Epigenetic Signatures at AQP3 and SOCS3 Engage in Low-Grade Inflammation across Different Tissues.
BACKGROUND
Elevated levels of C-reactive protein (CRP, determined by a high-sensitivity assay) indicate low-grade inflammation which is implicated in many age-related disorders. Epigenetic studies on CRP might discover molecular mechanisms underlying CRP regulation. We aimed to identify DNA methylation sites related to CRP concentrations in cells and tissues regulating low-grade inflammation.


RESULTS
Genome-wide DNA methylation was measured in peripheral blood in 1,741 participants of the KORA F4 study using Illumina HumanMethylation450 BeadChip arrays. Four CpG sites (located at BCL3, AQP3, SOCS3, and cg19821297 intergenic at chromosome 19p13.2, P ≤ 1.01E-07) were significantly hypomethylated at high CRP concentrations independent of various confounders including age, sex, BMI, smoking, and white blood cell composition. Findings were not sex-specific. CRP-related top genes were enriched in JAK/STAT pathways (Benjamini-Hochberg corrected P < 0.05). Results were followed-up in three studies using DNA from peripheral blood (EPICOR, n = 503) and adipose tissue (TwinsUK, n = 368) measured as described above and from liver tissue (LMU liver cohort, n = 286) measured by MALDI-TOF mass spectrometry using EpiTYPER. CpG sites at the AQP3 locus (significant p-values in peripheral blood = 1.72E-03 and liver tissue = 1.51E-03) and the SOCS3 locus (p-values in liver < 2.82E-05) were associated with CRP in the validation panels.


CONCLUSIONS
Epigenetic modifications seem to engage in low-grade inflammation, possibly via JAK/STAT mediated pathways. Results suggest a shared relevance across different tissues at the AQP3 locus and highlight a role of DNA methylation for CRP regulation at the SOCS3 locus.
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health Neuherberg, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Carola
C
Marzi
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Lesca M
LM
Holdt
Human Genetics Foundation (HuGeF)-Torino, Turin, Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
Giovanni
G
Fiorito
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Pei-Chien
PC
Tsai
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health Neuherberg, Germany.
Anja
A
Kretschmer
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health Neuherberg, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Simone
S
Wahl
Human Genetics Foundation (HuGeF)-Torino, Turin, Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
Simonetta
S
Guarrera
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Daniel
D
Teupser
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Tim D
TD
Spector
Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy.
Licia
L
Iacoviello
Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy.
Carlotta
C
Sacerdote
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
Konstantin
K
Strauch
Department of Surgery, Ludwig-Maximilians-Universität München, Munich, Germany.
Serene
S
Lee
Department of Surgery, Ludwig-Maximilians-Universität München, Munich, Germany.
Wolfgang E
WE
Thasler
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Annette
A
Peters
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Barbara
B
Thorand
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, München, Germany.
Petra
P
Wolf
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, München, Germany.
Holger
H
Prokisch
Cancer Registry and Histopathology Unit, "Civile-M.P. Arezzo" Hospital, ASP 7, Ragusa, Italy.
Rosario
R
Tumino
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health Neuherberg, Germany.
Christian
C
Gieger
Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale Tumori, Milan, Italy.
Vittorio
V
Krogh
Department of Clinical and Medicine and Surgery, Federico II University, Naples, Italy.
Salvatore
S
Panico
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Jordana T
JT
Bell
Human Genetics Foundation (HuGeF)-Torino, Turin, Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
Giuseppe
G
Matullo
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health Neuherberg, Germany.
Melanie
M
Waldenberger
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health Neuherberg, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Harald
H
Grallert
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.|Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.|DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Wolfgang
W
Koenig
D000273:Adipose Tissue / Q000503:physiopathology; D051400:Aquaporin 3 / Q000235:genetics / Q000502:physiology*; D002097:C-Reactive Protein / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology; D053612:Janus Kinases / Q000502:physiology; D008099:Liver / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000502:physiology*
C496027:AQP3 protein, human; C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; D000071223:Suppressor of Cytokine Signaling 3 Protein; D051400:Aquaporin 3; D002097:C-Reactive Protein; D053612:Janus Kinases