Genetic epidemiology of inflammatory bowel disease, early twin and family studies

Abstract

The influence of genetics in the etiology of inflammatory bowel disease (IBD) was initially demonstrated by epidemiological data, including differences in prevalence among different ethnic groups, familial aggregation of IBD, concordance in twins, and association with genetic syndromes. These early observations commenced the successful era of molecular genetics in IBD that has illuminated the complexity of the genetic and environmental interaction in IBD. Recent advances in molecular genetics have dramatically improved the resolution of the IBD genome. Yet, some of the key epidemiological observations are still unanswered from a molecular perspective. Based on analyzes of the DNA sequence, the observed high heritability in Crohn's disease is only partly understood. Possible contributions of other molecular mechanisms of heritability, such as epigenetics, are yet to be explored. Similarly, pronounced phenotypic similarities have been observed within multiplex families and especially within concordant monozygotic twin pairs with Crohn's disease, suggesting that genetics also influences the phenotype of the disease. However, it has been difficult to establish any firm genotype-phenotype associations beyond NOD2. Thus, it can be questioned if the observed phenotypic concordance within epidemiological studies rather reflects the exposure to shared environmental factors. The possible influence of disease tolerance, that is, differences in susceptibility to tissue damage, in contrast to disease resistance, also needs to be taken into consideration in this perspective. Future longitudinal studies with periodic measurements in subjects at high risk, that is, siblings and offspring below or around the peak age of onset of IBD, will probably become an important tool to elucidate the genetic and environmental interactions underlying these archetypal complex diseases.