The PNPLA3 rs738409 variant can increase the risk of liver toxicity in multiple sclerosis patients treated with beta-interferon

Background: Liver toxicity can limit the use of interferon-beta (IFNβ), a well-established treatment for multiplesclerosis (MS). Unfortunately, known risk-factors for IFNβ-associated liver toxicity are few and of limited clinicalutility. Susceptibility to drug-induced toxicity is influenced by genetic factors affecting hepatic lipid metabolism and drug-metabolizing activity.Methods: We designed a retrospective, multicentre study to evaluate whether specific polymorphisms in genesinvolved in hepatic lipid metabolism are associated with a higher risk of developing IFNβ-induced hepatotoxicity.The following single nucleotide polymorphisms were examined: rs738409 C > G in PNPLA3; rs4880 C > T inSOD2; rs3750861 C > T in KLF6; rs13412852 C > T in LPIN1; rs58542926 C > T in TM6SF2. Liver toxicity wasdefined as a new increase of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) plasmalevels above the laboratory upper normal limit after the start of IFNβ treatment.Results: One-hundred-thirteen MS patients were enrolled and twenty-nine experienced liver toxicity. Logisticregression analysis revealed that the PNPLA3 variant was significantly associated with the occurrence of livertoxicity. No associations were found between other polymorphisms and liver toxicity.Conclusions: The results of our exploratory study suggest that the PNPLA3 variant can help to identify thosepatients at higher risk of IFNβ toxicity. The stratification of the risk of liver toxicity could increase the safety ofIFNβ therapy.