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Linkage of Crohn’s disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBir1 and ASCA, and show reduced NF-κB activation
  1. H Takedatsu1,
  2. K D Taylor2,
  3. L Mei2,
  4. D P B McGovern1,
  5. C J Landers1,
  6. R Gonsky1,
  7. Y Cong3,
  8. E A Vasiliauskas1,
  9. A Ippoliti1,
  10. C O Elson3,
  11. J I Rotter2,
  12. S R Targan1
  1. 1
    Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
  2. 2
    Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  3. 3
    Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama, USA
  1. Dr S R Targan, Division of Gastroenterology, Inflammatory Bowel Disease Center and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles, CA 90048, USA; targans{at}cshs.org

Abstract

Background and aims: Genetics studies of the serum expression of antibodies to microbial antigens may yield important clues to the pathogenesis of Crohn’s disease. Our aim was to conduct a linkage study using expression of anti-CBir1, anti-I2, anti-OmpC and ASCA as quantitative traits.

Methods: Expression of antibodies to microbial antigens was measured by enzyme-linked immunosorbant assay (ELISA) and a standard ∼10 cM whole genome microsatellite study was conducted. Single nucleotide polymorphism genotyping was performed using either Illumina or TaqMan MGB technology. Nuclear factor Kappa B (NF-κB) activation in cells from Epstein–Barr virus (EBV)-transformed cell lines was assessed using an electrophoretic mobility shift assay and protein was measured using ELISA and western blotting.

Results: Evidence for linkage to anti-CBir1 expression was detected on human chromosome 4 (logarithm of odds (LOD) 1.82 at 91 cM). We therefore directly proceeded to test the association of haplotypes in NFKB1, a candidate gene. One haplotype, H1, was associated with anti-CBir1 (p = 0.003) and another, H3, was associated with ASCA (p = 0.023). Using cell lines from Crohn’s disease patients with either H1 or H3, NF-κB activation and NF-κB p105 and p50 production were significantly lower for patients with H1 compared to patients with H3.

Conclusions: These results suggest that NFKB1 haplotypes induce dysregulation of innate immune responses by altering NF-κB expression. The results also show the use of EBV-transformed lymphoblastoid cell lines to conduct phenotypic studies of genetic variation.

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Footnotes

  • Funding: Supported by USPHS Grants PO1DK071176 and PO1DK046763, the Feintech Chair in Inflammatory Bowel Disease (SRT) and the Cedars-Sinai Board of Governor’s Chair in Medical Genetics (JIR). Genotyping was supported in part by M01-RR00425 to the Cedars-Sinai GCRC genotyping core (KDT).

  • Competing interests: None.

  • Ethics approval: Ethics approval for the study was given by the Cedars-Sinai Institutional Review Board on 1 January 2008.

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