A Particular SORL1 Micro-haplotype May Prevent Severe Liver Disease in a French Cohort of Alpha 1-Antitrypsin-deficient Children

Philippe Joly, Mathias Ruiz, Roman Garin, Esra Karatas, Alain Lachaux, Lioara Restier, Abdelouahed Belmalih, Céline Renoux, Christine Lombard, Magali Dechomet, Marion Bouchecareilh, Philippe Joly, Mathias Ruiz, Roman Garin, Esra Karatas, Alain Lachaux, Lioara Restier, Abdelouahed Belmalih, Céline Renoux, Christine Lombard, Magali Dechomet, Marion Bouchecareilh

Abstract

The presence of modifier genes is now well recognized in severe liver disease outcome associated with alpha-1-antitrypsin deficiency (A1ATD) but their identification remains to be fully elucidated. To address this goal, we performed a candidate gene study with the SORL1 gene, already identified as risk gene in early-onset Alzheimer Disease families. A particular SORL1 micro-haplotype constituted with 3 SNPs (wild-type form TTG) was genotyped on 86 ZZ A1ATD children issued from 66 families. Interestingly, the mutated forms of this micro-haplotype (CAT most of the time) were associated with lower occurrence of severe liver disease and in cellulo studies showed that SORL1 influences Z-A1ATD cellular toxicity and biogenesis. These data suggest that the mutated CAT form of SORL1 micro-haplotype may partly prevent from severe liver disease in A1ATD children. Overall, these findings support a replication study on an independent cohort and additional in cellulo studies to confirm these promising results.

Trial registration: ClinicalTrials.gov NCT01862211.

Conflict of interest statement

The authors report no conflicts of interest.

Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

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Source: PubMed

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