title: Cardiac autonomic dysfunction: particulate air pollution effects are modulated by epigenetic immunoregulation of Toll-like receptor 2 and dietary flavonoid intake.
abstract: BACKGROUND
  Short-term fine particles (PM(2.5)) exposure is associated with reduced heart rate variability, a strong predictor of cardiac mortality among older people. Identifying modifiable factors that confer susceptibility is essential for intervention. We evaluated whether Toll-like receptor 2 (TLR2) methylation, a reversible immune-epigenetic process, and its dietary modulation by flavonoids and methyl nutrients, modify susceptibility to heart rate variability effects following PM(2.5) exposure.
  
  
  RESULTS
  We measured heart rate variability and PM(2.5) repeatedly over 11 years (1275 total observations) among 573 elderly men from the Normative Aging Study. Blood TLR2 methylation was analyzed using pyrosequencing. Daily flavonoid and methyl nutrients intakes were assessed through the Food Frequency Questionnaire (FFQ). Every 10 μg/m(3) increase in 48-hour PM(2.5) moving average was associated with 7.74% (95% CI: -1.21% to 15.90%; P=0.09), 7.46% (95% CI: 0.99% to 13.50%; P=0.02), 14.18% (95% CI: 1.14% to 25.49%; P=0.03), and 12.94% (95% CI: -2.36% to 25.96%; P=0.09) reductions in root mean square of successive differences, standard deviation of normal-to-normal intervals, low-frequency power, and high-frequency power, respectively. Higher TLR2 methylation exacerbated the root mean square of successive differences, standard deviation of normal-to-normal intervals, low-frequency, and high-frequency reductions associated with heightened PM2.5 (P(interaction)=0.006, 0.03, 0.05, 0.04, respectively). Every interquartile-range increase in flavonoid intake was associated with 5.09% reduction in mean TLR2 methylation (95% CI: 0.12% to 10.06%; P=0.05) and counteracted the effects of PM2.5 on low frequency (P(interaction)=0.05). No significant effect of methyl nutrients on TLR2 methylation was observed.
  
  
  CONCLUSIONS
  Higher TLR2 methylation may confer susceptibility to adverse cardiac autonomic effects of PM2.5 exposure in older individuals. Higher flavonoid intake may attenuate these effects, possibly by decreasing TLR2 methylation.
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Jia
authors: J
authors: Zhong
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Elena
authors: E
authors: Colicino
authors: Department of Biostatistics, Harvard School of Public Health, Boston, MA (X.L., M.A.B.) Singapore Institute for Clinical Sciences, Singapore (X.L.).
authors: Xinyi
authors: X
authors: Lin
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Amar
authors: A
authors: Mehta
authors: Department of Geography and Environmental Development, Ben-Gurion University of the Negev, Beer Sheva, Israel (I.K.).
authors: Itai
authors: I
authors: Kloog
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Antonella
authors: A
authors: Zanobetti
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Hyang-Min
authors: HM
authors: Byun
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.) Department of Biostatistics, Harvard School of Public Health, Boston, MA (X.L., M.A.B.).
authors: Marie-Abèle
authors: MA
authors: Bind
authors: Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy (L.C., L.T.).
authors: Laura
authors: L
authors: Cantone
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Diddier
authors: D
authors: Prada
authors: Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy (L.C., L.T.).
authors: Letizia
authors: L
authors: Tarantini
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Letizia
authors: L
authors: Trevisi
authors: VA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of Medicine, Boston University School of Medicine, Boston, MA (D.S., P.V.).
authors: David
authors: D
authors: Sparrow
authors: VA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of Medicine, Boston University School of Medicine, Boston, MA (D.S., P.V.).
authors: Pantel
authors: P
authors: Vokonas
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Joel
authors: J
authors: Schwartz
authors: Department of Environmental Health, Harvard School of Public Health, Boston, MA (J.Z., E.C., A.M., A.Z., H.M.B., M.A.B., D.P., L.T., J.S., A.A.B.).
authors: Andrea A
authors: AA
authors: Baccarelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000502:physiology*; D001342:Autonomic Nervous System Diseases / Q000453:epidemiology; D001919:Bradycardia / Q000453:epidemiology* / Q000503:physiopathology; D015331:Cohort Studies; D004032:Diet; D057890:Epigenomics; D005419:Flavonoids / Q000008:administration & dosage*; D015577:Geriatric Assessment; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D008297:Male; D008745:Methylation; D052638:Particulate Matter / Q000009:adverse effects*; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D052638:Particulate Matter; D051195:Toll-Like Receptor 2
keywords: epidemiology; epigenetics; heart rate variability; inflammation; nutrition
references: Am Heart J. 1999 Nov;138(5 Pt 1):804-7
references: 10539808
references: Am Heart J. 1999 Nov;138(5 Pt 1):890-9
references: 10539820
references: Environ Health Perspect. 2000 May;108(5):419-26
references: 10811568
references: Am J Respir Cell Mol Biol. 2002 Nov;27(5):611-8
references: 12397021
references: Lancet. 2002 Oct 19;360(9341):1233-42
references: 12401268
references: Cancer Res. 2003 Nov 15;63(22):7563-70
references: 14633667
references: Toxicol Appl Pharmacol. 2004 Feb 15;195(1):1-11
references: 14962500
references: J Immunol. 2004 Mar 15;172(6):3712-8
references: 15004175
references: Environ Health Perspect. 2005 Mar;113(3):304-9
references: 15743719
references: J Nutr. 2005 Jun;135(6):1382-6
references: 15930441
references: Mol Pharmacol. 2005 Oct;68(4):1018-30
references: 16037419
references: Am J Epidemiol. 1992 May 15;135(10):1114-26; discussion 1127-36
references: 1632423
references: Environ Health Perspect. 2005 Dec;113(12):1693-7
references: 16330349
references: Cell. 2006 Feb 24;124(4):783-801
references: 16497588
references: Int J Epidemiol. 2006 Oct;35(5):1347-54
references: 16844771
references: J Nutr. 2007 Jan;137(1 Suppl):223S-228S
references: 17182830
references: Am J Respir Crit Care Med. 2007 Aug 15;176(4):370-6
references: 17463411
references: Inhal Toxicol. 2008 Feb;20(4):435-44
references: 18302051
references: Circulation. 2008 Apr 8;117(14):1802-9
references: 18378616
references: BMC Mol Biol. 2008 Apr 21;9:39
references: 18423053
references: J Cardiovasc Electrophysiol. 2008 Nov;19(11):1169-74
references: 18631274
references: J Occup Environ Med. 2008 Nov;50(11):1253-60
references: 19001951
references: Environ Health Perspect. 2009 Apr;117(4):522-9
references: 19440489
references: J Epidemiol Community Health. 2010 Jan;64(1):49-56
references: 19602472
references: Eur J Immunol. 2009 Nov;39(11):3052-65
references: 19882655
references: Epigenetics. 2010 Apr;5(3):222-8
references: 20305373
references: Circulation. 2010 Jun 1;121(21):2331-78
references: 20458016
references: Am J Clin Nutr. 2011 Feb;93(2):338-47
references: 21106916
references: Epigenomics. 2011 Jun;3(3):267-77
references: 22122337
references: Epidemiology. 2012 Mar;23(2):332-40
references: 22237295
references: Adv Nutr. 2012 Jan;3(1):21-38
references: 22332098
references: Environ Health Perspect. 2012 May;120(5):674-80
references: 22336131
references: Methods Mol Biol. 2012;863:359-76
references: 22359306
references: Hypertension. 2012 May;59(5):899-905
references: 22431584
references: Heart. 2012 Aug;98(15):1127-35
references: 22628541
references: Sci Total Environ. 2012 Aug 15;432:85-92
references: 22721687
references: Environ Sci Technol. 2012 Nov 6;46(21):11913-21
references: 23013112
references: Environ Health Perspect. 2013 Feb;121(2):192-6
references: 23204289
references: Epidemiology. 2013 Jul;24(4):555-61
references: 23676266
references: Am J Epidemiol. 1985 Jul;122(1):51-65
references: 4014201
references: Circulation. 1996 Mar 1;93(5):1043-65
references: 8598068