MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis

Abstract

The clinical picture of autoimmune hepatitis (AIH) varies markedly between patients, potentially due to genetic modifiers. The aim of this study was to evaluate genetic variants previously associated with fatty liver as potential modulators of the AIH phenotype. The study cohort comprised 313 non-transplanted adults with AIH. In all patients, the MARC1 (rs2642438), HSD17B13 (rs72613567), PNPLA3 (rs738409), TM6SF2 (rs58542926), and MBOAT7 (rs641738) variants were genotyped using TaqMan assays. Mitochondrial damage markers in serum were analyzed in relation to the MARC1 variant. Carriers of the protective MARC1 allele had lower ALT and AST (both P < 0.05). In patients treated for AIH for ≥ 6 months, MARC1 correlated with reduced AST, ALP, GGT (all P ≤ 0.01), and lower APRI (P = 0.02). Patients carrying the protective MARC1 genotype had higher total antioxidant activity (P < 0.01) and catalase levels (P = 0.02) in serum. The PNPLA3 risk variant was associated with higher MELD (P = 0.02) in treated patients, whereas MBOAT7 increased the odds for liver cancer (OR = 3.71). None of the variants modulated the risk of death or transplantation. In conclusion, the MARC1 polymorphism has protective effects in AIH. Genotyping of MARC1, PNPLA3, and MBOAT7 polymorphisms might help to stratify patients with AIH.

MTARC1 and HSD17B13 Variants Have Protective Effects on Non-Alcoholic Fatty Liver Disease in Patients Undergoing Bariatric Surgery

“…The second protective variant, MTARC1, was shown to have beneficial effects on hepatic steatosis and cirrhosis and to correlate with improved plasma liver tests and lipoprotein profile [12]. Our candidate gene study demonstrated the protective effects of MTARC1 p.A165T polymorphism on liver injury in patients with autoimmune hepatitis (AIH) [13]. A brief report from Luukkonen et al highlighted that individuals carrying the minor allele of the MTARC1 p.A165T polymorphism are characterized by higher blood phosphatidylcholine levels and decreased parameters of NAFLD severity as compared to carriers of the wildtype MTARC1 genotype [14].…”

The clinically relevant MTARC1 p.Ala165Thr variant impacts neither the fold nor active site architecture of the human mARC1 protein

“…A protective effect of the mARC1 p.Ala165Thr variant against liver disease and changes to lipid metabolism were first published in 2020 by Emdin et al . (Emdin et al ., 2020, Emdin et al ., 2021) and has since been confirmed by the work of other groups in additional studies (Luukkonen et al ., 2020, Mann et al ., 2020, Parisinos et al ., 2020, Gao et al ., 2021, Ghodsian et al ., 2021, Janik et al ., 2021). It has consequently been suggested, that mARC1 could present a target for future NALFD or NASH therapies (Bianco et al ., 2021).…”

Association of MARC1, ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men

“…Previously, the MARC1 gene has been associated with protection for all-cause cirrhosis and lower blood hepatic enzyme levels [ 9 , 27 , 28 ]. In this study, we did not find a significant association with hepatic enzymes (data not shown).…”