Linkage of Crohn's disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBiri and ASCA, and show reduced NF-κB activation

H. Takedatsu, K. D. Taylor, L. Mei, D. P B McGovern, C. J. Landers, R. Gonsky, Yingzi Cong, E. A. Vasiliauskas, A. Ippoliti, C. O. Elson, J. I. Rotter, S. R. Targan

Research output: Contribution to journalArticle

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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-12, 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.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalGut
Volume58
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

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NF-kappa B
Crohn Disease
Haplotypes
Phenotype
Transformed Cell Line
Human Herpesvirus 4
Antigens
Chromosomes, Human, Pair 4
Antibodies
Human Chromosomes
Electrophoretic Mobility Shift Assay
Enzymes
Innate Immunity
Microsatellite Repeats
Single Nucleotide Polymorphism
Western Blotting
Genome
Technology
Cell Line
Serum

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Takedatsu, H., Taylor, K. D., Mei, L., McGovern, D. P. B., Landers, C. J., Gonsky, R., ... Targan, S. R. (2009). Linkage of Crohn's disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBiri and ASCA, and show reduced NF-κB activation. Gut, 58(1), 60-67. https://doi.org/10.1136/gut.2008.156422

Linkage of Crohn's disease-related serological phenotypes : NFKB1 haplotypes are associated with anti-CBiri and ASCA, and show reduced NF-κB activation. / Takedatsu, H.; Taylor, K. D.; Mei, L.; McGovern, D. P B; Landers, C. J.; Gonsky, R.; Cong, Yingzi; Vasiliauskas, E. A.; Ippoliti, A.; Elson, C. O.; Rotter, J. I.; Targan, S. R.

In: Gut, Vol. 58, No. 1, 01.2009, p. 60-67.

Research output: Contribution to journalArticle

Takedatsu, H, Taylor, KD, Mei, L, McGovern, DPB, Landers, CJ, Gonsky, R, Cong, Y, Vasiliauskas, EA, Ippoliti, A, Elson, CO, Rotter, JI & Targan, SR 2009, 'Linkage of Crohn's disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBiri and ASCA, and show reduced NF-κB activation', Gut, vol. 58, no. 1, pp. 60-67. https://doi.org/10.1136/gut.2008.156422
Takedatsu, H. ; Taylor, K. D. ; Mei, L. ; McGovern, D. P B ; Landers, C. J. ; Gonsky, R. ; Cong, Yingzi ; Vasiliauskas, E. A. ; Ippoliti, A. ; Elson, C. O. ; Rotter, J. I. ; Targan, S. R. / Linkage of Crohn's disease-related serological phenotypes : NFKB1 haplotypes are associated with anti-CBiri and ASCA, and show reduced NF-κB activation. In: Gut. 2009 ; Vol. 58, No. 1. pp. 60-67.
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AU - Taylor, K. D.

AU - Mei, L.

AU - McGovern, D. P B

AU - Landers, C. J.

AU - Gonsky, R.

AU - Cong, Yingzi

AU - Vasiliauskas, E. A.

AU - Ippoliti, A.

AU - Elson, C. O.

AU - Rotter, J. I.

AU - Targan, S. R.

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N2 - 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-12, 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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