SuperTAG methylation-specific digital karyotyping reveals uremia-induced epigenetic dysregulation of atherosclerosis-related genes.
BACKGROUND
Accelerated atherosclerosis is a hallmark of chronic kidney disease (CKD). Although the role of epigenetic dysregulation in atherosclerosis is increasingly appreciated, only a few studies focused on epigenetics in CKD-associated cardiovascular disease, virtually all of which assessed epigenetic dysregulation globally. We hypothesized that gene-specific epigenetic dysregulation in CKD exists, affecting genes pertinent to inflammation and atherosclerosis.


RESULTS
Ten clinically stable patients undergoing hemodialysis therapy and 10 healthy age- and sex-matched controls were recruited. Genome-wide analysis of DNA methylation was performed by SuperTAG methylation-specific digital karyotyping, in order to identify genes differentially methylated in CKD. Analysis of 27 043 436 tags revealed 4288 genomic loci with differential DNA methylation (P<10(-10)) between hemodialysis patients and control subjects. Annotation of UniTags to promoter databases allowed us to identify 52 candidate genes associated with cardiovascular disease and 97 candidate genes associated with immune/infection diseases. These candidate genes could be classified to distinct proatherogenic processes, including lipid metabolism and transport (eg, HMGCR, SREBF1, LRP5, EPHX2, and FDPS), cell proliferation and cell-cycle regulation (eg, MIK67, TP53, and ALOX12), angiogenesis (eg, ANGPT2, ADAMTS10, and FLT4), and inflammation (eg, TNFSF10, LY96, IFNGR1, HSPA1A, and IL12RB1).


CONCLUSIONS
We provide a comprehensive analysis of genome-wide epigenetic alterations in CKD, identifying candidate genes associated with proatherogenic and inflammatory processes. These results may spur further research in the field of epigenetics in kidney disease and point to new therapeutic strategies in CKD-associated atherosclerotic disease.
Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany.
Adam M
AM
Zawada
Kyrill S
KS
Rogacev
Björn
B
Hummel
Oliver S
OS
Grün
Annika
A
Friedrich
Björn
B
Rotter
Peter
P
Winter
Jürgen
J
Geisel
Danilo
D
Fliser
Gunnar H
GH
Heine
D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D006801:Humans; D007621:Karyotyping / Q000379:methods*; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D015203:Reproducibility of Results; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood; D014511:Uremia / Q000097:blood / Q000235:genetics*
D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine