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J E Lennard-Jones

Publications and source records attributed to J E Lennard-Jones.

At least 19 recordsLinked to original sources
PubMed2001

Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.

Background Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent populations. The recently identified NOD2 gene is a good positional and functional candidate gene since it is located in the region of linkage on chromosome 16q12, and activates nuclear factor (NF) kappaB in response to bacterial lipopolysaccharides. Methods We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls. We then tested for association with Crohn's disease and ulcerative colitis. Findings Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combined p<0.0001); the association was confirmed in the 304 German trios with Crohn's disease. No association was seen in the 115 sibling pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 (95% CI 1.5-4.5) and 42.1 (4.3-infinity), respectively. Interpretation The insertion mutation in the NOD2 gene confers a substantially increased susceptibility to Crohn's disease but not to ulcerative colitis.

Alleles↗
PubMed2001

Fine mapping of the chromosome 3p susceptibility locus in inflammatory bowel disease.

BACKGROUND AND AIMS: Genetic predisposition for inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic linkage studies. Genetic linkage of IBD to chromosome 3 has been observed previously. A high density analysis of chromosome 3p was performed to confirm prior linkages and elucidate potential genetic associations. METHODS: Forty three microsatellite markers on chromosome 3 were genotyped in 353 affected sibling pairs of North European Caucasian extraction (average marker density 2 cM in the linkage interval). Marker order was defined by genetic and radiation hybrid techniques. RESULTS: The maximum single point logarithm of odds (LOD) score was observed for Crohn's disease at D3S3591. Peak multipoint LOD scores of 1.65 and 1.40 for the IBD phenotype were observed near D3S1304 (distal 3p) and near D3S1283 in the linkage region previously reported. Crohn's disease contributed predominantly to the linkage. The transmission disequilibrium test showed significant evidence of association (p=0.009) between allele 4 of D3S1076 and the IBD phenotype (51 transmitted v 28 non-transmitted). Two known polymorphisms in the CCR2 and CCR5 genes were analysed, neither of which showed significant association with IBD. Additional haplotype associations were observed in the vicinity of D3S1076. CONCLUSIONS: This study provides confirmatory linkage evidence for an IBD susceptibility locus on chromosome 3p and suggests that CCR2 and CCR5 are unlikely to be major susceptibility loci for IBD. The association findings in this region warrant further investigation.

Alleles↗
PubMed2000

Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene for association with inflammatory bowel disease.

Genetic linkage analysis in families with multiple cases of inflammatory bowel disease (IBD) has mapped a gene which confers susceptibility to IBD to the pericentromeric region of chromosome 16 (IBD1). The linked region includes the interleukin(IL)-4 receptor gene (IL4R). Since IL-4 regulation and expression are abnormal in IBD, the IL4R gene is thus both a positional and functional candidate for IBD1. We screened the gene for single-nucleotide polymorphisms (SNPs) by fluorescent chemical cleavage analysis, and tested a subset of known and novel SNPs for allelic association with IBD in 355 families, which included 435 cases of Crohn's disease and 329 cases of ulcerative colitis. No association was observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A) and either the Crohn's disease or ulcerative colitis phenotypes using the transmission disequilibrium test. There was also no evidence for association when the four markers were analyzed individually. The results indicate that these variants are not significant genetic determinants of IBD, and that the IL4R gene is unlikely to be IBD1. Linkage disequilibrium analyses showed that the val50ile and gln576arg variants are in complete equilibrium with each other, although they are separated by only about 21 kilobases of genomic DNA. This suggests that a very dense SNP map may be required to exclude or detect disease associations with some candidate genes.

Alleles↗
PubMed2000

Disease outcome in inflammatory bowel disease: mortality, morbidity and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).

BACKGROUND: The course of inflammatory bowel diseases (IBD) has mainly been studied using different methods in single patient cohorts. The aim of the present study was to assess clinical aspects of disease outcome in a population-based cohort of IBD patients over a 4-year period in multiple centres across Europe. METHODS: A total of 796 patients with IBD diagnosed in 10 centres between October 1991 and October 1993, registered at the EC IBD study centre (98% of the original cohort), participated in the study. Investigators filled out a standard follow-up form containing questions on the method of follow-up, vital status of the patient, change in diagnosis, extraintestinal manifestations, medical and surgical treatment, and physician's global assessment of disease activity. RESULTS: Complete relief of the complaints was reported in 255 (48%) patients with ulcerative colitis (UC), 9 (50%) with indeterminate colitis (IC), but only in 87 (35%) of patients with Crohn disease (CD). Improvement was reported in 195 (37%) patients with UC, 113 (45%) with CD and 6 (33%) with IC. During the 4-year follow-up period, 23 patients died (14 UC, 8 CD. and 1 IC). The mean age at death was 69.3 years (s, 14.9 years). The deaths of three patients were recorded as directly due to IBD. CONCLUSIONS: With the present approach to therapeutic management the short-term outcome of patients with IBD seems to be favourable in 10 medical centres in the north and south of Europe. However, more detailed studies including both objective and subjective measures are necessary.

Adult↗
PubMed1999

A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort.

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis-factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes.

Cohort Studies↗
PubMed1999

Linkage of inflammatory bowel disease to human chromosome 6p.

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Given the immunologic dysregulation in IBD, the human-leukocyte-antigen region on chromosome 6p is of significant interest. Previous association and linkage analysis has provided conflicting evidence as to the existence of an IBD-susceptibility locus in this region. Here we report on a two-stage linkage and association analysis of both a basic population of 353 affected sibling pairs (ASPs) and an extension of this population to 428 white ASPs of northern European extraction. Twenty-eight microsatellite markers on chromosome 6 were genotyped. A peak multipoint LOD score of 4.2 was observed, at D6S461, for the IBD phenotype. A transmission/disequilibrium test (TDT) result of P=.006 was detected for D6S426 in the basic population and was confirmed in the extended cohort (P=.004; 97 vs. 56 transmissions). The subphenotypes of Crohn disease, ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting a general role for the chromosome 6 locus in IBD. Analysis of five single-nucleotide polymorphisms in the TNFA and LTA genes did not reveal evidence for association of these important candidate genes with IBD. In summary, we provide firm linkage evidence for an IBD-susceptibility locus on chromosome 6p and demonstrate that TNFA and LTA are unlikely to be susceptibility loci for IBD.

Alleles↗
PubMed1999

Detection of anti-colon antibodies in inflammatory bowel disease using human cultured colonic cells.

BACKGROUND: Investigation of anti-colon antibodies may be simplified if a sensitive method and homogeneous source of antigen were available. AIMS: To examine the anti-colon antibody response using human colonic carcinoma cell lines as antigen. SUBJECTS: Patients with inflammatory bowel disease and other gastrointestinal disorders and healthy controls were studied. METHODS: Comparative enzyme linked immunosorbent assays (ELISAs) were performed to assess the value of whole Caco-2, HT-29, and LS-180 cells as antigen. The antigenic determinants of the immune response were characterised by western blot analysis. RESULTS: Sera demonstrated immunoreactivity against each of the cell lines, but different epitopes were recognised. Applying whole Caco-2 cells as antigen in an ELISA, the prevalence of anti-colon antibodies was significantly greater in patients with ulcerative colitis (36%) than Crohn's disease (13%), other gastrointestinal disorders (13%) and healthy controls (0) (p<0. 05). The immune response was not associated with one predominant antigen. CONCLUSIONS: Fixed whole cell ELISA is a simple and feasible method for studying the anti-colon antibody response. This response is non-specific, being directed against multiple antigens, and is likely to be an epiphenomenon of inflammatory bowel disease, more so for ulcerative colitis than Crohn's disease.

Adolescent↗
PubMed1998

Circulating gastrointestinal hormone abnormalities in patients with severe idiopathic constipation.

OBJECTIVE: This study aimed to determine if there is an abnormality of circulating gastrointestinal hormones in patients with severe idiopathic constipation. METHODS: Twelve patients, all female (median age 34 yr) and 12 healthy controls (eight female, median age 32 yr) were studied. A radioisotope-labeled solid/liquid meal was ingested, and the serum hormone response, as well as the relationship between serum hormones and rates of gastric emptying and small intestinal transit, were studied for 180 min postprandially. RESULTS: Somatostatin levels were higher in patients with constipation (basal level, controls vs patients, 31 vs 57 pmol/L, p < 0.05, median values; peak level, 48 vs 60, p < 0.05). Patients showed a significantly lower somatostatin integrated incremental meal response (2182 vs 104, p < 0.05). No correlation was found between the somatostatin levels and rates of upper gastrointestinal transit in patients. Pancreatic glucagon was significantly decreased (p=0.04). Enteroglucagon levels were significantly lower (p > 0.05) in patients between 30 and 60 min after the meal. The peak found after the meal in normal subjects was absent. Basal levels of pancreatic glucagon correlated with small bowel transit by two different measures: head of meal (r=0.69, p=0.03) and cecal filling at the time of 50% gastric emptying (r=0.84, p=0.002). No significant differences between the two groups could be found for basal and peak levels at different times and integrated incremental response to the meal for insulin, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), gastrin, pancreatic polypeptide (PP), motilin, neurotensin, and peptide tyrosine tyrosine (PYY). CONCLUSION: Patients with severe idiopathic constipation have specific abnormalities of circulating gut hormones that most likely play a role in gastrointestinal motility and that may be of pathophysiological significance.

Acute Disease↗
PubMed1998

Evidence of linkage of the inflammatory bowel disease susceptibility locus on chromosome 16 (IBD1) to ulcerative colitis.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown aetiology which are characterised by chronic inflammation of the gastrointestinal tract. Epidemiological studies suggest the presence of a genetic component in the aetiology of both CD and UC. A susceptibility gene for Crohn's disease has recently been mapped to the pericentromeric region of chromosome 16 (IBD1), and this finding has been replicated in two subsequent studies. Although CD and UC are distinct clinical entities, the fact that both disorders occur in a significant proportion of families with multiple cases of IBD suggests that overlapping sets of susceptibility genes may be involved. We have addressed this question for IBD1 by typing eight microsatellite markers from the locus in 70 kindreds affected with either UC only or with both UC and CD and analysing the data for linkage by both non-parametric and parametric methods. Evidence for linkage was detected in families affected with only UC, with a mean proportion of 0.70 affected sib pairs sharing alleles identical by descent at D16S3136 (p=0.01), and a peak non-parametric linkage score of 2.02 at D16S3120 with the GENEHUNTER program (p=0.02). The estimated sib relative risk attributable to IBD1 in these families was 1.46. Surprisingly, no evidence of linkage was detected in the families affected with both UC and CD (p>0.2). The data suggest that IBD1 may also contribute to susceptibility to ulcerative colitis, and that it is likely to be located in the 12 cM interval between D16S419 and D16S409.

Chromosomes, Human, Pair 16↗
PubMed1997

The fascination of IBD.

Explore the source record for details and available documents.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

Clinical uniformity of inflammatory bowel disease a presentation and during the first year of disease in the north and south of Europe. EC-IBD Study Group.

OBJECTIVE: To compare the methods used for diagnosis and the clinical features of non-specific inflammatory bowel disease (IBD) in the north and south of Europe. DESIGN: A prospective study over 2 years in 1991-3 at eight centres in the north and 12 in the south of Europe using the same criteria for disease definition and same protocol for recording data. SETTING: Specialist gastroenterological centres with good diagnostic facilities at which every effort was made to ascertain all new cases of IBD seen in other departments and primary care in a defined geographical area of known population. PARTICIPANTS: A total of 2201 patients newly diagnosed as suffering from IBD, 1397 with ulcerative colitis (UC), 706 with Crohn's disease (CD) and 116 with indeterminate colitis (IND). RESULTS: Diagnostic methods used were similar in north and south, a biopsy or resection specimen was available for examination in 94 and 95%, of cases of UC and 92 and 87% of CD in north and south, respectively. The type, clinical presentation, site and extent of disease were similar in north and south. Treatment followed a common pattern and mortality from IBD was low in the first year after diagnosis. In both areas, age of onset of UC tended to be later than CD. CONCLUSION: The standard of diagnosis and clinical features of IBD are similar in specialist centres throughout Europe so providing a valid basis for this aspect of collaborative epidemiological or other studies.

Adult↗
PubMed1996

Mapping of a susceptibility locus for Crohn's disease on chromosome 16.

Crohn's disease (CD) and ulcerative colitis are the major forms of chronic inflammatory bowel diseases in the western world, and occur in young adults with an estimated prevalence of more than one per thousand inhabitants. The causes of inflammatory bowel diseases remain unknown, but genetic epidemiology studies suggest that inherited factors may contribute in part to variation in individual susceptibility to Crohn's disease. A genome-wide search performed on two consecutive and independent panels of families with multiple affected members, using a non-parametric two-point sibling-pair linkage method, identified a putative CD-susceptibility locus on chromosome 16 (P less than 0.01 for each panel). The localization was centered around loci D16S409 and D16S419 by using multipoint sibpair analysis (P less than 1.5x10(-5)). This region of the genome contains candidate genes which may be relevant to the pathogenic mechanism of inflammatory bowel diseases.

Alleles↗
PubMed1996

Inflammatory bowel disease in 67 families each with three or more affected first-degree relatives.

BACKGROUND & AIMS: Some families have multiple members with inflammatory bowel disease (IBD). Do clinical features of familial differ from sporadic cases? Is there concordance between affected family members? Do environmental factors affect familial clustering? METHODS: In 67 families, each with three or more first-degree relatives with IBD, the 213 affected family members were interviewed, and their case records were reviewed. RESULTS: The clinical manifestations of familial cases did not differ from IBD reported in a large series. There was concordance for type of disease (P < 0.001) but not greater than expected concordance for age at diagnosis, site and extent of disease, or transmural aggressiveness of Crohn's disease. A significant association between smoking with Crohn's disease and non-smoking with ulcerative colitis was found (P < 0.001), even in families with both disorders. The intervals between diagnosis of successive family cases varied so greatly that a single etiologic factor with a constant latent period seems to be unlikely. When IBD affected successive generations, parents were diagnosed at a later age than the children (P < 0.001) and after the child in 12 of 49 cases. CONCLUSIONS: Analysis has not identified any clinically significant differences between familial and sporadic cases of IBD. Tobacco smoking affects disease type in familial cases.

Adolescent↗