Polymorphism in the endoplasmic reticulum mannosidase I (MAN1B1) gene is not associated with liver disease in individuals homozygous for the Z variant of the alpha1-antitrypsin protease inhibitor (PiZZ individuals)
Authors: Sally Chappell, Tamar Guetta-Baranés, Nedim Hadzic, Robert Stockley, Noor Kalsheker
Journal: Hepatology (2009)

In a recent issue of HEPATOLOGY, Pan et al. reported an increased frequency of the rs4567 AA genotype in infants homozygous for the Z variant of the alpha1-antitrypsin protease inhibitor ("PiZZ infants") who developed end-stage liver disease before the age of 2 years.1 In order to confirm their findings, we determined the genotype at rs4567 in our collection of samples from PiZZ children with moderate to severe liver disease (n = 42), as well as a selection of samples from PiZZ adult individuals with chronic obstructive pulmonary disease (COPD), in whom established liver disease had been excluded (n = 115). Recruitment criteria for these groups have been described.2 The genotype for rs4567 was determined using polymerase chain reaction followed by restriction digestion with Bsu36I. Genotypes were independently assigned by two investigators, and samples of each genotype were sequenced to confirm that the assay was working correctly. All of the genotyping results were shown to be in Hardy-Weinberg equilibrium. Genotype frequencies were compared in the two groups, using a chi-squared test. The results of this analysis are shown in Table 1. In contrast to the study by Pan et al., our results clearly indicate that there is no difference in genotype frequency between those PiZZ individuals with liver disease compared to those who have no evidence of liver dysfunction. These genotype frequencies are also similar to those reported in the HapMap Caucasian population (0.28, 0.57, and 0.15 for AA, AG, and GG, respectively). In the original publication, the increased frequency of the AA genotype was observed in a group of 10 children who had undergone liver transplantation. The equivalent group in our study is the severe disease group (n = 18), who had a median age of presentation of 0.22 years, ranging from 0.11-0.79 years. There was no significant difference in genotype frequencies in this group compared to the patients with moderate disease (P = 0.148). Although our results indicate that this polymorphism is unlikely to play a role in the development of liver disease in PiZZ children, selection criteria for liver transplants vary in different centers, and this may account for the discrepant results reported in the two studies. Although deficiency of alpha-1 antitrypsin is the principal indication for liver transplantation in children, the low frequency means that genetic studies in these groups are necessarily small and likely to be underpowered. This makes it difficult to identify other genetic contributions to disease, and it means that replication studies are essential. The possibility of combining resources to increase sample size may be a preferred option for future studies. Sally Chappell*, Tamar Guetta-Baranés*, Nedim Hadzic , Robert Stockley , Noor Kalsheker*, * School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK, Department of Child Health and Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, London, UK, Lung Investigation Unit, First Floor, Nuffield House, Queen Elizabeth Hospital, Birmingham, UK.