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

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

Edité par CCSD ; Lippincott, Williams & Wilkins -

International audience. 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.

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