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PubMed1988

Epidemiology of inflammatory bowel disease in a defined northern California population.

The epidemiology of inflammatory bowel disease is described among the more than 1.5 million members of the Kaiser Permanente Medical Care Program (KPMCP) in northern California. We reviewed a 20% random sample of the medical records of 2,067 persons first admitted to hospital in the period 1971 through 1982 with codes indicating inflammatory bowel disease. We also examined all new outpatient cases for a 1-year period from records at the Oakland KPMCP facility. Criteria used to establish valid cases adhered to standards used in previous studies but were revised to reflect current diagnostic methods. The disadvantages of using hospital discharge data have been identified and quantified. In this population, only 21% of ambulatory patients with inflammatory bowel disease were admitted to hospital in a 3 1/2-year period. There was no difference in the incidence of the disorder by sex or between whites and blacks, but it was rare in Asians. A bimodal age distribution was suggested for Crohn's disease but not for ulcerative colitis. During the 12 years of this study, rates of hospital admissions for ulcerative colitis decreased and for Crohn's disease were slightly increased.

Adolescent↗
PubMed2001

Glucocorticoids and IL-10, but not 6-MP, 5-ASA or sulfasalazine block endothelial expression of MAdCAM-1: implications for inflammatory bowel disease therapy.

BACKGROUND: Enhanced MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the aetiology of inflammatory bowel disease, but little is known about MAdCAM-1: regulation, or how inflammatory bowel disease therapies modulate MAdCAM-1. AIM: To examine how agents currently used to treat inflammatory bowel disease affect MAdCAM-1: induced by tnf-alpha in an in vitro model of inflammatory bowel disease. METHODS: Endothelial monolayers were pretreated with dexamethasone (DEX): 5-aminosalicylic acid (5-ASA), 6-mercaptopurine (6-MP), sulfasalazine or interleukin-10: (IL-10: prior to TNF-alpha (20 ng/mL), and MAdCAM-1: measured by Western blotting, RT-PCR, EMSA and lymphocyte adhesion assays. RESULTS: MAdCAM-1: was induced dose- and time-dependently by TNF-alpha on endothelial cells. Either dexamethasone or IL-10: reduced TNF-alpha-induced MAdCAM-1: protein, mRNA and lymphocyte adhesion. However, neither 5-ASA, sulfasalazine nor 6-MP blocked MAdCAM-1 induction. CONCLUSIONS: Our data indicate that dexamethasone or IL-10 can exert therapeutic activity in inflammatory bowel disease through MAdCAM-1 inhibition. 5-ASA, sulfasalazine and 6-MP, while beneficial in inflammatory bowel disease, do not directly control MAdCAM-1, and are beneficial through inhibition of other inflammatory processes.

Animals↗
PubMed2000

Inflammatory bowel disease: epidemiology and management in an English general practice population.

BACKGROUND: Inflammatory bowel diseases have significant long-term morbidity and healthcare resource consequences. Studies based on secondary care records may have underestimated the contribution of general practitioners (GPs) to its management. AIMS: To describe the epidemiology and management of inflammatory bowel disease using GP records as the primary data source. METHODS: A systematic search of GP clinical records in northern England, identifying cases of inflammatory bowel disease, patient consultation behaviour, prescribing patterns, and extent of specialist care. RESULTS: In a population of 135 723, the incidence of ulcerative colitis was 13. 9/100 000 per year (CI: 7.5-20.3) and for Crohn's disease 8.3/100 000 per year (CI: 3.4-13.2). The age-sex adjusted point prevalence for ulcerative colitis on 1st January 1995 was 243.4/100 000 (CI: 217.4-269.4) and for Crohn's disease 144.8/100 000 (CI: 124.8-168.8). The mean number of consultations (s.d.) with specialists and GPs were similar, both in the first 12 months after referral (specialists 3.94 +/- 3.15, GPs 3.34 +/- 3.55) and in the most recent 12 months (1.02 +/- 2.02, 1.04 +/- 2.04). Only 29.9% of all patients were definitely under specialist care. CONCLUSIONS: Prevalence rates, but not incidence rates, for inflammatory bowel disease are substantially higher than previously described in UK populations. General practitioners make a significant contribution to meeting the healthcare needs of these patients.

Adult↗
PubMed2004

Systematic review: is ingestion of paracetamol or non-steroidal anti-inflammatory drugs associated with exacerbations of inflammatory bowel disease?

AIM: To examine the published evidence on the association between paracetamol or non-steroidal anti-inflammatory drugs and relapse in inflammatory bowel disease. METHODS: Medline searches were performed till June 2004 and Embase till April 2003. Abstracts published in Gut and Gastroenterology from 1999 to 2004 were hand-searched. Twenty-nine relevant abstracts and papers were identified. RESULTS: Twenty-two patients with relapse of inflammatory bowel disease following exposure to non-steroidal anti-inflammatory drugs have been described in case-reports. Four patients were re-exposed to non-steroidal anti-inflammatory drugs and relapsed again. Two had relapsed after taking a cyclo-oxygenase 2 inhibitor. One study described increased inflammatory activity and clinical relapse in some patients after challenge with naproxen or nabumetone. Fifteen epidemiological studies were identified. All had small sample sizes and many had methodological problems. Six studies found evidence for an association between non-steroidal anti-inflammatory drug use and relapse of inflammatory bowel disease, but the association was significant in only two. Three studies suggested a relationship between paracetamol use and exacerbations of inflammatory bowel disease. CONCLUSIONS: Non-steroidal anti-inflammatory drugs may precipitate a relapse in some patients with inflammatory bowel disease. This may be an idiosyncratic reaction. The published evidence does not support the view that non-steroidal anti-inflammatory drugs are important in inducing relapse of inflammatory bowel disease. There is weak evidence that paracetamol may be more important.

Acetaminophen↗
PubMed2003

Complications of pregnancy and child development after cessation of treatment with 6-mercaptopurine for inflammatory bowel disease.

PURPOSE: 6-Mercaptopurine (6-MP) has proven efficacy in the therapy of inflammatory bowel disease. Its teratogenicity is demonstrated in animal studies when used at very high doses, whereas human data suggest that 6-MP at maintenance doses is safe. We report the outcome of 72 pregnancies in patients with inflammatory bowel disease who were previously treated with 6-MP with three different doses of 50, 75, and 100 mg/d, for a median duration of 18 months, along with long-term follow-up of the children. METHODS: We have compared the outcome of pregnancies and development of the offspring in the following two groups: group 1, patients with inflammatory bowel disease who conceived 6 months to 22 years after stopping 6-MP (median 72 months); and group 2, patients with inflammatory bowel disease who never received 6-MP prior to conception. All pregnancies were evaluated in terms of outcome: live full-term birth, premature delivery, stillbirth, spontaneous abortion, ectopic pregnancy, and therapeutic dilatation and curettage. Data on children were obtained regarding birth weight, congenital anomalies, and development. RESULTS: Group 1 included 72 pregnancies carried by 29 women. There were 51 live births (4 premature), 16 spontaneous abortions, 1 stillbirth, 2 therapeutic abortions due to abnormal amniocentesis, and 2 ectopic pregnancies. The total incidence of fetal loss was 29.2%. In group 2, 75 women had 140 pregnancies resulting in 120 live births (8 premature), 18 spontaneous abortions, and 2 stillbirths. There were no cases of ectopic pregnancies or abnormal amniocentesis. The total incidence of fetal loss was 14.3%. There was no increase in the incidence of developmental defects when the mothers had been treated with 6-MP prior to pregnancy. CONCLUSIONS: The incidence of fetal loss is higher in women with inflammatory bowel disease who had been previously treated with 6-MP compared with those who had not. Whether this was related to the older age at conception in 6-MP group, longer duration of disease, initially more severe disease, or use of 6-MP we cannot tell.

Abortion, Spontaneous↗
PubMed1997

Differential excretion of leucocyte granule components in inflammatory bowel disease: implications for pathogenesis.

1. Faecal excretion of the leucocyte primary granule component, myeloperoxidase, and of the secondary granule component, lactoferrin, were compared in inflammatory bowel disease and infective diarrhoea. 2. Faecal lactoferrin correlated with faecal myeloperoxidase in both inflammatory bowel disease (P = 0.0018; n = 32) and infective diarrhoea (P = 0.00013; n = 37), but inflammatory bowel disease was associated with a much higher faecal excretion of lactoferrin but lower excretion of myeloperoxidase than infective diarrhoea. As a consequence, the median ratio of lactoferrin/myeloperoxidase excretion (both expressed as ng/mg of protein) for inflammatory bowel disease was 7.5 (range 3.5-21.3) with similar values for ulcerative colitis (n = 18) and Crohn's disease (n = 14) compared with only 0.9 (range 0.4-2.3; P < 0.0001) for infective diarrhoea. In inflammatory bowel disease faecal lactoferrin and myeloperoxidase excretion remained increased even in clinical remission. 3. In subsequent immunohistochemical studies to assess the possible explanation for these findings, lactoferrin and myeloperoxidase were demonstrated within crypt abscesses and surface mucus, both in inflammatory bowel and in infective diarrhoea mucosal samples. There was a slight increase in the number of lactoferrin-containing cells in the mucosal samples from ulcerative colitis and in the submucosa of samples from Crohn's disease compared with infective diarrhoea, but these changes were not sufficient to account for the marked increase in faecal lactoferrin excretion in inflammatory bowel disease. 4. In all mucosal samples, including those from normal mucosa, lactoferrin was also shown to be contained within mast cells. 5. These results could best be explained by a different mechanism for leucocyte activation in inflammatory bowel disease compared with infective diarrhoea, and are compatible with selective secretion of secondary granule components, which include lactoferrin but not myeloperoxidase, as a result of leucocyte activation by N-formylated bacterial peptides in inflammatory bowel disease.

Bacterial Infections↗
PubMed1994

Evolving concepts of psychopathology in inflammatory bowel disease. Implications for treatment.

The role of psychiatric factors in inflammatory bowel disease has been increasingly relegated, according to Aronowitz and Spiro, to "patient's illness, but not to disease, to therapy, but not to etiology, to symptoms, but not to pathology, and finally to the course of the disease, but not to its cause." This is not surprising in view of the fact that to attribute psychological factors to an illness is seen by the patient and physician alike as an attempt to "blame the victim." As a result, there has been a concerted effort in the past two decades in the field to replace the seemingly archaic, developmental, romantic psychoanalytic concepts of causation with more "enlightened," "scientific" paradigms of psychoneuroimmunology and psychiatric comorbidity. Despite major advances in the biomedical understanding of inflammatory bowel disease and its treatment, however, the essential questions about the complex relationship between emotional and physical symptoms remain a source of frustration both to the patient and to the treating physician in the management of the chronic diseases of the bowel. Thus, early assumptions of a psychogenic basis of ulcerative colitis and Crohn's disease may have been imprecise, but the genuine contributions of investigators such as Alexander, Karush, and Engels ought not to be cast aside completely. Experience with the treatment of patients with inflammatory bowel disease shows that attention to psychiatric comorbidity, quality of adaptation to illness, and the patient-physician relationship are essential components of a comprehensive, successful approach to these chronic illnesses.

Affective Symptoms↗
PubMed1984

Loss of suppressor T-cells in active inflammatory bowel disease.

The proportions and absolute numbers of helper and suppressor T-cells in 40 patients with inflammatory bowel disease and 22 control subjects were determined, using the monoclonal antibodies OKT 4 and OKT 8. There were no significant differences in helper or suppressor cell proportions among 15 steroid treated patients with active inflammatory bowel disease, 10 patients with inactive inflammatory bowel disease, 10 patients with other gastrointestinal diseases, or 12 normal control subjects. In contrast, 15 patients with active inflammatory bowel disease not treated with corticosteroids manifested increased proportions of helper cells and decreased proportions of suppressor cells (p less than 0.001), compared with all other patient groups and to normal controls. When absolute numbers of helper and suppressor subsets were measured, these alterations in proportions of helper and suppressor cells were primarily attributable to decreased counts of suppressor T-cells both in patients with active Crohn's disease and in those with ulcerative colitis (p less than 0.01). In four patients undergoing serial study, the helper/suppressor ratios appeared to rise and fall respectively with clinical exacerbations and remissions of disease. These data provide additional evidence for the involvement of cellular immune systems in these disease processes.

Adolescent↗
PubMed2004

Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease.

BACKGROUND: Azathioprine is a useful agent in the management of inflammatory bowel disease. Its use is limited by its side-effect profile. Marrow toxicity occurs in approximately 3.2% of patients and is known to be associated with diminished thiopurine methyltransferase enzyme activity resulting from genetic polymorphisms. AIM: To evaluate the cost-effectiveness of screening for thiopurine methyltransferase gene polymorphisms prior to initiation of azathioprine therapy. METHODS: Analysis of the literature was undertaken to calculate the expected frequency of leucopenia and its relationship with thiopurine methyltransferase polymorphisms in a model of theoretical inflammatory bowel disease patients. Decision analysis was then applied to assess the cost of a pre-treatment genotyping strategy, taking account of direct costs and cost per life-year saved. RESULTS: In 1000 inflammatory bowel disease patients treated with azathioprine, 32 will develop myelosuppression and one will die because of this. Of those who develop myelosuppression during azathioprine therapy, 32% are attributable to lower thiopurine methyltransferase activity. Pre-treatment genotyping costs pound 347 per life-year saved for a 30 year old and pound 817 per life-year saved for a 60 year old. This compares favourably with other health care technologies. CONCLUSION: The use of pre-treatment screening for thiopurine methyltransferase polymorphisms in inflammatory bowel disease patients commencing azathioprine therapy represents good value for money.

Adult↗
PubMed2000

Psychosocial aspects of inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are known as inflammatory bowel disease (IBD), chronic and potentially disabling diseases, affecting about 90 to 300 per 100,000 people in the general population. Although significant gains have been made in our understanding of these diseases, particularly with respect to pathophysiology and treatment, its etiology is still unknown. IBD is a significant disease that can severely impact one's psychological and social well-being. This article reviews the literature on the psychosocial aspects of IBD. We also address the importance of conceptualizing IBD from a biopsychosocial perspective, considering psychosocial factors along with disease activity. The biopsychosocial approach offers a broadened perspective that reflects the many factors that may contribute to the expression and maintenance of IBD symptoms. Issues of concerns for patients with IBD are also discussed. Finally, we highlight the importance of establishing a collaborative therapeutic relationship between patients and their physicians, facilitating open and honest discussions acknowledging patients' fears and concerns. In doing so, much of these IBD-related issues of concerns may be ameliorated, potentially improving one's coping abilities, and lead to an improved quality of life for individuals with inflammatory bowel disease.

Humans↗
PubMed2004

Prevalence of the K469E polymorphism of intercellular adhesion molecule 1 gene in Italian patients with inflammatory bowel disease.

BACKGROUND: Intercellular adhesion molecule 1 plays an important role in the recruitment of leucocytes at sites of inflammation and is up-regulated in intestinal mucosa of inflammatory bowel disease. Intercellular adhesion molecule 1 gene lies on chromosome 19p13, implicated in determining susceptibility to inflammatory bowel disease. Recently, the polymorphism K469E of intercellular adhesion molecule 1 gene has been identified. AIM: To assess the potential association of this polymorphism with inflammatory bowel disease. PATIENTS: A total of 165 inflammatory bowel disease patients, 75 with Crohn's disease and 90 with ulcerative colitis, and 187 controls were studied. METHODS: The K469E polymorphism was detected by polymerase chain reaction and restriction enzyme analysis. Statistical analysis was performed by chi2-test. RESULTS: In inflammatory bowel disease, the distribution of intercellular adhesion molecule 1 genotypes was 24.9% E/E, 44.2% E/K and 30.9% K/K. In controls, 11.8% showed E/E genotype, 55.6% E/K and 32.6% K/K. The frequency of the E/E genotype was significantly higher in inflammatory bowel disease (Crohn's disease and ulcerative colitis) patients than in controls. Subgroup analysis showed that the frequency of the E469 allele was significantly increased only in Crohn's disease patients with ileocolonic location of disease and penetrating behaviour compared with controls. CONCLUSIONS: We found an association of inflammatory bowel disease with the E/E genotype of intercellular adhesion molecule 1 gene, while allele E469 was associated with a subgroup of Crohn's disease patients with more extensive location of disease and penetrating behaviour. However, further studies are needed to confirm our findings.

Adolescent↗
PubMed1993

Intestinal mast cell responses in idiopathic inflammatory bowel disease. Histamine release from human intestinal mast cells in response to gut epithelial proteins.

Mucosal and submucosal mast cell hyperplasia is a feature of the chronic inflammatory bowel diseases--ulcerative colitis and Crohn's disease. The mast cells are often seen to be degranulated in areas of active disease, suggesting that the inflammatory mediators released from these cells contribute to the pathophysiology of these disorders. We examined the hypothesis that epithelial cell-derived proteins, intestinal epithelial cell-associated components (ECAC), interact with the mast cells of patients with chronic inflammatory bowel disease to trigger the local release of mast cell mediators. Aliquots of human intestinal mucosal mast cell suspensions obtained from surgically resected specimens of colon or small intestine (ulcerative colitis, 12; Crohn's disease, 3; histologically normal controls, 8) were incubated with 1-100 micrograms/ml of colon or small bowel-derived murine ECAC or control kidney protein, or 1 microgram/ml goat anti-human IgE positive control for 30 min at 37 degrees C. Supernatants were analyzed in duplicate for histamine content by fluorometric assay. The median percent total histamine released by chronic inflammatory bowel disease mast cell suspensions to colonic epithelium-derived protein (ECAC-C) was 4% histamine (range 0-20%), such that the distribution of histamine release values in inflammatory bowel disease specimens was significantly different from the distribution of values in mast cells taken from normal mucosa (median 0%, P < 0.05). The median histamine release by all chronic inflammatory bowel disease specimens was also increased in response to the ECAC preparations derived from small bowel epithelium in that a third of the inflammatory bowel disease specimens showed greater than 10% histamine release to ECAC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Regulatory cytokines in inflammatory bowel disease.

Several immunological alterations have been described in inflammatory bowel disease, but their role in the pathogenesis of tissue damage of these disorders is not fully known. Activated immune cells produce proinflammatory and regulatory cytokines able to mediate immune mechanisms underlying intestinal inflammation in both ulcerative colitis and Crohn's disease. Although there is no evidence for an aberrant cytokine secretion in the intestinal mucosa of patients with inflammatory bowel disease, observations seem to indicate that locally released cytokines trigger the preferential differentiation of mucosal lymphocytes into TH1 or TH2 subsets. The unresponsiveness of intestinal mononuclear cells to the inhibiting effects of regulatory cytokines may, also, contribute to this differentiation.

Animals↗
PubMed1996

Immunological abnormality in C3H/HeJ mice with heritable inflammatory bowel disease.

To explore the immunological abnormality of a heritable inflammatory bowel disease developed in a new substrain of C3H/HeJ mice, we examined the expression of integrins beta7 and other cell adhesion molecules on normal and disease mice lymphocytes by flow cytometry. We also examined the cytotoxicity of small intestinal intraepithelial lymphocytes to epithelial cells and the proliferation and aggregation of intestinal lymphocytes. There are several significant changes in the expression levels of alpha4 and alphaM290beta7 integrins, CD11a, ICAM-1, CD45RB, CD4, CD44, and CD45 in different lymphocyte populations. The cytotoxicity of small intestinal intraepithelial lymphocytes from disease mice was higher than that from normal mice and could be stimulated by PHA and inhibited by mAb to alphaM290beta7. The proliferation of both normal and disease small intestinal intraepithelial lymphocytes was enhanced by costimulation by mAb to CD2 or CD3 and ProNectin. In comparison to disease mice, normal small intestinal intraepithelial lymphocytes proliferated at a significantly higher rate in response to sheep RBC and mAb to CD2 or CD3 and ProNectin costimulation. Homotypic aggregation of small intestinal intraepithelial lymphocytes isolated from disease mice was greater than in those from normal mice. The abnormality of expression of integrin beta7 and other cell adhesion molecules and cytotoxic, proliferative, and aggregative responses of lymphocytes from disease mice may play important roles in the pathogenesis of this heritable inflammatory bowel disease.

Animals↗
PubMed2006

Cancer surveillance in inflammatory bowel disease: new molecular approaches.

PURPOSE OF REVIEW: Patients with chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, have an increased risk of colorectal cancer. Life-long colonoscopy surveillance is performed to detect the presence of dysplasia, but this approach is expensive and time-consuming. Thus, there is intensive research to identify molecular factors with prognostic value. This review summarizes recent research, with a special emphasis on the mechanisms underlying these molecular alterations. RECENT FINDINGS: The role of chromosomal instability in the progression to inflammatory bowel disease-associated colorectal cancer is clear and likely relates to chronic cycles of injury, inflammation, repair and telomere shortening. The role of microsatellite instability has been a subject of discussion, and data suggest that microsatellite instability in inflammatory bowel disease might be different from microsatellite instability in sporadic colorectal cancer. Methylation, as a mechanism of gene silencing, also plays a role in ulcerative colitis tumorigenesis. Chronic inflammation has been linked to p53 activation and oxidative stress, contributing to the extensive genomic DNA damage observed in ulcerative colitis. SUMMARY: Improved understanding of the molecular biology of cancer progression in inflammatory bowel disease will hopefully lead to the identification of useful prognostic biomarkers. Efforts are needed to prove the clinical utility of the most promising markers now identified.

Biomarkers, Tumor↗
PubMed2001

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21.

In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.

Alleles↗
PubMed1999

IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease.

There is evidence of a disbalance in the inflammatory regulation of patients with inflammatory bowel diseases (IBD). Interleukin-1 beta plays an important role in the pro-inflammatory response. Our aim was to study the influence which IL1B gene polymorphisms may have on the severity and course of these diseases. Ninety-six patients with ulcerative colitis (UC), 98 patients with Crohn's disease (CD), and 132 ethnically matched healty individuals (HC) were typed for the polymorphic sites in the promoter region (position -511) and in exon 5 (position +3953) of the IL1B gene, using polymerase chain reaction (PCR)-based methods. In the CD group a significant association (P = 0.009) was found in this pair of genes. Homozygotes for allele 1 at position +3953 were more often present (69% vs 31%) in the subgroup of patients carrying at least one copy of allele 2 at position -511. This association was significant in patients with non-perforating disease (P = 0.002), but was not present in patients with perforating-fistulizing disease. The distribution of both allelic pairs in the non-fistulizing group proved to be significantly different from HC (P < 0.05), UC (P < 0.03), and the fistulizing group (P < 0.05). There was a similar association in non-operated patients (P = 0.024), whereas no such association was found in surgically treated patients. Among carriers of allele 2 at position -511, UC patients with more severe bleeding symptoms (P = 0.006) were less frequently found. These results suggest that IL1B gene polymorphisms participate in determining the course and severity of inflammatory bowel disease and contribute to explain the heterogeneity of these diseases.

Adolescent↗
PubMed2001

Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p.

Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 "unknown." Significance at the central peak, corresponding to the genomic location of NOD2, then decreased from 3.2 to 1.2. The maximal lod scores on the proximal p-arm (lod = 2.1) and central q-arm (lod = 2.6) changed only moderately. An exploratory association analysis (TRANSMIT) yielded a strong lead at D16S3068 (P = 0.00028). The region around this marker was further investigated by using anonymous SNPs. An associated haplotype containing three SNPs was identified (peak significance P = 0.00027, IBD phenotype). On stratification based on NOD2 genotype, this significance increased to P = 0.0001. These results confirm the importance of NOD2 and provide evidence for a second IBD gene located on chromosome 16p.

Carrier Proteins↗