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Linkage of CD-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBir1 & ASCA, and show reduced NF-kB activation
  1. Hidetoshi Takedatsu (hidetoshi.takedatsu{at}cshs.org)
  1. Cedars-Sinai Medical Center, United States
    1. Kent D Taylor (kent.taylor{at}cshs.org)
    1. Cedars-Sinai Medical Center, United States
      1. Ling Mei (ling.mei{at}cshs.org)
      1. Cedars-Sinai Medical Center, United States
        1. Dermot P. B. McGovern (dermot.mcgovern{at}cshs.org)
        1. Cedars-Sinai Medical Center, United States
          1. Carol J Landers (landersc{at}cshs.org)
          1. Cedars-Sinai IBD Center, United States
            1. Rivkah Gonsky (gonskyr{at}cshs.org)
            1. Cedars-Sinai Medical Center, United States
              1. Yingzi Cong (ycong{at}uab.edu)
              1. University of Alabama, Birmingham, United States
                1. Eric A Vasiliauskas (vasiliauskase{at}cshs.org)
                1. Cedars-Sinai Medical Center, United States
                  1. Andrew Ippoliti (andrew.ippoliti{at}cshs.org)
                  1. Cedars-Sinai Medical Center, United States
                    1. Charles O Elson (coelson{at}uab.edu)
                    1. University of Alabama, Birmingham, United States
                      1. Jerome I Rotter (jerome.rotter{at}cshs.org)
                      1. Cedars-Sinai Medical Center, United States
                        1. Stephan R Targan (targans{at}cshs.org)
                        1. Cedars-Sinai Medical Center, United States

                          Abstract

                          Background & Aims: Genetic 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 ELISA and a standard ~10cM whole genome microsatellite study was conducted. SNP genotyping was performed using either Illumina or TaqMan MGB technology. NFKB1 activation in cells from EBV-transformed cell lines was assessed using EMSA and protein was measured using ELISA and Western blotting.

                          Results: Evidence for linkage to anti-CBir1 expression was detected on human chromosome 4 (LOD 1.82 at 91cM). 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 CD patients with either H1 or H3, NF-κB activation and NFKB1 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 NFKB1 expression. The results also show the use of EBV-transformed lymphoblastoid cell lines to conduct phenotypic studies of genetic variation.

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