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Anticipation in Crohn's disease may be influenced by ethnicity of the transmitting parent
April 1998 19-57), we assessed the procoagulant activity profile: thrombophilia (levels of antithrombin III, protein C, protein S, Factor II and Factor V Leiden, hyperhomocysteinemia), antiphospholipid syndrome (lupus anticoagulant, anti-phospholipid antibodies), abnormal activation of coagulation (plasma levels of prothrombin fragments 1+2 and D-dimer). No patient had a personal or familial history of thrombotic episodes. Results: abnormalities of coagulation were detected in 12/18 patients: defect in protein C (n=l), protein S (n=3), lupus anticoagulant (n=l), antiphospholipid antibodies (51 GPL) (n=l), abnormal activation of coagulation (n=3). Hyperhomocysteinemia was found in 3 malnourished and severely ill patients. Assays for Factor II or Factor V Leiden were negative in all patients. Conclusion: in 18 patients with acute CD and without history of thrombotic episodes, no increased prevalence of Factor II or Factor V Leiden was found. We observed an enhanced procoagulant activity in 12/18 patients. Other assays are needed in the same patients after remission of their CD to determine if the procoagulant activity is transitory or constitutional. The results of our study suggest the interest of a prospective study assessing the procoagulant activity in a large series of patients with acute CD and after remission. • G4053 ANTICIPATION IN CROHN'S DISEASE MAY BE INFLUENCED BY ETHNICITY OF THE TRANSMITTING PARENT. B. Gulwani-Akolkar. D. Heresbach, M. Lesser*, P.N. Akolkar, X. Y. Lin, N. Heresbach-Le Berre, J. F. Bretagnet, S. Katz, and J. Silver. Department of Medicine and *Department of Environmental Medicine, North Shore University Hospital/New York Medical School, Manhasset, New York 11030, tGastroenterology Department, University Hospital, Pontchaillou, 35033 Rennes. Background and aims: A recent report suggests that anticipation occurs in Crohn's disease. However, whether true anticipation or ascertainment bias is responsible for these effects remains unclear. We have examined whether a population of Crohn's disease patients displays properties consistent with anticipation and whether there are differences in the degree of anticipation with respect to gender and ethnicity of the affected parent. Patients and methods: Sixty-one parent-child pairs both affected by CD were identified; about half of the pairs were of Ashkenazi Jewish descent. An additional 17 pairs of second-degree relatives with CD were also identified. The intergenerational difference in age at diagnosis (AAD) was used to perform regression analysis and a novel "bootstrap" method was used to compare the degree of anticipation among subsets of patients separated on the basis of sex and ethnicity of the transmitting parent. Results: The AAD was consistently (90% of the time) lower in the younger member of the 61 parent-child pairs (35.3 yr+-1.6 vs 20.8 yr-+ 1.1, p=0.0001). However, when the patient population where the parent had an AAD of <28 was examined by regression analysis and the "bootstrap" method, there was a lack of clearcut evidence of anticipation in the population as a whole; only when the population was analyzed by ethnicity was there convincing evidence of anticipation in the Jewish population. Conclusions: Ascertainment bias may be responsible for the apparent anticipation observed in the CD population as a whole or in the non-Jewish CD subgroup. However, the Jewish CD population displays strong evidence of anticipation even after correction for ascertainment bias. This work was supported by a grant from the NIH (A122005) and funds from the Litwin Foundation, the Albert Cohen foundation and the Reach Out for Youth with Ileitis and Colitis organization. G4054 PROTECTIVE AND SUSCEPTIBLE HLA CLASS II ALLELES FOR CROHN'S DISEASE (CD) IN THE ASHKENAZI JEWISH POPULATION. B. Gulwani-Akolkar. P. N. Akolkar, X. Y. Lin, R. Manji, S. Katz, S. Y. Yang* and J. Silver. Department of Medicine, North Shore University Hospital/New York Medical School, Manhasset, New York 11030, *Memorial Sloan-Kettering Cancer Center, Manhantan, New York 10021. Previous studies on HLA associations with CD have suggested that different HLA class II alleles may be associated with disease in different ethnic populations. Some studies have shown an association of DR1, DQ5 or DR7 with CD in the Caucasian population while others have shown an association with DR4 in the Japanese population. Furthermore, some studies have shown a negative association of DR3 with CD. To examine HLA associations with Crohn's disease in the Ashkenazi Jewish population, serologic and DNA-based methods were used to determine HLA class II type among 129 CD patients and 97 ethnically-matched controls within the greater New York City area. A weak association was observed with DQ6 (OR=2.3, p=0.006) but not with DR1, DR4, DR7 or DQ5. A negative association was also observed with DR3 (OR=0.27, p=0.0005). When the patient and control populations were divided on the basis of ethnicity the negative association with DR3 was found to be much more striking in the Jewish (OR=0.15, p=0.0007) than nonJewish (OR=0.56) population. In contrast, the DQ6 association was similar for both groups (OR=3.2 vs 1.7). These studies suggest that genetically disparate populations may differ in the genes that make them susceptible to CD and that DR3 may be protective against CD, especially in the Jewish population.
Immunology, Microbiology, and Inflammatory Disorders A989
This work was supported by a grant from the NIH (A122005) and funds from the Litwin Foundation, the Albert Cohen foundation and the Reach Out for Youth with Ileitis and Colitis organization. • G4055 GENETIC ANTICIPATION IN FIFTEEN THREE-GENERATION FAMILIES WITH INFLAMMATORY BOWEL DISEASE. Gurubhagavatula, S., Gold, L. LaBuda, M., Picco, M. Brandt, S., and Bayless, TM. Dept. of Medicine, GI Division, Johns Hopkins Univ., Baltimore, MD. Genetic anticipation is a phenomenon characterized by earlier age of onset, increased severity of disease, or both in succeeding generations of families affected by a genetic disorder. Preliminary reports have supported a role for genetic anticipation in Crohn's disease. Lancet 1996;347:798-800 We studied anticipation in a cadre of fifteen families, identified both at Johns Hopkins Hospital and through an Intemet web site. There were 38 affected child/parent pairs. The child was affected at a younger age in 28 pairs, equal in 3; and the parent was affected younger in 7. In these families, three separate generations of first-degree relatives were affected with either CD or Ulcerative Colitis (UC). In four families, all members were diagnosed with CD, in one family, all three members had UC; and ten families had a mix of both CD and UC. In 10 of the 15 families, the age at diagnosis of the inflammatory bowel disease (IBD) in the two succeeding generations of family members was earlier than in the parent. The average difference between the age of onset in the oldest generation (generation 1) family member affected and the middle generation (generation 2) family member affected was 19.4 years; and the mean difference between age of onset in generation 2 and generation 3 (the youngest generation affected) was 14.6 years. Thus, the interval was shorter with successive generations. In the 38 parent/child pairs in this study 28 of them had an earlier onset averaging 18.3 years. In 3 of the 38 pairs, the age of onset was equal; and in the remaining 7 of the 38 parent/child pairs, the child's diagnosis was made at an older age than that of the parent. These data provide further evidence for genetic anticipation in IBD. The three-generation families are a valuable resource for studying this phenomenon, specifically for the purpose of identifying potential genomic triplet repeats. Finally, the findings of threegeneration families suggest that it is unlikely that IBD occurs via a recessive trait, given that its overall prevalence in the general population is 0.1% G4056 MESENTERIC OBESITY IN CROHN'S DISEASE (CD). S Hafraoui (1), O Emst (2), P Desreumaux (1), T Asselah (1), A Cortot (1), JF Colombel (1). Services des Maladies de l'Appareil Digestif (CRI4U004B) (1) et de Radiologie (2), CHRU, Lille, France. Background: Abnormalities of fat in the mesentery including adipose tissue hypertrophy and "fat wrapping" have been long recognized as characteristic features of CD on surgical specimens. However, the distribution of abdominal fat tissue and the importance of fat hypertrophy in non operated patients with CD are still unknown. Aims: To assess the distribution of abdominal fat tissue and to quantify the intra-abdominal and abdominal subcutaneous depots in patients with CD using a specific and sensible method of magnetic resonance imaging (MRI). Patients/Methods: 21 patients with CD (12F, 9M, mean age 28 yrs, range 18-55 yrs) and 13 healthy volunteers (7F, 5M, mean age 33 yrs, range 23-59 yrs) were studied. Patients with CD have not been operated on. The mean duration of the disease was 3.7 years (5 mo-12 yrs). Five of the 21 patients had an active disease defined by a CDAI < 150 and were treated by steroids. Areas of intra-abdominal and subcutaneous fat tissues assessed by MRI were measured in a transverse 6 mm thick slice centered on the umbilicus as previously described (1). Results (mean _+SD) were expressed in cm2. Patients with CD and controls had similar age, height, weight and body mass index. Mesenteric fat was homogenous in all patients and controls. Similar intra-abdominal fat areas were observed in patients with CD (79-+ 28 cm2) and controls (63-+ 15 cm2(p=0.29). The levels of subcutaneous fat areas in patients with CD (154-.+ 51 cm2) and controls (218-+ 77 cm2) were not significantly different (p=0.15). However, the ratio of intra-abdominal to abdominal subcutaneous fat was twice greater in patients with CD (0.60 -+ 0.2) than in normal subjects (0.30 -+0.17) (p<0.01). No correlation was found between the CDAI, duration of the disease, steroid therapy and the importance and distribution of abdominal fat tissue. Conclusions: Patients with CD have an accumulation of intra-abdominal fat. This "mesenteric obesity" is present from the begining of the disease and is not affected by CDAI. Enlarged mesenteric adipose tissue associated with its capacity to synthesize TNFa (2) suggests that it could participate to the intestinal inflammatory process in CD. [1] Bjtmtop P. Lancet 1997; 350: 423-6; [2] Desreumaux Pet al. Gastroenterology 1997; 112: A959.
Immunology, Microbiology, and Inflammatory Disorders A989
This work was supported by a grant from the NIH (A122005) and funds from the Litwin Foundation, the Albert Cohen foundation and the Reach Out for Youth with Ileitis and Colitis organization. • G4055 GENETIC ANTICIPATION IN FIFTEEN THREE-GENERATION FAMILIES WITH INFLAMMATORY BOWEL DISEASE. Gurubhagavatula, S., Gold, L. LaBuda, M., Picco, M. Brandt, S., and Bayless, TM. Dept. of Medicine, GI Division, Johns Hopkins Univ., Baltimore, MD. Genetic anticipation is a phenomenon characterized by earlier age of onset, increased severity of disease, or both in succeeding generations of families affected by a genetic disorder. Preliminary reports have supported a role for genetic anticipation in Crohn's disease. Lancet 1996;347:798-800 We studied anticipation in a cadre of fifteen families, identified both at Johns Hopkins Hospital and through an Intemet web site. There were 38 affected child/parent pairs. The child was affected at a younger age in 28 pairs, equal in 3; and the parent was affected younger in 7. In these families, three separate generations of first-degree relatives were affected with either CD or Ulcerative Colitis (UC). In four families, all members were diagnosed with CD, in one family, all three members had UC; and ten families had a mix of both CD and UC. In 10 of the 15 families, the age at diagnosis of the inflammatory bowel disease (IBD) in the two succeeding generations of family members was earlier than in the parent. The average difference between the age of onset in the oldest generation (generation 1) family member affected and the middle generation (generation 2) family member affected was 19.4 years; and the mean difference between age of onset in generation 2 and generation 3 (the youngest generation affected) was 14.6 years. Thus, the interval was shorter with successive generations. In the 38 parent/child pairs in this study 28 of them had an earlier onset averaging 18.3 years. In 3 of the 38 pairs, the age of onset was equal; and in the remaining 7 of the 38 parent/child pairs, the child's diagnosis was made at an older age than that of the parent. These data provide further evidence for genetic anticipation in IBD. The three-generation families are a valuable resource for studying this phenomenon, specifically for the purpose of identifying potential genomic triplet repeats. Finally, the findings of threegeneration families suggest that it is unlikely that IBD occurs via a recessive trait, given that its overall prevalence in the general population is 0.1% G4056 MESENTERIC OBESITY IN CROHN'S DISEASE (CD). S Hafraoui (1), O Emst (2), P Desreumaux (1), T Asselah (1), A Cortot (1), JF Colombel (1). Services des Maladies de l'Appareil Digestif (CRI4U004B) (1) et de Radiologie (2), CHRU, Lille, France. Background: Abnormalities of fat in the mesentery including adipose tissue hypertrophy and "fat wrapping" have been long recognized as characteristic features of CD on surgical specimens. However, the distribution of abdominal fat tissue and the importance of fat hypertrophy in non operated patients with CD are still unknown. Aims: To assess the distribution of abdominal fat tissue and to quantify the intra-abdominal and abdominal subcutaneous depots in patients with CD using a specific and sensible method of magnetic resonance imaging (MRI). Patients/Methods: 21 patients with CD (12F, 9M, mean age 28 yrs, range 18-55 yrs) and 13 healthy volunteers (7F, 5M, mean age 33 yrs, range 23-59 yrs) were studied. Patients with CD have not been operated on. The mean duration of the disease was 3.7 years (5 mo-12 yrs). Five of the 21 patients had an active disease defined by a CDAI < 150 and were treated by steroids. Areas of intra-abdominal and subcutaneous fat tissues assessed by MRI were measured in a transverse 6 mm thick slice centered on the umbilicus as previously described (1). Results (mean _+SD) were expressed in cm2. Patients with CD and controls had similar age, height, weight and body mass index. Mesenteric fat was homogenous in all patients and controls. Similar intra-abdominal fat areas were observed in patients with CD (79-+ 28 cm2) and controls (63-+ 15 cm2(p=0.29). The levels of subcutaneous fat areas in patients with CD (154-.+ 51 cm2) and controls (218-+ 77 cm2) were not significantly different (p=0.15). However, the ratio of intra-abdominal to abdominal subcutaneous fat was twice greater in patients with CD (0.60 -+ 0.2) than in normal subjects (0.30 -+0.17) (p<0.01). No correlation was found between the CDAI, duration of the disease, steroid therapy and the importance and distribution of abdominal fat tissue. Conclusions: Patients with CD have an accumulation of intra-abdominal fat. This "mesenteric obesity" is present from the begining of the disease and is not affected by CDAI. Enlarged mesenteric adipose tissue associated with its capacity to synthesize TNFa (2) suggests that it could participate to the intestinal inflammatory process in CD. [1] Bjtmtop P. Lancet 1997; 350: 423-6; [2] Desreumaux Pet al. Gastroenterology 1997; 112: A959.