A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon

Klaus Fellermann, Daniel E. Stange, Elke Schaeffeler, Hartmut Schmalzl, Jan Wehkamp, Charles L Bevins, Walter Reinisch, Alexander Teml, Matthias Schwab, Peter Lichter, Bernhard Radlwimmer, Eduard F. Stange

Research output: Contribution to journalArticle

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Abstract

Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. It has been suggested that deficient defensin expression may underlie the chronic inflammation of Crohn disease (CD). The DNA copy number of the beta-defensin gene cluster on chromosome 8p23.1 is highly polymorphic within the healthy population, which suggests that the defective beta-defensin induction in colonic CD could be due to low beta-defensin-gene copy number. Here, we tested this hypothesis, using genomewide DNA copy number profiling by array-based comparative genomic hybridization and quantitative polymerase-chain-reaction analysis of the human beta-defensin 2 (HBD-2) gene. We showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 (range 2-10) HBD-2 gene copies per genome. In a surgical cohort with ileal or colonic CD and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median HBD-2 copy number of 4, whereas those with colonic CD had a median of only 3 copies per genome (P = .008 for the surgical cohort; P = .032 for the second cohort). Overall, the copy number distribution in colonic CD was shifted to lower numbers compared with controls (P = .002 for both the surgical cohort and the cohort with inflammatory bowel diseases). Individuals with ≤3 copies have a significantly higher risk of developing colonic CD than did individuals with ≤4 copies (odds ratio 3.06; 95% confidence interval 1.46-6.45). An HBD-2 gene copy number of <4 was associated with diminished mucosal HBD-2 mRNA expression (P = .033). In conclusion, a lower HBD-2 gene copy number in the beta-defensin locus predisposes to colonic CD, most likely through diminished beta-defensin expression.

Original languageEnglish (US)
Pages (from-to)439-448
Number of pages10
JournalAmerican Journal of Human Genetics
Volume79
Issue number3
DOIs
StatePublished - Sep 2006

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Chromosomes, Human, Pair 8
Colonic Diseases
Gene Dosage
Multigene Family
beta-Defensins
Crohn Disease
Colon
Defensins
Inflammatory Bowel Diseases
Ileal Diseases
Genome
Comparative Genomic Hybridization
DNA
Intestinal Mucosa
human DEFB4A protein
Ulcerative Colitis
Genes
Chromosomes
Odds Ratio
Confidence Intervals

ASJC Scopus subject areas

  • Genetics

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A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. / Fellermann, Klaus; Stange, Daniel E.; Schaeffeler, Elke; Schmalzl, Hartmut; Wehkamp, Jan; Bevins, Charles L; Reinisch, Walter; Teml, Alexander; Schwab, Matthias; Lichter, Peter; Radlwimmer, Bernhard; Stange, Eduard F.

In: American Journal of Human Genetics, Vol. 79, No. 3, 09.2006, p. 439-448.

Research output: Contribution to journalArticle

Fellermann, K, Stange, DE, Schaeffeler, E, Schmalzl, H, Wehkamp, J, Bevins, CL, Reinisch, W, Teml, A, Schwab, M, Lichter, P, Radlwimmer, B & Stange, EF 2006, 'A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon', American Journal of Human Genetics, vol. 79, no. 3, pp. 439-448. https://doi.org/10.1086/505915
Fellermann, Klaus ; Stange, Daniel E. ; Schaeffeler, Elke ; Schmalzl, Hartmut ; Wehkamp, Jan ; Bevins, Charles L ; Reinisch, Walter ; Teml, Alexander ; Schwab, Matthias ; Lichter, Peter ; Radlwimmer, Bernhard ; Stange, Eduard F. / A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. In: American Journal of Human Genetics. 2006 ; Vol. 79, No. 3. pp. 439-448.
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abstract = "Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. It has been suggested that deficient defensin expression may underlie the chronic inflammation of Crohn disease (CD). The DNA copy number of the beta-defensin gene cluster on chromosome 8p23.1 is highly polymorphic within the healthy population, which suggests that the defective beta-defensin induction in colonic CD could be due to low beta-defensin-gene copy number. Here, we tested this hypothesis, using genomewide DNA copy number profiling by array-based comparative genomic hybridization and quantitative polymerase-chain-reaction analysis of the human beta-defensin 2 (HBD-2) gene. We showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 (range 2-10) HBD-2 gene copies per genome. In a surgical cohort with ileal or colonic CD and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median HBD-2 copy number of 4, whereas those with colonic CD had a median of only 3 copies per genome (P = .008 for the surgical cohort; P = .032 for the second cohort). Overall, the copy number distribution in colonic CD was shifted to lower numbers compared with controls (P = .002 for both the surgical cohort and the cohort with inflammatory bowel diseases). Individuals with ≤3 copies have a significantly higher risk of developing colonic CD than did individuals with ≤4 copies (odds ratio 3.06; 95{\%} confidence interval 1.46-6.45). An HBD-2 gene copy number of <4 was associated with diminished mucosal HBD-2 mRNA expression (P = .033). In conclusion, a lower HBD-2 gene copy number in the beta-defensin locus predisposes to colonic CD, most likely through diminished beta-defensin expression.",
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AU - Wehkamp, Jan

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AU - Reinisch, Walter

AU - Teml, Alexander

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AU - Radlwimmer, Bernhard

AU - Stange, Eduard F.

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