BACKGROUND/AIMS: Chronic liver disease is a well-recognised complication of cystic fibrosis. Recent reports suggest that its development is not determined by specific mutations within the cystic fibrosis gene; however, familial clustering of portal hypertension cases and inappropriate immune responses against liver membrane antigens demonstrated in children with cystic fibrosis and chronic liver disease suggest that other genetic loci may be relevant. As the major histocompatibility complex has an important immunoregulatory role, we have investigated for associations with this complex and chronic liver disease in cystic fibrosis. METHODS: We have determined human leucocyte antigen class I (A and B) and class II (DR) phenotypes by serological tissue typing and class II (DR and DQ) and class III (complement component C4 and 21-hydroxylase) gene polymorphisms in 274 children and young adults with cystic fibrosis, of whom 82 had evidence of chronic liver disease with portal hypertension in 49, and 146 healthy controls. RESULTS: A marked difference in human leucocyte antigen frequency was limited to DQ6, which was found in 66.7% of cystic fibrosis patients with liver disease compared to 32.9% of patients with no liver disease (Pc < 0.03) and 28.8% of controls (Pc < 0.006). An increased frequency of the two antigens in strong linkage disequilibrium with DQ6 was also observed within this patient group, namely DR15 and B7. When the patients were stratified for the presence of portal hypertension, these observations were confirmed, but the human leucocyte antigen associations were significant only for male patients and there was no association with the age of onset of liver disease. CONCLUSIONS: These data suggest that the haplotype B7-DR15-DQ6 may carry an increased risk of development of liver disease in male cystic fibrosis patients.
BACKGROUND/AIMS: Chronic liver disease is a well-recognised complication of cystic fibrosis. Recent reports suggest that its development is not determined by specific mutations within the cystic fibrosis gene; however, familial clustering of portal hypertension cases and inappropriate immune responses against liver membrane antigens demonstrated in children with cystic fibrosis and chronic liver disease suggest that other genetic loci may be relevant. As the major histocompatibility complex has an important immunoregulatory role, we have investigated for associations with this complex and chronic liver disease in cystic fibrosis. METHODS: We have determined human leucocyte antigen class I (A and B) and class II (DR) phenotypes by serological tissue typing and class II (DR and DQ) and class III (complement component C4 and 21-hydroxylase) gene polymorphisms in 274 children and young adults with cystic fibrosis, of whom 82 had evidence of chronic liver disease with portal hypertension in 49, and 146 healthy controls. RESULTS: A marked difference in human leucocyte antigen frequency was limited to DQ6, which was found in 66.7% of cystic fibrosispatients with liver disease compared to 32.9% of patients with no liver disease (Pc < 0.03) and 28.8% of controls (Pc < 0.006). An increased frequency of the two antigens in strong linkage disequilibrium with DQ6 was also observed within this patient group, namely DR15 and B7. When the patients were stratified for the presence of portal hypertension, these observations were confirmed, but the human leucocyte antigen associations were significant only for male patients and there was no association with the age of onset of liver disease. CONCLUSIONS: These data suggest that the haplotype B7-DR15-DQ6 may carry an increased risk of development of liver disease in male cystic fibrosispatients.