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. 2025 Jan 16;17(1):6.
doi: 10.1186/s13148-024-01803-x.

Epigenetic age acceleration and methylation differences in IgG4-related cholangitis and primary sclerosing cholangitis

Alexandra Noble #  1 , Rodrigo Motta #  1 , Silvia Cabras  1 , Belen Moron Flores  1 , Jan Nowak  2 , Aleksandra Glapa-Nowak  2 , Alessandra Geremia  1 , Jack Satsangi #  3   4 , Emma Culver #  1
Affiliations

Epigenetic age acceleration and methylation differences in IgG4-related cholangitis and primary sclerosing cholangitis

Alexandra Noble et al. Clin Epigenetics. .

Abstract

Background: IgG4-related cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC) are chronic fibro-inflammatory hepatobiliary conditions, with genetic, environmental, and immunologic risk factors, in which epigenetic alterations may provide insights into pathophysiology and novel biomarkers. This study is the first to assess methylation signatures in IgG4-SC.

Results: Whole blood DNA methylation profiling and genotyping was performed in 264 individuals; 47 with IgG4-SC, 65 with PSC, 64 with ulcerative colitis (UC), and 88 healthy controls. We identified 19 significant methylation differences between IgG4-SC and controls and 38 between PSC and controls. IgG4-SC and PSC shared 8 probes. Inflammatory genes (including CEP97, IFNAR1, TXK, HERC6, C5orf36, PYY, and MTRNR2L1) were predominantly involved in dysregulated methylation. Epigenetic age acceleration was observed in patients with IgG4-SC, but not in those with PSC or UC. meQTL analyses to identify genetic determinants of methylation revealed a strong human leucocyte antigen (HLA) signal in both PSC and IgG4-SC (HLA-DQB2, HLA-DPA1, HLA-F and HLA-DRA).

Conclusions: We identify novel epigenetic alterations in IgG4-SC and PSC, with biological age acceleration in IgG4-SC, providing insights into disease pathogenesis, and highlight the role of genetic variation especially within the HLA region in shaping the methylome.

Keywords: Age acceleration; DNA methylation; Epigenetic clock; HLA; IgG4-RD; Infinium Methylation EPIC arrays; PSC.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Ethical approval for the study was obtained from the Research Ethics Committee Oxfordshire (10/H0604/51) and the Oxford Radcliffe Biobank (19/SC/0173). Competing interests: EC provides educational material and consults for Amgen (Horizon Therapeutics), Zenus BioPharma, Falk Pharma, Ipsen, Mirum, Intercept, Advance Therapeutics and Moderna. JS has received lecture fees from Takeda and from the Falk Foundation.

Figures

Fig. 1
Fig. 1
EWAS Manhattan plot of differentially methylated probes in patients with IgG4-SC compared to healthy controls
Fig. 2
Fig. 2
EWAS Manhattan plot showing differently methylated positions in patients with PSC when compared to healthy controls
Fig. 3
Fig. 3
Epigenetic ageing estimated using Horvath’s Clock. A Correlation between expected epigenetic age and chronological age; B age acceleration distribution in each group (bars represent SD and bold lines inside the box plot median levels). Levels of significance: ***p = 0.001; using Kruskal–Wallis test
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References

    1. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15:505–22. - PMC - PubMed
    1. Fernandes Q, Inchakalody VP, Bedhiafi T, et al. Chronic inflammation and cancer; the two sides of a coin. Life Sci. 2024;338: 122390. - PubMed
    1. Schiattarella GG, Alcaide P, Condorelli G, et al. Immunometabolic mechanisms of heart failure with preserved ejection fraction. Nat Cardiovas Res. 2022;1:211–22. - PMC - PubMed
    1. Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023;8:239. - PMC - PubMed
    1. Rabiee A, Silveira MG. Primary sclerosing cholangitis. Transl Gastroenterol Hepatol. 2021;6:29. - PMC - PubMed

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