Anti-Saccharomyces cerevisiae antibody (ASCA) positivity is associated with increased risk for early surgery in Crohn's disease.

BACKGROUND: Anti-Saccharomyces cerevisiae antibodies (ASCA) are a specific but only moderately sensitive diagnostic marker for Crohn's disease. We sought to explore the role of ASCA as a prognostic marker for aggressive disease phenotype in Crohn's disease. AIMS: To determine the role of ASCA status as a risk factor for early surgery in Crohn's disease. SUBJECTS: We performed a case control study in a cohort of patients, newly diagnosed with Crohn's disease, between 1991 and 1999. All patients were followed for at least three years. Case subjects (n = 35) included those who had major surgery for Crohn's disease within three years of diagnosis. Controls (n = 35) included patients matched to cases for age, sex, disease location, and smoking status, and who did not undergo major surgery for Crohn's disease within three years of diagnosis. METHODS: Blinded assays were performed on serum for ASCA (immunoglobulin (Ig)A and IgG). A paired analysis of cases-controls was performed to test for the association between ASCA status and risk of early surgery. RESULTS: ASCA IgA was strongly associated with early surgery (odds ratio (OR) 8.5 (95% confidence interval (CI) 2.0-75.9); p = 0.0013). ASCA IgG+ and ASCA IgG+/IgA+ patients were also at increased risk for early surgery (OR 5.5 (95% CI 1.2-51.1), p = 0.0265; and OR 5.0 (95% CI 1.1-46.9), p = 0.0433, respectively). The association between ASCA and early surgery was evident in patients requiring surgery for ileal or ileocolonic disease. CONCLUSIONS: Patients with Crohn's disease who are positive for ASCA IgA, IgG, or both, may define a subset of patients with Crohn's disease at increased risk for early surgery.

Genetic susceptibility to breast cancer: HLA DQB*03032 and HLA DRB1*11 may represent protective alleles.

Tumors are believed to emerge only when immune surveillance fails. We wished to ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer. We molecularly typed HLA DPB1, DQB1, DRB1, and DRB3 alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB*03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P = 0.0001). HLA DRB1*11 alleles were also significantly overrepresented (P < 0.0001) in controls (16. 3%) as compared with patients with early-onset breast cancer (3.5%). HLA DQB*03032 and HLA DRB1*11 alleles may have a protective role in human breast cancer.

Analysis of MHC class II DP, DQ and DR alleles in Crohn's disease.

BACKGROUND: Although inflammation in Crohn's disease is believed to be mediated by activated T cells, genotyping of all MHC class II alleles in white people with this disease has not been reported. AIMS: To perform a detailed molecular analysis of HLA DPB, DQB, and DRB genes in white patients with Crohn's disease and controls in order to determine if the inheritance of any class II genes confers susceptibility or resistance to this disease. METHODS: Complete molecular typing of HLA class II DPB, DQB, and DRB alleles was performed in 58 white patients with Crohn's disease and 93 healthy controls using a polymerase chain reaction-sequence specific oligonucleotide based approach. RESULTS: No significant association with any DPB or DQB alleles was noted in patients with Crohn's disease. Since our previous studies had shown a strong association of an HLA DRB3*0301/DRB1*1302 haplotype with Crohn's disease, we re-examined this association using more stringent genotyping criteria. This haplotype was present in 20.7% of patients and 5.4% of controls (p = 0.0066; relative risk = 4.59). CONCLUSIONS: The DRB3*0301/DRB1*1302 haplotype is the only significant MHC class II association noted in white people with Crohn's disease and represents the strongest association of any MHC or non-MHC locus with this disease.

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele.

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.