Ischemic heart disease and stroke in relation to blood DNA methylation.
BACKGROUND
Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke.


METHODS
We quantified blood DNA methylation of Long Interspersed Nucleotide Element-1 (LINE-1) repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases), and during follow-up (44 new cases; median follow-up, 63 months), as well as subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months).


RESULTS
Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR = 2.1 [95% confidence interval = 1.2-4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9-7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8-8.9]) or stroke (5.7 [0.8-39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3-8.4]) and stroke (2.8 [0.6-14.3]). Total mortality was also increased (2.0 [1.2-3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable.


CONCLUSIONS
Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality.
Baccarelli
Andrea
A
Center of Molecular and Genetic Epidemiology, Università degli Studi di Milano & IRCCS Ca', Granda Policlinico Maggiore Hospital Foundation, Milan, Italy. abaccare@hsph.harvard.edu
Wright
Robert
R
Bollati
Valentina
V
Litonjua
Augusto
A
Zanobetti
Antonella
A
Tarantini
Letizia
L
Sparrow
David
D
Vokonas
Pantel
P
Schwartz
Joel
J
D000368:Aged; D001900:Boston / Q000453:epidemiology; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D017202:Myocardial Ischemia / Q000235:genetics* / Q000401:mortality; D016133:Polymerase Chain Reaction; D020521:Stroke / Q000235:genetics* / Q000401:mortality
Circulation. 2005 Aug 30;112(9):1353-61
16116050
J Nutr. 2005 Jan;135(1):5-8
15623824
DNA Cell Biol. 2007 Aug;26(8):603-11
17688412
N Engl J Med. 2008 Jul 3;359(1):61-73
18596274
Environ Health Perspect. 2009 Feb;117(2):217-22
19270791
Nucleic Acids Res. 2005 Dec 02;33(21):6823-36
16326863
Cancer Epidemiol Biomarkers Prev. 2007 Jan;16(1):108-14
17220338
J Biomed Biotechnol. 2006;2006(1):83672
16877821
J Biol Chem. 2004 Jul 9;279(28):29147-54
15131116
Biochim Biophys Acta. 2009 Sep;1790(9):886-91
19233248
Ann Hum Genet. 2004 May;68(Pt 3):196-204
15180700
Nucleic Acids Res. 2004 Feb 18;32(3):e38
14973332
Eur Heart J. 2009 Jan;30(1):6-15
19029125
Cardiovasc Res. 1999 Sep;43(4):985-91
10615426
Vasc Med. 2002 Feb;7(1):5-11
12083735
Med Hypotheses. 1999 Nov;53(5):421-4
10616044
Arterioscler Thromb Vasc Biol. 2003 Oct 1;23(10):1750-3
12947012
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13056-61
17670942
Lancet. 2003 Feb 1;361(9355):393-5
12573379
Hum Mol Genet. 2001 Mar 1;10(5):433-43
11181567
Nature. 2004 May 20;429(6989):268-74
15152245
Lancet. 2003 May 17;361(9370):1693-9
12767735
Annu Rev Genet. 2001;35:501-38
11700292
Circulation. 1996 Nov 1;94(9):2090-5
8901656
Clin Chem. 2003 Aug;49(8):1292-6
12881445
JAMA. 2008 Jun 25;299(24):2877-83
18577732
Am J Cardiol. 2003 Oct 15;92(8):901-6
14556863
Gene. 2001 Oct 3;276(1-2):135-41
11591480
Physiol Genomics. 2006 Apr 13;25(2):314-24
16418318
Nature. 2007 May 24;447(7143):433-40
17522677
Psychosom Med. 2001 Nov-Dec;63(6):910-6
11719629
Cochrane Database Syst Rev. 2009 Oct 07;(4):CD006612
19821378
Mech Ageing Dev. 2009 Apr;130(4):234-9
19150625
Cancer Res. 2007 Feb 1;67(3):876-80
17283117
Am J Respir Crit Care Med. 2009 Apr 1;179(7):572-8
19136372
FEBS Lett. 2004 Jun 1;567(1):136-41
15165906