Wednesday, July 05, 2006

Alpha-1 Carrier State a Genetic Modifier?

Presentation Time: 10/31/2004 12:30:00 PM
Author Block: Kathleen M. Campbell, Gajra Arya, Frederick C. Ryckman, Maria Alonso, Gregory Tiao, William F. Balistreri, Jorge A. Bezerra, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Purpose: Homozygous alpha-1-antitrypsin (A1AT) deficiency is the most common genetic cause of liver disease in children; however, the role of polymorphic heterogeneity in A1AT as a modifier of other forms of pediatric liver disease has not been explored. Therefore, we designed a study to determine A1AT allele frequencies in a population of pediatric patients with chronic liver disease, and compare these findings with published population-based data. We hypothesized that non-M alleles are more common in patients with chronic liver disease than in the general population.Methods: In this retrospective, single-center study, A1AT phenotypes were obtained by chart review of patients with chronic liver disease followed at the Cincinnati Children’s Hospital Pediatric Liver Care Center. Chi square analysis was used to compare allele frequencies in the liver disease population to published epidemiologic survey data including more than 27,000 individuals in the United States, and to compare allele frequencies among disease subgroups.Results: A1AT phenotypes were available on 264 children with chronic liver disease. Of these, 23 patients with A1AT deficiency (ZZ phenotype) were excluded from analysis. The distribution of A1AT alleles in the remaining 241 patients was significantly different than published population-based data (p<0.001). The differences in distribution were due to an increased frequency of “Z” and “other” alleles in the chronic liver disease population. When this population was divided into subsets, “biliary atresia” (N=67) and “other liver disease” (N=174), the distribution of A1AT alleles remained significantly different than published data for each subset (p<0.001). Among children with “other liver disease”, allele frequencies did not vary between those with long-term survival with native liver and those requiring liver transplantation. In contrast, among biliary atresia patients referred for liver transplant evaluation, the presence of a non-M allele was associated with a lower mean age at transplant listing than the MM phenotype (235 vs. 779 days, p=0.036), and more frequent loss of native liver by 24 months of age (90% vs. 65%, p=0.04).Conclusion: A1AT non-M alleles are more frequent in children with chronic liver disease than in the general population. Among those with biliary atresia, the presence of non-M alleles is highly prevalent in the subgroup with more rapidly progressive disease. We speculate that these non-M alleles may act as genetic modifiers in pediatric liver disease in general, and modulate disease progression in children with biliary atresia in particular.

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