title: Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease.
abstract: OBJECTIVE
  In a recent genome-wide study, cytosine bases in the F2RL3 gene, which codes for a protein relevant for cardiovascular physiology, were discovered to be hypomethylated in smokers. We aimed to determine the clinical importance of methylation at the F2RL3 locus.
  
  
  RESULTS
  In the KAROLA prospective cohort study, 1206 participants of inpatient cardiovascular rehabilitation programmes after experiencing an acute coronary syndrome, myocardial infarction, or coronary intervention were recruited in two clinics in Germany. Active follow-up was conducted over 8 years. Methylation at loci in F2RL3 was characterized by Sequenom matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Associations of methylation and smoking with secondary cardiovascular events, and cause-specific and all-cause mortality were examined by multiple Cox's regression estimating confounder-controlled hazard ratios. A total of 49 non-fatal myocardial infarctions, 41 non-fatal strokes, 64 cardiovascular deaths, and 50 deaths due to other causes were observed. In Cox's models controlling for established prognostic factors, F2RL3 methylation was strongly associated with mortality. Adjusted hazard ratios (95% confidence intervals) for death from cardiovascular, non-cardiovascular, or any cause were 2.32 (0.97-5.58), 5.16 (1.81-14.7), and 3.19 (1.64-6.21) in subjects in the lowest quartile of methylation in comparison to the highest quartile. In contrast, no association was seen with the combined secondary event outcome. The strong association of smoking with all outcomes was markedly attenuated when F2RL3 was included in the regression models.
  
  
  CONCLUSIONS
  The results seem to indicate methylation in F2RL3 to be a potential mediator of the detrimental impact of smoking and to be strongly related to mortality among patients with stable coronary heart disease. Multidisciplinary research efforts are needed to unravel prognostic, preventive, and therapeutic potentials of these pronounced associations.
authors.affiliation: Division of Clinical Epidemiology and Aging Research C070, German Cancer Research Center (DKFZ), Heidelberg, Germany. lutz.breitling@gmail.com
authors.forename: Lutz Philipp
authors.initials: LP
authors.lastname: Breitling
authors.forename: Katrin
authors.initials: K
authors.lastname: Salzmann
authors.forename: Dietrich
authors.initials: D
authors.lastname: Rothenbacher
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000328:Adult; D000368:Aged; D003327:Coronary Disease / Q000235:genetics* / Q000401:mortality / Q000534:rehabilitation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018179:Receptors, Thrombin / Q000235:genetics*; D012907:Smoking / Q000235:genetics* / Q000401:mortality
chemical_list: D018179:Receptors, Thrombin; C112908:protease-activated receptor 4