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HLA phenotypes and gene polymorphisms in juvenile liver disease associated with alpha 1-antitrypsin deficiency
D G Doherty1, P T Donaldson, D B Whitehouse
1Department of Child Health, King's College Hospital Medical School, London, United Kingdom.
Insights
The human leukocyte antigen (HLA) DR3-Dw25 gene is associated with chronic liver disease in individuals with alpha 1-antitrypsin deficiency (PiZZ genotype). However, other genetic factors likely contribute to liver damage pathogenesis.
Area of Science:
- Genetics
- Immunology
- Hepatology
Background:
- Chronic liver disease affects up to 20% of children with alpha 1-antitrypsin deficiency (PiZZ genotype).
- Familial occurrence and abnormal immune responses suggest immunoregulatory genes' involvement in liver damage.
- Human leukocyte antigen (HLA) phenotypes and class II (HLA-DR) gene polymorphisms are investigated in PiZZ subjects.
Purpose of the Study:
- To identify HLA phenotypes and class II (HLA-DR) gene polymorphisms associated with liver disease in PiZZ individuals.
- To investigate the role of specific HLA-DR alleles and polymorphisms in the pathogenesis of liver damage.
Main Methods:
- Genotyping of HLA phenotypes and HLA-DR gene polymorphisms in 140 white PiZZ subjects (92 with liver disease) and 206 relatives.
- Southern blot analysis using HLA-DRB and DQB DNA probes to identify DR3 polymorphisms.
- Segregation analysis of HLA haplotypes in 77 families.
Main Results:
- The HLA DR3* phenotype was significantly more frequent in PiZZ individuals with liver disease (46.7%) compared to those without (17.8%) and controls (p<0.01).
- HLA DR4 was increased in PiZZ individuals without liver disease (60.7%) compared to those with liver disease (38.7%) and controls (p<0.05).
- A specific DR3 polymorphism, Dw25, was elevated in PiZZ individuals with liver disease (16.4%) compared to those without (4.4%) and controls (3.9%) (p<0.05).
Conclusions:
- The HLA DR3-Dw25 allele is associated with liver disease in alpha 1-antitrypsin deficiency (PiZZ genotype).
- No direct HLA haplotype concordance for liver disease was found in affected sibships, indicating other pathogenic factors.
- Further research is needed to elucidate the complete genetic basis of liver damage in alpha 1-antitrypsin deficiency.
Abstract:
Chronic liver disease affects up to 20% of children with alpha 1-antitrypsin deficiency owing to the PiZZ genotype. Previous observations of a familial occurrence and abnormal immune responses to liver antigens in these patients suggests that immunoregulatory genes may be involved in the pathogenesis of liver damage. We have identified HLA phenotypes and class II (HLA-DR) gene polymorphisms in 140 white PiZZ subjects, of whom 92 (83 index patients) had liver disease, and 206 first-degree relatives. DR3* was present in 35 of 75 (46.7%) unrelated patients with liver disease compared with 5 of 28 (17.8%) patients without (p less than 0.01) and 23 of 100 controls (p less than 0.001). DR4 was increased in patients without liver disease; it was present in 17 of 28 (60.7%) compared with 29 of 75 (38.7%) patients with liver disease (p less than 0.05) and 36 of 100 controls (p less than 0.025). Using Southern blot analysis with HLA-DRB and DQB DNA probes, we identified two polymorphisms of DR3, only one (Dw25) of which is raised in PiZZ individuals with liver disease (9 of 55: 16.4%) compared with 1 of 23 (4.4%) without and 2 of 52 (3.9%) controls (p less than 0.05). Analysis of the segregation of HLA haplotypes in 77 families revealed no concordance for liver disease with HLA in those with affected sibships, indicating that, although DR3-Dw25 is associated with liver disease in alpha 1-antitrypsin deficiency, other factors must play a pathogenic role.