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A common CTLA4 haplotype associated with coeliac disease
Karen A Hunt1, Dermot P B McGovern, Parveen J Kumar
1Department of Gastroenterology, Imperial College London, Du Cane Road, London W12 0NN, UK.
European Journal of Human Genetics : EJHG
|January 20, 2005
Summary
Genetic variants in the CTLA4 gene are strongly associated with coeliac disease, suggesting a role for T-cell regulation in this inherited autoimmune disorder. These findings highlight potential genetic factors influencing immune responses to dietary antigens.
Area of Science:
- Immunogenetics
- Gastroenterology
- Autoimmune Diseases
Background:
- Coeliac disease is an inherited enteropathy triggered by gluten, involving T-cell activation.
- Genetic linkage to 2q33 is established, but association studies of candidate genes like CD28/CTLA4/ICOS have yielded inconsistent results.
- CTLA4 (Cytotoxic T-Lymphocyte Associated protein 4) is crucial for regulating T-cell responses, and its variants are linked to other autoimmune conditions.
Purpose of the Study:
- To investigate the association of specific CTLA4 and ICOS gene variants and haplotypes with coeliac disease in a UK Caucasian population.
- To identify genetic markers that may contribute to the inherited risk and pathogenesis of coeliac disease.
Main Methods:
- Genotyping of CTLA4 variants (-1722 C/T, -658 T/C, -318 C/T, +49 A/G, +1822 C/T, CT60 A/G) and an ICOS variant (IVS+173 C/T) in 340 coeliac disease cases and 973 controls.
- Analysis of common CTLA4 haplotypes (>5% frequency).
- Strict case ascertainment requiring villous atrophy and positive serology.
Main Results:
- Weak associations were observed for CTLA4 alleles +1822T (P=0.019) and CT60 G (P=0.047).
- A common CTLA4 haplotype showed a strong association with coeliac disease (P=0.00067, odds ratio 1.41), present in 32.7% of cases versus 25.5% of controls.
- This associated haplotype contains multiple alleles known to influence immune function.
Conclusions:
- A common CTLA4 haplotype is strongly associated with coeliac disease, implicating T-cell regulatory gene variants in its pathogenesis.
- Heritable variations in co-signalling genes regulating T-cell responses may contribute to the loss of tolerance to dietary antigens in coeliac disease.