title: Is hyperhomocysteinemia a causal factor for heart failure? The impact of the functional variants of MTHFR and PON1 on ischemic and non-ischemic etiology.
abstract: BACKGROUND
  Hyperhomocysteinemia was found to be uniformly associated with the development of heart failure (HF) and HF mortality; however, it is uncertain whether this relation is causative or not. We used Mendelian randomization to examine the associations of the methylene tetrahydrofolate gene (MTHFR) and paraoxonase 1 gene (PON1) variants as a proxy for lifelong exposure to high Hcy and Hcy-thiolactone concentrations with the development of HF in men aged ≤60years and the occurrence of adverse effects at one-year follow-up.
  
  
  METHODS
  The study enrolled 172 men with HF: 117 with ischemic etiology (iHF) related to coronary artery disease (CAD) and 55 with non-ischemic etiology (niHF) related to dilated cardiomyopathy (DCM). The reference group of 329 CAD patients without HF and the control group of 384 men were also analyzed.
  
  
  RESULTS
  Hyperhomocysteinemia (OR=2.0, P<0.05) and the MTHFR 677TT/1298AA, 677CC/1298CC genotypes (OR=1.6, P=0.03) were associated with HF regardless of its etiology, especially among normotensives (OR=4.6, P=0.001 and OR=2.3, P=0.003, respectively). In niHF, the PON1 162AA (OR=2.3, P=0.03) and 575AG+GG (OR=0.46, P=0.01) genotypes also influenced the risk. The interaction between HDLC<1mmol/L and the PON1 575GG genotype was found to influence the risk of iHF (OR=7.2, P=0.009). Hyperhomocysteinemia improved the classification of niHF patients as 'high-risk' by 10.1%. Ejection fraction <30% and DCM increased the probability of HF death or re-hospitalization within one year.
  
  
  CONCLUSIONS
  Our results provide evidence that hyperhomocysteinemia is a causal factor for niHF in DCM, while dysfunctional HDL could contribute to the pathogenesis of iHF.
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland; Department of General and Vascular Surgery, Poznan University of Medical Sciences, Dluga 1/2, 61-848 Poznan, Poland. Electronic address: strauss@man.poznan.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Strauss
authors.affiliation: Regional Public Hospital, Dekerta 1, 66-400 Gorzow Wielkopolski, Poland.
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Supinski
authors.affiliation: Department of Hypertension, Angiology and Internal Medicine, Poznan University of Medical Sciences, Dluga 1/2, 61-848 Poznan, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Radziemski
authors.affiliation: Department of General and Vascular Surgery, Poznan University of Medical Sciences, Dluga 1/2, 61-848 Poznan, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Oszkinis
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland.
authors.forename: Andrzej Leon
authors.initials: AL
authors.lastname: Pawlak
authors.affiliation: The State Higher Vocational School in Kalisz, Nowy Swiat 4, 62-800 Kalisz, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Gluszek
mesh_terms: D000368:Aged; D043303:Aryldialkylphosphatase / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000150:complications; D015984:Causality; D005260:Female; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology / Q000401:mortality; D006710:Homocysteine / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000453:epidemiology / Q000235:genetics; D008297:Male; D057182:Mendelian Randomization Analysis; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications; D011044:Poland / Q000453:epidemiology; D012307:Risk Factors; D013318:Stroke Volume
chemical_list: D006710:Homocysteine; C007957:homocysteine thiolactone; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
keywords: Dilated cardiomyopathy; Ejection fraction; Heart failure; Homocysteine; MTHFR; PON1