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Population-based case-control study of alpha 1-antitrypsin and SLC11A1 in Crohn's disease and ulcerative colitis
Roman Kotlowski1, Charles N Bernstein, Mark S Silverberg
1Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada.
Insights
Genetic variations in Alpha-1 Antitrypsin (AAT) and Soluble Carrier Family 11 Member A1 (SLC11A1) genes are linked to inflammatory bowel diseases like Crohn's disease (CD) and ulcerative colitis (UC). Specific alleles and mutations were associated with increased disease risk.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic digestive tract disorders.
- Genetic predisposition and aberrant immune responses to infections are implicated in IBD pathogenesis.
Purpose of the Study:
- To investigate the association between genetic variations in Alpha-1 Antitrypsin (AAT) and Soluble Carrier Family 11 Member A1 (SLC11A1) genes and the risk of CD and UC.
- To analyze specific AAT alleles (M, S, Z) and SLC11A1 gene polymorphisms in patients with IBD.
Main Methods:
- Genotyping of 300 individuals (100 CD, 100 UC, 100 controls) using PCR and capillary electrophoresis.
- Detection of AAT M, S, Z alleles and SLC11A1 promoter C-to-T transition.
- Evaluation of SLC11A1 (gt)n promoter length polymorphism and 3' UTR insertion/deletion polymorphisms (TGTG, CAAA).
Main Results:
- The AAT Z allele showed a significant association with CD (P < 0.05).
- SLC11A1 alleles 1 and 2 were significantly associated with UC (P < 0.05), while allele 3 was associated with CD (P < 0.05).
- A CAAA insertion in the SLC11A1 3' UTR was significantly associated with CD (P < 0.05).
Conclusions:
- Mutations in AAT and SLC11A1 genes may influence the balance of leukocyte elastase during phagocytosis.
- These genetic factors could play a role in the immune dysregulation observed in inflammatory bowel diseases.
Background:
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the digestive tract. Genetic factors and an abnormal immune response to infections are suspected to be involved in inflammatory bowel diseases.
Methods:
In the present study 300 blood samples from CD patients (n = 100), UC patients (n = 100), and healthy controls (n = 100) were taken from a population-based case-control study. PCR assays and capillary electrophoresis were used to detect alpha 1 antitrypsin M, S, and Z alleles and the C-to-T transition at the -237 nucleotide position of the SLC11A1 promoter. Additionally, length polymorphism of (gt)n alleles in the promoter region and TGTG and CAAA insertion/deletion in the untranslated region (3' UTR) of the SLC11A1 gene were evaluated.
Results:
The Z allele only for AAT was associated (P < 0.05) with CD. No other significant results were detected for AAT alleles. For SLC11A1, alleles 1 and 2 were significant (P < 0.05) for UC, but only allele 3 was significant (P < 0.05) for CD. There was a significant (P < 0.05) association of a CAAA insertion with CD but not for deletion in the 3' UTR. No differences (P < 0.05) were detected for TAAA.
Conclusions:
Because AAT and SLC11A1 proteins directly or indirectly function as inhibitors of human leukocyte elastase, mutations in the AAT and SLC11A1 genes may change the balance between elastase produced by leukocytes during phagocytosis.
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