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Alpha-defensin DEFA1A3 gene copy number elevation in Danish Crohn's disease patients
Cathrine Jespersgaard1, Peder Fode, Marianne Dybdahl
1Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark.
Insights
Higher DEFA1A3 gene copy number is linked to Crohn's disease (CD), suggesting a role in colonic inflammation. Alpha-defensins are involved in CD pathogenesis, with DEFA1A3 copy number potentially impacting inflammatory responses.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- The DEFA1A3 gene exhibits significant copy number variation.
- Alpha-defensins (1-3) are encoded by the DEFA1A3 gene.
Purpose of the Study:
- To investigate the role of alpha-defensins in colonic tissue of Crohn's disease (CD) patients.
- To determine the genetic association between DEFA1A3 and CD.
Main Methods:
- Studied 240 ethnic Danish CD patients.
- Assessed DEFA1A3 expression via RT-PCR and alpha-defensin peptides via immunohistochemistry.
- Compared DEFA1A3, DEFA1, and DEFA3 copy numbers with controls using qPCR and pyrosequencing.
Main Results:
- DEFA1A3 mRNA expression and alpha-defensin peptides were found in colonic tissue, linked to inflammation.
- CD patients showed higher DEFA1A3 (7.2 vs 6.7) and DEFA1 (5.6 vs 5.1) copy numbers compared to controls.
- Increased DEFA1A3 copy number strongly correlated with colonic disease location.
Conclusions:
- Alpha-defensins are implicated in CD inflammation through local expression.
- A high DEFA1A3 copy number is significantly associated with CD, particularly colonic CD.
- Elevated DEFA1A3 copy number may impair normal inflammatory responses in CD.
Background And Purpose Of Study:
Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD.
Methods:
Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location.
Results:
Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001).
Conclusions:
Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.
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