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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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.