Biomedical subjects

Jochen Hampe

Publications and source records attributed to Jochen Hampe.

60 records · Page 4Linked to original sources

PubMed2002

Mutation detection and physical mapping of the CD11 gene cluster in association with inflammatory bowel disease.

A genetic component in the etiology of inflammatory bowel disease (IBD) has clearly been demonstrated by epidemiological and genetic linkage studies. Linkage to IBD on proximal Chromosome (Chr) 16p is well established and replicated. A stratification experiment showed that the recent identification of a disease gene on the q arm does not interfere with the approach on the p arm, and the linkage peak is still significant. Here we present a candidate gene study of the alpha integrins (CD11A-D) on Chr 16. The alpha integrins play a key role in inflammatory processes, including leukocyte adhesion and migration. Their genes are located on the p arm of Chr 16, and therefore represent excellent positional and functional candidates. Since the assignment of the CD11 genes in the genome was not clear, we performed physical, radiation hybrid, and fluorescent in situ hybridization mapping of the gene family. All CD11 genes map on Chr 16p11-12. CD11B-D are arranged in a gene cluster within 300 kb and CD11A is located about 2.5 Mb telomeric. Thirteen new single nucleotide polymorphisms (SNPs) and eight SNPs from databases were identified through full-length sequencing. Case-control statistics demonstrated an association lead in the CD11 gene cluster, which was not confirmed in further family based association/linkage analyses using single markers and haplotypes. It is unlikely that the CD11 genes play an important role in the pathogenesis of IBD. The marginally significant results could indicate a disease gene in the vicinity of the gene cluster.

CD11 Antigens↗

PubMed2002

Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6.

Inflammatory bowel disease (IBD) is a multifactorial disorder, with both genetic and environmental factors contributing to the two clinical phenotypes of Crohn's disease (CD) and ulcerative colitis (UC). The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus. Several genome-wide linkage studies have identified candidate regions, but there has been little replication across studies. Here we investigate the role of sex-specific loci in susceptibility to IBD. Linkage data from our previously reported genome search and follow-up study were stratified by the sex of the affected sib pair. Non-parametric linkage analysis was performed using Genehunter Plus. Simulation studies were used to assess the significance of differences in LOD scores between male and female families for each chromosome. Several regions of sex-specific linkage were identified, including existing and novel candidate loci. The major histocompatibility region on chromosome 6p, referred to as IBD3, showed evidence of male-specific linkage with a maximum LOD score of 5.9 in both CD and UC male-affected families. Regions on chromosomes 11, 14 and 18 showed strong evidence of linkage in male-affected families but not in female-affected families. No evidence of sex-specific linkage was found in the IBD1 or IBD2 candidate regions of chromosomes 16 and 12. The existence of sex-specific linkage is further evidence of the complex mechanisms involved in IBD and will facilitate future studies to identify susceptibility genes.

Chromosome Mapping↗

PubMed2002

The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.

BACKGROUND & AIMS: Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease. METHODS: Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD- and 337 ulcerative colitis-affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes. RESULTS: R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004). CONCLUSIONS: The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.

Carrier Proteins↗

PubMed2002

Response to infliximab treatment in Crohn's disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials.

Infliximab induces remission in 30-40% of patients with active Crohn's disease. Treatment response is a stable trait over repeated doses yet the clinical predictors of response are still unknown. Recently, three variants in the CARD15 gene have been identified as major genetic risk factors for Crohn's disease. Single nucleotide polymorphisms (SNPs) 8, 12 and 13, have been shown to be independently associated with Crohn's disease susceptibility. The aim of the present study was to investigate these variants in relation to the therapeutic efficacy of infliximab. SNPs were genotyped (TaqMan) in two cohorts ( n= 90 and n= 444 (ACCENT I)) of active Crohn's disease patients (CDAI 220-450). The patients were recruited from independent multicenter trials conducted according to GCP. At the start of both trials, patients received a single infusion of open label infliximab (5 mg/kg bodyweight). The genotypic and allelic frequencies of each SNP were significantly associated with Crohn's disease in comparison to 370 healthy controls as reported previously. Response to infliximab (drop in CDAI 70 points or remission, respectively) was not associated with the genetic variants in the CARD15 gene in either cohort. The subsequent negative findings in a two-cohort model exclude SNPs 8, 12 and 13 of the CARD15 gene as predictors for therapeutic response to infliximab treatment.

Antibodies, Monoclonal↗

PubMed2001

Investigation of HLA-DPA1 genotypes as predictors of inflammatory bowel disease in the German, South African, and South Korean populations.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a polygenic disorder, as demonstrated by epidemiological evidence, genetic linkage, and the identification of the first susceptibility gene, NOD2. Genetic linkage analysis has identified and replicated several genomic regions as locations for susceptibility genes, including chromosome 6p (termed IBD3). The HLA-DP genes play an important role in antigen presentation and are located within the chromosome 6p linkage region. PATIENTS AND METHODS: We investigated HLA-DPA1 as a positional and functional candidate gene for IBD using 249 German multiplex IBD families, 174 unrelated German controls, 48 monoplex families from a mixed South African population, 87 IBD patients, and 71 controls from a South Korean sample. Polymorphisms in exon 2 at amino acid positions 31, 37-38 and 50 were genotyped using direct sequencing. Analyses were performed using chi(2) statistics, multipoint transmission disequilibrium test and nonparametric linkage analysis. RESULTS: A marginally significant association for Crohn's disease was detected in the German family cohort for DPA1*02021. This finding was not replicated in ulcerative colitis or any of the other populations. CONCLUSION: HLA-DPA1 is not a major determinant of IBD risk in any of the three populations. The transmission distortion observed in the German cohort may indicate an extended haplotype, suggesting another disease relevant gene in the vicinity of HLA-DPA.

Case-Control Studies↗

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↗