Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation

Hari K. Somineni, Suresh Venkateswaran, Varun Kilaru, Urko M. Marigorta, Angela Mo, David T. Okou, Richard Kellermayer, Kajari Mondal, Dawayland Cobb, Thomas D. Walters, Anne Griffiths, Joshua D. Noe, Wallace V. Crandall, Joel Rosh, David R. Mack, Melvin B. Heyman, Susan S. Baker, Michael C. Stephens, Robert N. Baldassano, James F. Markowitz & 9 others Marla C. Dubinsky, Judy Cho, Jeffrey S. Hyams, Lee A. Denson, Greg Gibson, David J. Cutler, Karen N. Conneely, Alicia K. Smith, Subra Kugathasan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background & Aims: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. Methods: We obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. Results: We identified 1189 5′-cytosine–phosphate–guanosine-3′ (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. Conclusions: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease–associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

Original languageEnglish (US)
Pages (from-to)2254-2265.e3
JournalGastroenterology
Volume156
Issue number8
DOIs
StatePublished - Jun 1 2019

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DNA Methylation
Crohn Disease
Inflammation
Methylation
Disease Progression
Genetic Phenomena
Pediatrics
Delayed Diagnosis
Random Allocation
C-Reactive Protein
Therapeutics
Phenotype

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Somineni, H. K., Venkateswaran, S., Kilaru, V., Marigorta, U. M., Mo, A., Okou, D. T., ... Kugathasan, S. (2019). Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation. Gastroenterology, 156(8), 2254-2265.e3. https://doi.org/10.1053/j.gastro.2019.01.270
Somineni, Hari K. ; Venkateswaran, Suresh ; Kilaru, Varun ; Marigorta, Urko M. ; Mo, Angela ; Okou, David T. ; Kellermayer, Richard ; Mondal, Kajari ; Cobb, Dawayland ; Walters, Thomas D. ; Griffiths, Anne ; Noe, Joshua D. ; Crandall, Wallace V. ; Rosh, Joel ; Mack, David R. ; Heyman, Melvin B. ; Baker, Susan S. ; Stephens, Michael C. ; Baldassano, Robert N. ; Markowitz, James F. ; Dubinsky, Marla C. ; Cho, Judy ; Hyams, Jeffrey S. ; Denson, Lee A. ; Gibson, Greg ; Cutler, David J. ; Conneely, Karen N. ; Smith, Alicia K. ; Kugathasan, Subra. / Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation. In: Gastroenterology. 2019 ; Vol. 156, No. 8. pp. 2254-2265.e3.
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title = "Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation",
abstract = "Background & Aims: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20{\%} of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. Methods: We obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. Results: We identified 1189 5′-cytosine–phosphate–guanosine-3′ (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. Conclusions: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease–associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.",
author = "Somineni, {Hari K.} and Suresh Venkateswaran and Varun Kilaru and Marigorta, {Urko M.} and Angela Mo and Okou, {David T.} and Richard Kellermayer and Kajari Mondal and Dawayland Cobb and Walters, {Thomas D.} and Anne Griffiths and Noe, {Joshua D.} and Crandall, {Wallace V.} and Joel Rosh and Mack, {David R.} and Heyman, {Melvin B.} and Baker, {Susan S.} and Stephens, {Michael C.} and Baldassano, {Robert N.} and Markowitz, {James F.} and Dubinsky, {Marla C.} and Judy Cho and Hyams, {Jeffrey S.} and Denson, {Lee A.} and Greg Gibson and Cutler, {David J.} and Conneely, {Karen N.} and Smith, {Alicia K.} and Subra Kugathasan",
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Somineni, HK, Venkateswaran, S, Kilaru, V, Marigorta, UM, Mo, A, Okou, DT, Kellermayer, R, Mondal, K, Cobb, D, Walters, TD, Griffiths, A, Noe, JD, Crandall, WV, Rosh, J, Mack, DR, Heyman, MB, Baker, SS, Stephens, MC, Baldassano, RN, Markowitz, JF, Dubinsky, MC, Cho, J, Hyams, JS, Denson, LA, Gibson, G, Cutler, DJ, Conneely, KN, Smith, AK & Kugathasan, S 2019, 'Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation', Gastroenterology, vol. 156, no. 8, pp. 2254-2265.e3. https://doi.org/10.1053/j.gastro.2019.01.270

Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation. / Somineni, Hari K.; Venkateswaran, Suresh; Kilaru, Varun; Marigorta, Urko M.; Mo, Angela; Okou, David T.; Kellermayer, Richard; Mondal, Kajari; Cobb, Dawayland; Walters, Thomas D.; Griffiths, Anne; Noe, Joshua D.; Crandall, Wallace V.; Rosh, Joel; Mack, David R.; Heyman, Melvin B.; Baker, Susan S.; Stephens, Michael C.; Baldassano, Robert N.; Markowitz, James F.; Dubinsky, Marla C.; Cho, Judy; Hyams, Jeffrey S.; Denson, Lee A.; Gibson, Greg; Cutler, David J.; Conneely, Karen N.; Smith, Alicia K.; Kugathasan, Subra.

In: Gastroenterology, Vol. 156, No. 8, 01.06.2019, p. 2254-2265.e3.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation

AU - Somineni, Hari K.

AU - Venkateswaran, Suresh

AU - Kilaru, Varun

AU - Marigorta, Urko M.

AU - Mo, Angela

AU - Okou, David T.

AU - Kellermayer, Richard

AU - Mondal, Kajari

AU - Cobb, Dawayland

AU - Walters, Thomas D.

AU - Griffiths, Anne

AU - Noe, Joshua D.

AU - Crandall, Wallace V.

AU - Rosh, Joel

AU - Mack, David R.

AU - Heyman, Melvin B.

AU - Baker, Susan S.

AU - Stephens, Michael C.

AU - Baldassano, Robert N.

AU - Markowitz, James F.

AU - Dubinsky, Marla C.

AU - Cho, Judy

AU - Hyams, Jeffrey S.

AU - Denson, Lee A.

AU - Gibson, Greg

AU - Cutler, David J.

AU - Conneely, Karen N.

AU - Smith, Alicia K.

AU - Kugathasan, Subra

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background & Aims: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. Methods: We obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. Results: We identified 1189 5′-cytosine–phosphate–guanosine-3′ (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. Conclusions: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease–associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

AB - Background & Aims: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. Methods: We obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. Results: We identified 1189 5′-cytosine–phosphate–guanosine-3′ (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. Conclusions: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease–associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

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DO - 10.1053/j.gastro.2019.01.270

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Somineni HK, Venkateswaran S, Kilaru V, Marigorta UM, Mo A, Okou DT et al. Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation. Gastroenterology. 2019 Jun 1;156(8):2254-2265.e3. https://doi.org/10.1053/j.gastro.2019.01.270