Crohn's disease: concordance for site and clinical type in affected family members--potential hereditary influences.

BACKGROUND & AIMS: The association of genetic influences between bowel location and clinical type of Crohn's disease may provide more information on the genetic heterogeneity of inflammatory bowel disease. The aim of this study was to analyze familial occurrences of Crohn's disease for concordance for site and type. METHODS: Of 554 consecutive patients, 95 (17%) had a family history of Crohn's disease. Sixty families were analyzed for concordance for site and clinical type and by a series of conditional logistic regression models to test the significance of concordance within families. RESULTS: Eighty-six percent of families were concordant in at least 2 members for the site of Crohn's disease, and 82% were concordant for clinical type. Pairing family members together, concordance greater than expected in an unrelated population was observed. Using a conditional logistic regression model, a statistically significant role for concordance in predicting site and type of Crohn's disease in other affected family members was found. CONCLUSIONS: Greater-than-expected concordance for site and clinical type of Crohn's disease within individual families is compatible with a concept of multiple, distinct forms of Crohn's disease, which, although possibly influenced by environment, seem more likely to be separate inheritable forms or phenotypes.

Crohn's disease: influence of age at diagnosis on site and clinical type of disease.

BACKGROUND & AIMS: Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals. The aim of this study was to examine the influences of age at diagnosis of Crohn's disease on disease site, type, and course. METHODS: Records of 552 consecutive patients with Crohn's disease were reviewed retrospectively. RESULTS: Younger age at diagnosis (younger than 20 years), compared with an older age (40 years or older), was associated with a greater prevalence of a family history of Crohn's disease (29.9% vs. 13.6%), greater small bowel involvement (88.7% vs. 57.5%), more stricturing disease (45.8% vs. 28.8%), and a higher frequency of surgery (70.6% vs. 55.3%). Older age at diagnosis was associated with a greater prevalence of colonic disease (84.8% vs. 71.2%) and the inflammatory subtype (54.5% vs. 34.4%). A conditional logistic regression analysis confirmed an independent effect of age at diagnosis on ileal disease and surgery for intractable disease. CONCLUSIONS: In Crohn's disease, early age at diagnosis is associated with more complicated disease and a greater likelihood of having affected relatives. Stratification of Crohn's disease by age at diagnosis provides support for the concept of genetic heterogeneity.

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 anticipation 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.