Gastroenterology

Gastroenterology

Volume 126, Issue 6, May 2004, Pages 1533-1549
Gastroenterology

Clinical relevance of advances in genetics and pharmacogenetics of IBD

https://doi.org/10.1053/j.gastro.2004.01.061Get rights and content

Abstract

Crohn’s disease and ulcerative colitis result from an inappropriate response of the mucosal immune system to the normal enteric flora in a genetically susceptible individual. During the past decade, exciting progress has been made in our understanding of the contribution of genetics to inflammatory bowel disease susceptibility and phenotype. This article reviews recent advances in the genetics of inflammatory bowel disease and explores how they might impact on clinical practice. Current knowledge of the genetic basis for disease susceptibility, phenotype, and response to therapy is explored and the factors currently limiting the translation of this knowledge to clinical practice is discussed.

Section snippets

Recent advances

The majority of early studies of genetic susceptibility in IBD used a case-control association design in which the allele frequencies of candidate genes—genes encoding proteins believed to be involved in disease pathogenesis—were compared in patients and matched healthy controls. These studies have been the focus of considerable criticism principally because of a lack of reproducibility. This is shown by a recent meta-analysis of 370 studies addressing 36 genetic associations with a number of

Other IBD susceptibility loci

The second genome scan identified significant linkage with a region on chromosome 12, termed IBD2.48 Unlike IBD1, convincing linkage to this region was not replicated in all datasets. This may be explained by the fact that linkage to IBD2 was stronger in studies with a higher number (and statistical power) of UC-relative pairs, suggesting that this locus may make a major contribution to UC susceptibility, but only a relatively minor effect with regard to CD. This hypothesis was supported by

Genes as determinants of IBD phenotype

IBD has been traditionally categorized as either UC or CD on the basis of clinical, radiologic, and histologic criteria. However, within these diseases, significant heterogeneity is recognized, suggesting the existence of phenotypic subtypes based on features such as location and behavior of disease. Evidence of a possible genetic basis for these subgroups first emerged in the 1990s from epidemiologic studies in multiple affected families that showed concordance for the clinical manifestations

Genes as determinants of response and side effects of drug therapy: pharmacogenetics

Individual variation in response to drugs is a major problem in clinical practice. Such variation may manifest as a lack of therapeutic benefit or by a spectrum of adverse drug reactions. A U.S. study estimated that 106,000 patients die each year from adverse reactions to prescribed drugs, implicating drug reactions as the fourth leading cause of death in the United States.100 In 1997, underdosing, overdosing, or missed doses cost the United States more than $100 billion in increased hospital

Conclusions and future prospects

The past decade has witnessed major advances in our understanding of IBD genetics. The emerging data suggest that IBD comprises a heterogeneous family of inflammatory disorders in which disease susceptibility, phenotype, and response to therapy are determined by the complex interaction of genetic and environmental factors. These discoveries have provided considerable insights for investigators but to date have not been translated into changes in clinical practice. Although routine genetic

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      Citation Excerpt :

      Epidemiological studies show however, that the incidence of NOD2 mutations explains only 20% of CD heritability and that there is no association with UC [110,111]. In addition, many susceptibility loci have been implicated in IBD, with varying degrees of replication, reproducibility and statistical support [111]. Nine such loci, termed IBD 1-9, have been reproduced in independent studies.

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