Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?
OBJECTIVE
The lifespan of dialysis patients is as short as in patients with metastatic cancer disease, mainly due to cardiovascular disease (CVD). DNA methylation is an important cellular mechanism modulating gene expression associated with ageing, inflammation and atherosclerotic processes.


METHODS
DNA methylation was analysed in peripheral blood leucocytes from three different groups of chronic kidney disease (CKD) populations (37 CKD stages 3 and 4 patients, 98 CKD stage 5 patients and 20 prevalent haemodialysis patients). Thirty-six healthy subjects served as controls. Clinical characteristics (diabetes mellitus, nutritional status and presence of clinical CVD), inflammation and oxidative stress biomarkers, homocysteine and global DNA methylation in peripheral blood leucocytes (defined as HpaII/MspI ratio by the Luminometric Methylation Assay method) were evaluated. CKD stage 5 patients (n=98) starting dialysis treatment were followed for a period of 36 +/- 2 months.


RESULTS
Inflamed patients had lower ratios of HpaII/MspI, indicating global DNA hypermethylation. Analysis by the Cox regression model demonstrated that DNA hypermethylation (HpaII/MspI ratio <median) was significantly associated with both all-cause (RR 5.0; 95% CI: 1.7-14.8; P<0.01) and cardiovascular (RR 13.9; 95% CI: 1.8-109.3; P<0.05) mortality, even following the adjustment for age, CVD, diabetes mellitus and inflammation.


CONCLUSIONS
The present study demonstrates that global DNA hypermethylation is associated with inflammation and increased mortality in CKD.
Stenvinkel
P
P
Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. peter.stenvinkel@ki.se
Karimi
M
M
Johansson
S
S
Axelsson
J
J
Suliman
M
M
Lindholm
B
B
Heimbürger
O
O
Barany
P
P
Alvestrand
A
A
Nordfors
L
L
Qureshi
A R
AR
Ekström
T J
TJ
Schalling
M
M
D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002908:Chronic Disease; D019175:DNA Methylation; D015257:DNA-Cytosine Methylases / Q000032:analysis / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000097:blood; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors
D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; C029641:DNA modification methylase HpaII; D015257:DNA-Cytosine Methylases