450s). The metabolic fate of a potential mutagen is not determined by a single gene but by the relative activities of enzymes within a pathway and their capacity for activation or detoxification of that substrate. Synergistic relationships between alleles at different loci may greatly modify disease risk.10 Unfortunately, investigation of gene-gene or gene-environment interactions requires much larger numbers of subjects than are necessary for a simple association study due to the diminishing size of subgroups in the analysis. Case only approaches do however provide a possible means of assessing gene-environment and gene-gene interactions and require fewer subjects.11

The authors suggest that population screening for the UGT1A7*3 allele would be “an attractive diagnostic tool with a negative predictive value of 73%”. This is a single study, based on only 78 cases of CRC. Confirmation of these results in other studies is required. If confirmed, these results might facilitate targeted surveillance or the development of targeted interventions for those at an increased risk. However, there are important ethical issues to be addressed in any genetic screening programme.12

This report is the first to demonstrate an increased risk of CRC due to polymorphisms in UGT1A7 and may represent a significant development in the understanding of the aetiology of this common malignancy. The number of cases reported is quite low and there has been no assessment of exposure but it provides a starting point for further investigations. In light of the human genome project, it is likely that association studies of genes and disease will become even more common. Improvements in the design of such studies, incorporating methods for assessing exposure and ensuring that populations are legitimately comparable, will greatly enhance the value of such work.13 Gut 2002;50:748–749

UDP-glucuronosyltransferase (UGT) 1A7 polymorphisms may be involved in the aetiology of colorectal cancer

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