Reply:

Abstract

We would like to thank Chappel et al. for their genuine interest in our published study. While it is unfortunate that their experimental design failed to confirm our results, several differences between the two studies should be considered as well as an apparent misunderstanding about our central conclusion. It was never our intention to suggest that a polymorphism in the endoplasmic reticulum mannosidase I gene plays a role in the development of liver disease that sometimes occurs in PiZZ patients (individuals who are homozygous for the Z variant of alpha1-antitrypsin protease inhibitor). Rather, our conclusion was that the nucleotide polymorphism functions as a modifier of the disorder by accelerating the onset of the end-stage liver disease, the latter of which is caused by an unknown primary defect.1 In terms of the comparative statistical analyses, unfortunately no consistent definition exists between their designation of “severe liver disease” and our terminology of “end-stage liver disease.” Also, both the age range and median age at the time of liver transplantation seem to indicate that severity of liver disease among members of their study population is less dramatic than the patients examined in our study set. As they note, differences in selection criteria and transplant delivery rates between clinics could impact the members of each study population, making an accurate comparison between the two data sets difficult. Chappel et al. correctly point out, as we also noted in our publication,1 that our sample size was necessarily small, rendering the legitimacy of statistical analysis somewhat uncertain. Unfortunately, the population studied by Chappel et al. was of a similar size, which likewise questions the validity of their conclusion. Finally, it is noteworthy that our cognizance of statistical limitations led to the inclusion in our publication1 of complementary functional studies, which are widely perceived as the “gold standard” for candidate single-nucleotide polymorphism validation. Importantly, these results strengthened our conclusion by providing a mechanistic explanation for a key observation that had been made by the members of Dr. David Perlmutter's group.2 The inclusion of functional studies in combination with the enhanced mechanistic insight led to the recent inclusion of our publication in the Editors' Choice column of the journal Science.3 Shujuan Pan*, Richard N. Sifers*, * Department of Pathology, Baylor College of Medicine, Houston, TX.