Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking.

By running the Swedish twin registry containing about 25,000 pairs of twins of the same sex together with the central national diagnosis register of hospital inpatients, 80 twin pairs suffering from inflammatory bowel disease were found. In the ulcerative colitis group one of 16 monozygotic pairs was concordant for the disease, but all the other 20 pairs (dizygotic or unknown zygosity) were discordant. In the Crohn's disease group eight of 18 monozygotic pairs and one of 26 dizygotic pairs were concordant. The proband concordance rate among monozygotic twins was 6.3% for ulcerative colitis and 58.3% for Crohn's disease. The calculated heritability of liability based on monozygotic pairs was 0.53 and 1.0 respectively. Thus heredity as an aetiological factor is stronger in Crohn's disease than in ulcerative colitis. Monozygotic twins with Crohn's disease were more likely to be smokers than monozygotic twins with ulcerative colitis. Smoking did not explain the discordance of twin pairs with either ulcerative colitis, or Crohn's disease. The combination of identical heredity and similar smoking habit is not sufficient to cause disease.     

Colonic glycoproteins in monozygotic twins with inflammatory bowel disease

Colonic glycoprotein composition was evaluated in monozygotic twins with inflammatory bowel disease using ion-exchange chromatography. Fifty-three individuals, 12 pairs and 1 single twin with ulcerative colitis and 14 pairs with Crohn's disease, were evaluated. Seven twin pairs were concordant for the presence of ulcerative colitis or Crohn's disease, whereas twin siblings of 10 ulcerative colitis probands and 9 Crohn's disease probands were not known to have inflammatory bowel disease. Content of one chromatographically defined component of colonic mucin, designated HCM species IV, was reduced in both patients with ulcerative colitis (1040 +/- 300 cpm/10,000 cpm total HCM) and their apparently healthy twins (1340 +/- 540 cpm/10,000 cpm total HCM) compared with control subjects (4030 +/- 1,000 cpm/10,000 cpm total HCM). Composition of mucin in Crohn's disease patients and their nonaffected twins was not significantly different than in controls. These observations suggest that altered profiles of mucin glycoprotein may be present before the onset of ulcerative colitis and may be genetically defined. Conversely, it appears that alterations in glycoproteins only are not sufficient to initiate mucosal inflammation.     

IgG subclass distribution in serum and rectal mucosa of monozygotic twins with or without inflammatory bowel disease.

Serum samples from 26 monozygotic twin pairs concordant or discordant with regard to inflammatory bowel disease, and rectal biopsies from 42 twins of the same subject group, were examined for IgG subclasses. They were all compared with normal controls. Almost all affected twins were in clinical remission. Paired immunofluorescence staining of the rectal mucosa showed that those with ulcerative colitis had a significantly higher (p < 0.01) proportion of IgG1 producing mucosal immunocytes than normal controls (78.1% v 55.9%). Conversely, the IgG2 cell fraction was significantly reduced (15.9% v 34.6%). Healthy twins from ulcerative colitis pairs tended to show a raised proportion of IgG1 cells and the IgG2 cell fraction was significantly reduced (p < 0.05). In discordant ulcerative colitis twin pairs, no difference appeared in the cellular IgG subclass pattern between healthy and affected twins. Furthermore, the proportion of IgG1 in these healthy and diseased twins showed good correlation (T = 0.867). The results in rectal mucosa of twins with Crohn's disease were widely scattered and affected twins did not differ significantly from normal controls. Healthy twins, however, showed a marginally raised IgG1 cell proportion, but no correlation was seen between the IgG subclass fractions in discordant Crohn's disease twin pairs. The serum concentrations of IgG1 and IgG2 did not differ from normal controls in twins of either category. These results suggested that in ulcerative colitis, the aberrant mucosal production of IgG1 and IgG2 does not depend on active disease, but is apparently at least partially explained by a genetic impact. Conversely, the mucosal IgG subclass pattern in Crohn's disease appears to be determined mainly by exogenous variables.     

Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics

BACKGROUND & AIMS: In 1988, we reported the first twin study in inflammatory bowel disease. The aim of the current study was to follow up these twins regarding new cases of inflammatory bowel disease and Crohn's disease characteristics using the Vienna classification. METHODS: The official Swedish population register and the cause of death register were used to search for the twins. All living patients were interviewed. RESULTS: Three monozygotic twins earlier classified as healthy had been diagnosed with inflammatory bowel disease (ulcerative colitis, n = 2; Crohn's disease, n = 1). Retrospectively, all 3 were symptomatic at the original survey. This changed the pair concordance in monozygotic twins from 6.3% to 18.8% in ulcerative colitis and from 44.4% to 50.0% in Crohn's disease. A high degree of concordance regarding age at diagnosis, disease location at diagnosis and during the course, and disease behavior was found in concordant monozygotic twin pairs with Crohn's disease. Seven of 9 pairs were identical in 3 or more of these disease characteristics compared with an expected number of 1.5 (P = 0.000076). CONCLUSIONS: This study confirms that the genetic influence is stronger in Crohn's disease than in ulcerative colitis. A remarkable phenotype similarity within concordant pairs with Crohn's disease was found using the Vienna classification.     

Antibody (IgG, IgA, and IgM) to baker''s yeast (Saccharomyces cerevisiae), yeast mannan, gliadin, ovalbumin and betalactoglobulin in monozygotic twins with inflammatory bowel disease.

To assess whether dietary antigens play a role in inflammatory bowel disease, 26 monozygotic twin pairs with inflammatory bowel disease and 52 healthy controls were investigated for serum antibodies (IgA, IgG, IgM) against ovalbumin, betalactoglobulin, gliadin, whole yeast (Saccharomyces cerevisiae) and yeast cell wall mannan. The twins were made up of five pairs concordant and nine pairs discordant for Crohn's disease, and two pairs concordant and 10 pairs discordant for ulcerative colitis. Two patients with Crohn's disease had a slight increase in disease activity, the others were in clinical remission. Two striking observations were made: first, individuals with ulcerative colitis were indistinguishable from healthy twins, and controls except for the response to gliadin. Both healthy and diseased twins had higher IgA levels to gliadin than controls. Second, twins who had developed Crohn's disease displayed higher antibody titres towards yeast cell wall mannan in particular, but also to whole yeast (Saccharomyces cerevisiae) of all antibody types (IgA, IgG, and IgM). In contrast, the response to gliadin, ovalbumin, and betalactoglobulin did not differ from healthy twins and was even lower than in the controls. The results argue against an increased systemic antigen presentation caused by an impaired mucosal barrier in the inflammatory bowel disease. Rather, they suggest that yeast cell wall material--that is, mannan, or some antigen rich in mannose and cross reacting with mannan, may play an aetiological role in Crohn's disease, but not in ulcerative colitis. The increases in IgA and IgM, as well as IgG suggest that local and systemic immune systems are selectively activated by antigen(s) present in the cell wall of baker's yeast.     

Anti-Saccharomyces cerevisiae antibodies in twins with inflammatory bowel disease

BACKGROUND AND AIMS: An increased occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) is reported in unaffected members of families with Crohn's disease. Whether ASCA is a familial trait due to genetic factors or is caused by exposure to environmental factors is unknown. To assess the genetic influence of ASCA we studied its occurrence in a twin population. PATIENTS AND METHODS: ASCA were analysed in 98 twin pairs with inflammatory bowel disease and were related to clinical phenotype and CARD15/NOD2 genotype. RESULTS: ASCA were more common in Crohn's disease than in ulcerative colitis (40/70 (57%) twins v 5/43 (12%) twins). Associations with ileal Crohn's disease, stricturing/penetrating behaviour, and young age, but not CARD15/NOD2 were confirmed. ASCA were found in 1/20 (5%) healthy siblings in discordant monozygotic pairs with Crohn's disease compared with 7/27 (26%) in discordant dizygotic pairs. Using the intraclass correlation coefficient (ICC), no agreement in ASCA titres was observed in discordant twin pairs with Crohn's disease, in monozygotic (ICC = -0.02) or dizygotic (ICC = -0.26) pairs. In contrast, strong agreement was seen within concordant monozygotic twin pairs with Crohn's disease (ICC = 0.76). CONCLUSIONS: These findings question the concept of ASCA as a marker of genetic susceptibility for Crohn's disease. The agreement in ASCA titres within concordant monozygotic twin pairs with Crohn's disease, suggests that the level of increase is genetically determined. We propose that ASCA are a marker of a response to an environmental antigen and that a specific gene(s) other than CARD15/NOD2 determines the level of response and perhaps also specific phenotypic characteristics.     

Concordance of Inflammatory Bowel Disease among Danish Twins: Results of a Nationwide Study

Background: Previous studies have shown an increased risk of inflammatory bowel disease (IBD) among relatives of patients with Crohn disease and ulcerative colitis. In the present study the probandwise concordance rates for ulcerative colitis and Crohn disease among mono- and dizygotic twins were estimated. Further we aimed to evaluate whether smoking habits might influence the concordance, and to look for clinical characteristics of concordant versus discordant twin pairs. Methods: Among the 38,507 identified twins born in Denmark from 1953 to 1982, a questionnaire was sent to the 34,076 who previously had accepted to participate in studies. For twins reporting IBD, the diagnosis was verified by applying standard criteria to records requested from hospitals or practitioners. Results: Among the 29,421 (86.3%) twins answering the questionnaire, 103 pairs had at least one twin who suffered from IBD. In the Crohn disease group five of 10 monozygotic pairs, but none of 27 dizygotic pairs were concordant. In the ulcerative colitis group three of 21 monozygotic, and two of 44 dizygotic pairs were concordant. The probandwise concordance rate among monozygotic pairs was 58.3% for Crohn disease and 18.2% for ulcerative colitis; among the dizygotic pairs the rates were 0 and 4.5%, respectively. The frequency of smokers was higher among twins with Crohn disease and lower among twins with ulcerative colitis compared to the frequency in the twin register. Furthermore, smoking habits were found to be of significance for discordance for disease. Regarding the clinical characteristics no homogenous pattern was observed within the concordant pairs and the differences between concordant and discordant pairs were not significant. Conclusion: The observation of a significantly higher concordance rate among monozygotic than among dizygotic twin pairs strongly points to a genetic influence on occurrence of IBD, which seems to be more pronounced with regard to Crohn disease than to ulcerative colitis. Differences in smoking habits among the members of the discordant twin pairs may influence the discordance.     

Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study

BACKGROUND: Previous studies have shown an increased risk of inflammatory bowel disease (IBD) among relatives of patients with Crohn disease and ulcerative colitis. In the present study the probandwise concordance rates for ulcerative colitis and Crohn disease among mono- and dizygotic twins were estimated. Further we aimed to evaluate whether smoking habits might influence the concordance, and to look for clinical characteristics of concordant versus discordant twin pairs. METHODS: Among the 38,507 identified twins born in Denmark from 1953 to 1982, a questionnaire was sent to the 34,076 who previously had accepted to participate in studies. For twins reporting IBD, the diagnosis was verified by applying standard criteria to records requested from hospitals or practitioners. RESULTS: Among the 29,421 (86.3%) twins answering the questionnaire, 103 pairs had at least one twin who suffered from IBD. In the Crohn disease group five of 10 monozygotic pairs, but none of 27 dizygotic pairs were concordant. In the ulcerative colitis group three of 21 monozygotic, and two of 44 dizygotic pairs were concordant. The probandwise concordance rate among monozygotic pairs was 58.3% for Crohn disease and 18.2% for ulcerative colitis; among the dizygotic pairs the rates were 0 and 4.5%, respectively. The frequency of smokers was higher among twins with Crohn disease and lower among twins with ulcerative colitis compared to the frequency in the twin register. Furthermore, smoking habits were found to be of significance for discordance for disease. Regarding the clinical characteristics no homogenous pattern was observed within the concordant pairs and the differences between concordant and discordant pairs were not significant. CONCLUSION: The observation of a significantly higher concordance rate among monozygotic than among dizygotic twin pairs strongly points to a genetic influence on occurrence of IBD, which seems to be more pronounced with regard to Crohn disease than to ulcerative colitis. Differences in smoking habits among the members of the discordant twin pairs may influence the discordance.     

CARD15/NOD2 polymorphisms do not explain concordance of Crohn''s disease in Swedish monozygotic twins

BACKGROUND: CARD15/NOD2 polymorphisms are associated with Crohn's disease. There is a high concordance for disease and disease phenotype in monozygotic twin pairs with Crohn's disease. AIM: We studied CARD15/NOD2 polymorphisms in a Swedish, population-based cohort of monozygotic twins with Crohn's disease to assess whether these variants explain disease concordance. SUBJECTS AND METHODS: Twenty-nine monozygotic twin pairs (concordant n=9, discordant n=20) with Crohn's disease and 192 healthy controls were investigated for the CARD15/NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC. RESULTS: CARD15/NOD2 mutations were found in 5/38 (13%) twins with Crohn's disease, corresponding to a total allele frequency of 6.6%. Only 2/9 concordant twin pairs carried any of the variants and the remaining seven were wild type genotype. The total allele frequency was 4.4 times higher (95% confidence interval 1.0-21.5, p=0.06) in concordant twins than in discordant ones, 11.1% versus 2.5%. In healthy controls the total allele frequency was 2.6%. CONCLUSIONS: CARD15/NOD2 polymorphisms contribute but do not alone explain concordance of Crohn's disease in monozygotic twins and, at least in a Swedish population, other polymorphisms are required. The low occurrence of CARD15/NOD2 mutations in the study and other Northern European populations suggests that these variants are of less importance in Northern Europe.     

Altered colonic glycoprotein expression in unaffected monozygotic twins of inflammatory bowel disease patients

BACKGROUND AND AIMS: Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose beta1, 3 N-acetylgalactosamine alpha-), among the same IBD twins. MATERIALS AND METHODS: Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn's disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor kappaB (NFkappaB) activation with investigators blinded to the diagnosis. RESULTS: Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p<0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NFkappaB was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p=0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NFkappaB. CONCLUSIONS: Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect "preinflammatory" NFkappaB activation.     

Longitudinal concordance for clinical characteristics in a Swedish-Danish twin population with inflammatory bowel disease

BACKGROUND: The genetic influence on disease course in inflammatory bowel disease (IBD) remains unknown. We therefore aimed to study longitudinal concordance for clinical characteristics and longitudinal stability using the Montreal Classification in an IBD twin population. METHODS: A total of 158 twins with ulcerative colitis (UC) (18 belonging to 9 concordant monozygotic pairs) and 141 twins with Crohn's disease (CD) (34 belonging to 17 concordant monozygotic pairs) were enrolled. Medical notes were scrutinized for clinical characteristics at diagnosis and after 10 years. Using the binominal distribution, we tested the hypothesis that clinical characteristics were independent within individuals in disease concordant monozygotic pairs. RESULTS: In CD, location was identical in 11/17 monozygotic concordant pairs at diagnosis (P = 0.008) and in 11/16 pairs after 10 years (P = 0.02). Behavior at diagnosis was identical in 13/17 pairs (P = 0.03) and in 11/16 pairs after 10 years (P = 0.01). Monozygotic UC twins were concordant (within 5 years) for age at diagnosis (6/9 pairs; P < 0.001) and symptomatic onset (4/9 pairs; P = 0.02) but not for extent of disease at diagnosis or after 10 years. The Montreal Classification did not demonstrate longitudinal stability, either regarding location or behavior of CD or extent of UC. CONCLUSIONS: The high phenotypic concordance, both at diagnosis and longitudinally, in monozygotic twins with CD supports a genetic influence not only on disease occurrence but also on disease course. This contrasts with UC, where the genetic impact appears less. Montreal Classification characteristics changed over time and should be used cautiously.     

Monozygotic twins with Crohn's disease and ulcerative colitis: a unique case report

Background—A large number of monozygotic anddizygotic twin pairs with inflammatory bowel disease have beenreported. To date no twin pair has developed phenotypically discordantinflammatory bowel disease. This case report is the first documentedoccurrence of discordant inflammatory bowel disease occurring inmonozygotic twins.
Case report—Twenty two year old identical maletwins presented within three months of each other with inflammatorybowel disease that proved to be discordant in overall disease type,disease distribution, clinical course, and histopathological findings. Twin 1 developed a severe pancolitis necessitating total colectomy while twin 2 developed a predominantly distal patchy colitis with frequent granulomas, controlled by aminosalicylates. Twin 1 was antineutrophil cytoplasmic antibody (ANCA) negative at the time oftesting while twin 2 (Crohn's disease) was ANCA positive.Significantly, the twins possessed the HLA type DR3-DR52-DQ2 previouslyassociated with extensive colitis.
Conclusion—This case report confirms the importantrole played by genetic factors in the development of inflammatory bowel disease. It also highlights the crucial role of undeterminedenvironmental agents in dictating disease expression and phenotype.

Keywords:monozygotic twins; ulcerative colitis; Crohn'sdisease; inflammatory bowel disease

     

Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease

OBJECTIVES: A Danish cohort of twins with inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), has previously been collected. The aim of the present study was to reassess this cohort in order to compare clinical characteristics in concordant versus discordant twin pairs, test twin zygosity genetically, follow-up on disease concordance, and examine NOD2/CARD15 genetic status. METHODS: The Danish cohort is one of two population-based cohorts worldwide and consists of 103 twin pairs. After median 13 yr of follow-up, all twins were contacted and hospital files were scrutinized to reassess disease concordance and obtain phenotype data. DNA was obtained from 123 twins for analysis of zygosity and prevalence of the three common NOD2/CARD15 mutations. RESULTS: Zygosity tested genetically was consistent with the former assessment based on questionnaires. The proband concordance for CD remained fairly stable: 63.6% among monozygotic (MZ) twins and 3.6% among dizygotic (DZ) twins. Clinical characteristics were similar in twins from concordant versus discordant pairs. Forty-four percent of patients with CD were positive for >or=1 mutant allele of NOD2/CARD15 compared to 2% of UC patients (p < 0.001) and 19% of healthy twins (p= 0.02). The allele mutation frequency was 43% among the healthy twins to patients with CD versus 9% among twins to UC patients (p= 0.01). CONCLUSIONS: Previous questionnaire assessment of twin zygosity was confirmed by genetic test. Concordance for CD remained quite stable and was significantly higher among MZ than DZ twins. A high NOD2/CARD15 mutation frequency was observed both among CD twins and their healthy siblings.     

1 Ulcerative colitis: a genetic disease?

A number of lines of evidence support the hypothesis that ulcerative colitis is an inherited disorder in a proportion of cases. First, there is a pattern of familial aggregation. Second, there are differences in the prevalence of the disease in different ethnic groups. Finally, the concordance rate in monozygotic twin pairs is higher than that of dizygotic twin pairs, although not as high as the concordance rates observed in Crohn's disease. Genetic models of the inheritance patterns suggest that ulcerative colitis is probably caused by one major gene, although that gene (or genes) remains to be identified. While at least one localization for susceptibility to Crohn's disease now seems certain, efforts to localize and characterize the susceptibility genes involved in the inheritance of ulcerative colitis are still underway. While the genes of the major histocompatibility complex have been imputed as causal in susceptibility to ulcerative colitis, a consensus of proof continues to elude us.     

Cytokine gene polymorphisms in inflammatory bowel disease.

BACKGROUND: Concordance rates in siblings and twins provide strong evidence that genetic susceptibility is important in the pathogenesis of inflammatory bowel disease. The number and identity of susceptibility genes is largely uncertain. Cytokine genes are attractive candidate loci. AIMS: To study allelic frequencies of polymorphisms of the interleukin-1 receptor antagonist (IL-1RA) gene and the tumour necrosis factor alpha gene in patients with inflammatory bowel disease. SUBJECTS: One hundred and twenty nine North European caucasoid patients with ulcerative colitis, 120 patients with Crohn's disease, and 89 healthy controls. METHODS: Genotyping was performed by polymerase chain reaction. A variable number of tandem repeats (VNTR) in the IL-1RA gene and a single base pair polymorphism in the TNF alpha gene promoter region (TNF-308) were analysed. RESULTS: No significant differences in IL-1RA VNTR allelic frequencies were noted between Crohn's disease (allele 1: 72.6%, allele 2: 24.7%, allele 3: 2.6%), ulcerative colitis (72.6%, 24.3%, 3.1%, respectively), and controls (76.9%, 20.8% and 2.3%). Some 42.4% of patients with ulcerative colitis and 43.4% patients with Crohn's disease were carriers of allele 2, compared with 34.8% healthy subjects. The TNF2 allele was modestly reduced in Crohn's disease (13.2%), compared with healthy subjects (21.3%; p = 0.04), and ulcerative colitis (21.6%). CONCLUSIONS: The associations demonstrated are modest: these polymorphisms are unlikely to be important determinants of overall disease susceptibility.     

HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.

The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.     

Anti-Neutrophil Cytoplasmic Antibodies in Inflammatory Bowel Disease with Special Attention for IgA-Class Antibodies

Perinuclear anti-neutrophil cytoplasmicantibodies (P-ANCA) of the IgG class have been reportedin inflammatory bowel disease, mainly in ulcerativecolitis. Since this disease affects the gastrointestinal tract, we determined whether IgA class ANCAwere present in inflammatory bowel disease. We used anindirect immunofluorescence assay for IgG and IgA ANCAtesting. Sera from 34 patients with Crohn's disease and 29 patients with ulcerative colitis werecollected together with clinical and laboratory data. Wefound IgA class ANCA of a perinuclear type in 52% ofpatients with ulcerative colitis and in 9% of Crohn's disease patients. There was a significantassociation between the presence of IgA ANCA and theoccurrence of blood in the feces in the ulcerativecolitis group (P = 0.03). IgG ANCA was found in 56% ofpatients with ulcerative colitis and in 7% of patientswith Crohn's disease. Because of partial overlap betweenIgG and IgA ANCA positivity, the sensitivity of ANCAtesting in ulcerative colitis increased from 56% up to 78% by combining IgG and IgA assays. Inconclusion, IgA ANCA occurs with a high prevalence inulcerative colitis. Moreover there is a possiblerelationship between IgA ANCA and disease activity in ulcerative colitis.     

Genetic epidemiology in inflammatory bowel disease

Family studies of different designs have been carried out in the last few years. Five to ten percent of patients have another case of inflammatory bowel disease (IBD) among their first-degree relatives, with about 75-80% concordance for the same disease within the family. About 20% of multi-affected families present both cases with ulcerative colitis and Crohn's disease. The population relative risk in first-degree relatives of patients show a 14-15 times higher prevalence of IBD. Prevalence values of 1.5-3.5% in first-degree relatives have been found, with an even higher calculated lifetime risk especially in offspring and siblings of patients with IBD. Earlier disease onset in offspring of patients with IBD have consistently been found, and genetic anticipation has been hypothesized. The phenomenon, however, may be a result of a combination of a time trend - increasing the incidence of Crohn's disease - and the fact that patients with early onset of IBD may have lower fertility and therefore may be underrepresented in the parent-child pairs studied. Twin studies have shown significantly higher concordance rates in monozygotic than in dizygotic twins. Further, the concordance rate in monozygotic twins is higher in Crohn's disease than in ulcerative colitis, indicating a stronger genetic influence in this condition. Disease course and prognosis within families have been studied without convincing concordance found in this respect among family members.     

A population-based study of chronic autoimmune hypothyroidism in Danish twins

Hashimoto's thyroiditis (HT), atrophic thyroiditis (AT), and Graves' disease are autoimmune thyroid diseases in which genetic factors are suspected to play an important role in disease susceptibility. In a recent population-based twin study we rendered it probable that a substantial part of the susceptibility to Graves' disease is attributable to genetic factors. At present there are no population-based twin studies supporting such a genetic influence in the etiology of HT/AT. To elucidate whether there is a genetic influence in the etiology of HT/AT, we studied the distribution of HT/AT in a population-based sample of 2945 Danish female-female twin pairs (5890 individuals) born between 1953 and 1972. Information on hypothyroidism was obtained from a nationwide questionnaire survey in 1994. Information from hospitals, out-patient clinics, general practitioners, and specialists was sought to verify the diagnosis. The overall prevalence of autoimmune hypothyroidism was 0.41% (24 of 5890). The prevalence did not differ between monozygotic and dizygotic twins (0.42% and 0.40%, respectively). The crude proband-wise concordance rates were significantly higher for monozygotic compared to dizygotic twin pairs: 0.55 (95% confidence interval, 0.23-0.83) vs. 0.0 (95% confidence interval, 0.0-0.25; P = 0.01). All of the healthy cotwins (n = 15) of twins with clinically overt autoimmune hypothyroidism were biochemically euthyroid. Overall, regardless of zygosity 53% (8 of 15) of the healthy cotwins were positive for antithyroid antibodies. The prevalence of autoantibodies among the monozygotic cotwins was 80% (4 of 5) and 40% (4 of 10) among dizygotic cotwins (P = 0.36). In conclusion, the higher concordance rate in monozygotic compared to dizygotic pairs indicates that genetic factors play a role in the etiology of HT/AT among Caucasian women living in areas with borderline iodine deficiency. However, the fact that the concordance rate among MZ twins was below 1 suggests that environmental factors also are of etiological importance.     

Function of exudative neutrophilic granulocytes in patients with Crohn's disease or ulcerative colitis

Chemotactic, phagocytic, and oxidative metabolic activity of exudative leukocytes was measured in patients with Crohn's disease (n = 20) and with ulcerative colitis (n = 20). Unstimulated and casein-stimulated migration in Boyden chambers did not differ from that of healthy controls (n = 21). Patients with Crohn's disease had reduced serum-independent phagocytosis compared with healthy controls (p less than 0.01) and patients with ulcerative colitis (p less than 0.01). Serum-dependent phagocytosis by leukocytes from patients with Crohn's disease did not differ from that in controls but was slightly increased in patients with ulcerative colitis (p less than 0.02). Unstimulated leukocytes showed increased oxidative metabolic activity in both patient groups compared with controls (p less than 0.01), which was negatively correlated with the disease activity in Crohn's disease (p less than 0.02). The study shows that mobilized leukocytes from patients with Crohn's disease differ from those mobilized in ulcerative colitis and supports the concept of an abnormal inflammatory reaction in Crohn's disease.