Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

被引：32

作者：

Kalla, R. ^{[1
,2
]}

Adams, A. T. ^{[1
,3
]}

Nowak, J. K. ^{[4
]}

Bergemalm, D. ^{[5
]}

Vatn, S. ^{[6
]}

Ventham, N. A. ^{[1
]}

Kennedy, N. A. ^{[1
,7
]}

Ricanek, P. ^{[6
,8
]}

Lindstrom, J. ^{[8
,9
]}

Soderholm, J. ^{[10
]}

Pierik, M. ^{[11
]}

D'Amato, M. ^{[12
,13
]}

Gomollon, F. ^{[14
]}

Olbjorn, C. ^{[6
,8
]}

Richmond, R. ^{[15
]}

Relton, C. L. ^{[15
]}

Jahnsen, J. ^{[6
,8
]}

Vatn, M. H. ^{[8
]}

Halfvarson, J. ^{[5
]}

Satsangi, J. ^{[1
,3
]}

机构：

[1] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[2] Univ Edinburgh, MRC Ctr Inflammat Res, Queens Med Res Inst, Edinburgh, Midlothian, Scotland

[3] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Expt Med Div,Translat Gastroenterol Unit, Oxford, England

[4] Poznan Univ Med Sci, Dept Paediat Gastroenterol & Metab Dis, Poznan, Poland

[5] Orebro Univ, Fac Med & Hlth, Dept Gastroenterol, Orebro, Sweden

[6] Akershus Univ Hosp, Dept Gastroenterol, Lorenskog, Norway

[7] Univ Exeter, Exeter IBD & Pharmacogenet Grp, Exeter, Devon, England

[8] Univ Oslo, Inst Clin Med, Campus Ahus, Oslo, Norway

[9] Akershus Univ Hosp, Hlth Serv Res Unit, Lorenskog, Norway

[10] Linkoping Univ, Dept Surg & Clin & Expt Med, Linkoping, Sweden

[11] Maastricht Univ Med Ctr MUMC, Dept Gastroenterol & Hepatol, Maastricht, Netherlands

[12] CIC bioGUNE BRTA, Derio, Spain

[13] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[14] IIS Aragon, CIBEREHD, HCU Lozano Blesa, Zaragoza, Spain

[15] Univ Bristol, Sch Social & Community Med, Med Res Council Integrat Epidemiol Unit MRC IEU, Bristol, Avon, England

来源：

JOURNAL OF CROHNS & COLITIS | 2023年 / 17卷 / 02期

基金：

英国惠康基金;

关键词：

DNA methylation; genetics; inflammatory bowel diseases [IBD; prognosis; methylation; quantitative trait loci; gene expression; epigenetic clock; Mendelian randomization; GENOME-WIDE ASSOCIATION; ONSET CROHNS-DISEASE; DNA METHYLATION; CELLS; ACTIVATION; PROGNOSIS; PATTERNS; PACKAGE; LINK;

D O I：

10.1093/ecco-jcc/jjac127

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn's disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

引用

页码：170 / 184

页数：15