Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease

Han Zhang; Rahul Kalla; Jie Chen; Jianhui Zhao; Xuan Zhou; Alex Adams; Alexandra Noble; Nicholas T Ventham; Judith Wellens; Gwo-Tzer Ho; Malcolm G Dunlop; Jan Krzysztof Nowak; Yuan Ding; Zhanju Liu; Jack Satsangi; Evropi Theodoratou; Xue Li

doi:10.1038/s41467-024-44841-y

Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease

Han Zhang, Rahul Kalla, Jie Chen, Jianhui Zhao, Xuan Zhou, Alex Adams, Alexandra Noble, Nicholas T Ventham, Judith Wellens, Gwo-Tzer Ho, Malcolm G Dunlop, Jan Krzysztof Nowak, Yuan Ding, Zhanju Liu^*, Jack Satsangi^*, Evropi Theodoratou^*, Xue Li^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

This work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn’s disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10−10) and UC (P < 2 × 10−16) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10−8) and UC (P = 1.04 × 10−4) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10−6), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD.

Original language	English
Article number	595
Number of pages	14
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-44841-y
Publication status	Published - 18 Jan 2024

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Colorectal cancer reduction through risk stratification of screening, follow-up and treatment
Theodoratou, E.
UK-based charities
1/05/17 → 30/04/23
Project: Research

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Zhang, H., Kalla, R., Chen, J., Zhao, J., Zhou, X., Adams, A., Noble, A., Ventham, N. T., Wellens, J., Ho, G.-T., Dunlop, M. G., Krzysztof Nowak, J., Ding, Y., Liu, Z., Satsangi, J., Theodoratou, E., & Li, X. (2024). Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease. Nature Communications, 15, Article 595 . https://doi.org/10.1038/s41467-024-44841-y

@article{5e6bf55e32a348758e5005d979a4353f,

title = "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease",

abstract = "This work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn{\textquoteright}s disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10−10) and UC (P < 2 × 10−16) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10−8) and UC (P = 1.04 × 10−4) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10−6), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD.",

author = "Han Zhang and Rahul Kalla and Jie Chen and Jianhui Zhao and Xuan Zhou and Alex Adams and Alexandra Noble and Ventham, {Nicholas T} and Judith Wellens and Gwo-Tzer Ho and Dunlop, {Malcolm G} and {Krzysztof Nowak}, Jan and Yuan Ding and Zhanju Liu and Jack Satsangi and Evropi Theodoratou and Xue Li",

note = "This study is supported by funding that are displayed as follow. X.L.: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (82204019), Healthy Zhejiang One Million People Cohort (K-20230085). E.T.: CRUK Career Development Fellowship (C31250/A22804). Z.L.: The National Nature Science Foundation of China (82370532). J.W.: The Research Foundation Flanders (FWO), Belgium by a PhD Fellowship strategic basic research (SB) grant (1S06023N). J.K.N.: The National Science Centre (Poland), 2020/39/D/NZ5/02720.",

year = "2024",

month = jan,

day = "18",

doi = "10.1038/s41467-024-44841-y",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Zhang, H, Kalla, R, Chen, J, Zhao, J, Zhou, X, Adams, A, Noble, A, Ventham, NT, Wellens, J, Ho, G-T , Dunlop, MG, Krzysztof Nowak, J, Ding, Y, Liu, Z, Satsangi, J, Theodoratou, E & Li, X 2024, 'Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease', Nature Communications, vol. 15, 595 . https://doi.org/10.1038/s41467-024-44841-y

TY - JOUR

T1 - Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease

AU - Zhang, Han

AU - Kalla, Rahul

AU - Chen, Jie

AU - Zhao, Jianhui

AU - Zhou, Xuan

AU - Adams, Alex

AU - Noble, Alexandra

AU - Ventham, Nicholas T

AU - Wellens, Judith

AU - Ho, Gwo-Tzer

AU - Dunlop, Malcolm G

AU - Krzysztof Nowak, Jan

AU - Ding, Yuan

AU - Liu, Zhanju

AU - Satsangi, Jack

AU - Theodoratou, Evropi

AU - Li, Xue

N1 - This study is supported by funding that are displayed as follow. X.L.: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (82204019), Healthy Zhejiang One Million People Cohort (K-20230085). E.T.: CRUK Career Development Fellowship (C31250/A22804). Z.L.: The National Nature Science Foundation of China (82370532). J.W.: The Research Foundation Flanders (FWO), Belgium by a PhD Fellowship strategic basic research (SB) grant (1S06023N). J.K.N.: The National Science Centre (Poland), 2020/39/D/NZ5/02720.

PY - 2024/1/18

Y1 - 2024/1/18

N2 - This work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn’s disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10−10) and UC (P < 2 × 10−16) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10−8) and UC (P = 1.04 × 10−4) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10−6), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD.

AB - This work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn’s disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10−10) and UC (P < 2 × 10−16) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10−8) and UC (P = 1.04 × 10−4) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10−6), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD.

U2 - 10.1038/s41467-024-44841-y

DO - 10.1038/s41467-024-44841-y

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 595

ER -

Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease

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Colorectal cancer reduction through risk stratification of screening, follow-up and treatment

Cite this