Investigations into the inheritance of the three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations, with regional variation across Europe for example, suggesting local founder effects. In non-Caucasian populations Crohn's disease continues to increase in incidence but this increase appears not to be a consequence of variation in NOD2, further advancing the accumulating evidence for other susceptibility loci. Frequencies of the known alleles are compared across populations in health and disease and evidence for additional alleles in NOD2 is reviewed. Based on its position on chromosome 16 coincident with some other autoimmune disease susceptibility localizations, research has targeted NOD2 variation as the potential cause of other autoimmune disorders. While these investigations have mostly returned negative findings, two diseases, Blau Syndrome and Graft versus Host Disease, have been shown to be caused by risk alleles in NOD2. As is frequent in complex disease investigations, some results await validation, but the identification of NOD2 and the differences within and across population raises intriguing questions about the population genetics of the variation at this locus.
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