title: Evaluation of the impact of genetic polymorphisms in glutathione-related genes on the association between methylmercury or n-3 polyunsaturated long chain fatty acids and risk of myocardial infarction: a case-control study.
abstract: BACKGROUND
  The n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, which are present in fish, are protective against myocardial infarction. However, fish also contains methylmercury, which influences the risk of myocardial infarction, possibly by generating oxidative stress. Methylmercury is metabolized by conjugation to glutathione, which facilitates elimination. Glutathione is also an antioxidant. Individuals with certain polymorphisms in glutathione-related genes may tolerate higher exposures to methylmercury, due to faster metabolism and elimination and/or better glutathione-associated antioxidative capacity. They would thus benefit more from the protective agents in fish, such as eicosapentaenoic+docosahexaenoic acid and selenium. The objective for this study was to elucidate whether genetic polymorphisms in glutathione-related genes modify the association between eicosapentaenoic+docosahexaenoic acid or methylmercury and risk of first ever myocardial infarction.
  
  
  METHODS
  Polymorphisms in glutathione-synthesizing (glutamyl-cysteine ligase catalytic subunit, GCLC and glutamyl-cysteine ligase modifier subunit, GCLM) or glutathione-conjugating (glutathione S-transferase P, GSTP1) genes were genotyped in 1027 individuals from northern Sweden (458 cases of first-ever myocardial infarction and 569 matched controls). The impact of these polymorphisms on the association between erythrocyte-mercury (proxy for methylmercury) and risk of myocardial infarction, as well as between plasma eicosapentaenoic+docosahexaenoic acid and risk of myocardial infarction, was evaluated by conditional logistic regression. The effect of erythrocyte-selenium on risk of myocardial infarction was also taken into consideration.
  
  
  RESULTS
  There were no strong genetic modifying effects on the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction risk. When eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury were divided into tertiles, individuals with GCLM-588 TT genotype displayed a lower risk relative to the CC genotype in all but one tertile; in most tertiles the odds ratio was around 0.5 for TT. However, there were few TT carriers and the results were not statistically significant. The results were similar when taking plasma eicosapentaenoic+docosahexaenoic acid, erythrocyte-selenium and erythrocyte-mercury into account simultaneously.
  
  
  CONCLUSIONS
  No statistically significant genetic modifying effects were seen for the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction. Still, our results indicate that the relatively rare GCLM-588 TT genotype may have an impact, but a larger study is necessary for confirmation.
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
authors.forename: Karin S
authors.initials: KS
authors.lastname: Engström
authors.forename: Maria
authors.initials: M
authors.lastname: Wennberg
authors.forename: Ulf
authors.initials: U
authors.lastname: Strömberg
authors.forename: Ingvar A
authors.initials: IA
authors.lastname: Bergdahl
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Jan-Håkan
authors.initials: JH
authors.lastname: Jansson
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundh
authors.forename: Margareta
authors.initials: M
authors.lastname: Norberg
authors.forename: Gerda
authors.initials: G
authors.lastname: Rentschler
authors.forename: Bengt
authors.initials: B
authors.lastname: Vessby
authors.forename: Staffan
authors.initials: S
authors.lastname: Skerfving
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002316:Cardiotonic Agents / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D004032:Diet; D004281:Docosahexaenoic Acids / Q000097:blood / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000097:blood / Q000378:metabolism*; D004912:Erythrocytes / Q000737:chemistry; D005260:Female; D005399:Fishes; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008628:Mercury / Q000097:blood; D008767:Methylmercury Compounds / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012306:Risk; D013548:Sweden
chemical_list: D002316:Cardiotonic Agents; D008767:Methylmercury Compounds; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase; D008628:Mercury; D005978:Glutathione