Clinical relevance of advances in genetics and pharmacogenetics of IBD
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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2012, Autoimmunity ReviewsCitation 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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