THE MAJOR HISTOCOMPATIBILITY COMPLEX INFLUENCES THE DEVELOPMENT OF CHRONIC LIVER-DISEASE IN MALE-CHILDREN AND YOUNG-ADULTS WITH CYSTIC-FIBROSIS

Background/Aims: Chronic liver disease is a well-recognised complicati on 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 inapprop riate 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 co mplex has an important immunoregulatory role, we have investigated for associations with this complex and chronic liver disease in cystic fi brosis. 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 IU (complement component C4 and 21-hydr oxylase) gene polymorphisms in 274 children and young adults with cyst ic fibrosis, of whom 82 had evidence of chronic liver disease with por tal hypertension in 49, and 146 healthy controls. Results: A marked di fference in human leucocyte antigen frequency was limited to DQ6, whic h was found in 66.7% of cystic fibrosis patients with liver disease co mpared 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 p atient group, namely DR15 and B7, When the patients were stratified fo r the presence of portal hypertension, these observations were confirm ed, 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 B 7-DR15-DQ6 may carry an increased risk of development of liver disease in male cystic fibrosis patients. (C) Journal of Hepatology.