Preliminary evidence for genetic anticipation in Crohn's disease

Background The term genetic anticipation is used to describe earlier onset of disease, increased severity, or both, in succeeding generations of families affected by a particular disease. This process has been linked with expanded genomic trinucleotide repeat regions in some neurological disorders. Crohn's disease, an inflammatory bowel disorder, has genetic influences, which remain undefined. We studied pairs of two-generation first-degree relatives with Crohn's disease to seek evidence for genetic participation in this disorder. Methods Through retrospective review of the records of 552 patients treated for Crohn's disease at Johns Hopkins Hospital, we identified 27 pairs of two-generation first-degree relatives. We also studied 32 such pairs identified through a multicentre survey. After exploratory analyses by t tests, a generalised estimating equations approach was used to fit a marginal regression model. Findings The age at diagnosis was earlier in the younger member of the pair both in the Johns Hopkins Hospital dataset (18.9 [SE 6.9] vs 31.4 [12.0] years) and in the multicentre survey dataset (16.9 [7.4] vs 33.1 [11.9] years). The regression model confirmed the findings:the best-fitting model for the Johns Hopkins Hospital data showed an average 10.8 (SE 4.2) year difference in age at diagnosis between parent and child; that for the multicentre data showed an average difference of 15.1 (1.5) years. There was evidence of a further difference between the second and third generations. Disease was more extensive in the offspring than in the parent for 15 of the 27 pairs at Johns Hopkins Hospital; in 13 of these pairs the affected parent was the father. Interpretation The evidence of a lower age at diagnosis and a greater extent of disease in the younger member of two-generation pairs affected by Crohn's disease, as well as the association with paternal transmission, suggest that genetic anticipation does occur in Crohn's disease. A search for triplet repeat regions is warranted.