title: Common Polymorphisms in the 5-Lipoxygenase Pathway and Risk of Incident Myocardial Infarction: A Danish Case-Cohort Study.
abstract: BACKGROUND
  The 5-lipoxygenase pathway (5-LOX) has been implicated in the development of cardiovascular disease and studies have suggested that genetic polymorphisms related to key enzymes in this pathway may confer risk of myocardial infarction (MI). This study investigated the association of pre-selected genetic polymorphisms in four candidate genes of 5-LOX (arachidonate 5-lipoxygenase and its activating protein (ALOX-5 and FLAP), leukotriene A4 hydroxylase (LTA4-H) and leukotriene C4 synthase (LTC4-S)) with incident MI.
  
  
  METHODS
  In a Danish cohort including 57,053 participants, aged 50-64 at enrolment and recruited from 1993-97, we conducted a case-cohort study including cases with incident MI and a randomly selected sub cohort of 3,000 participants. Cases were identified from national registries through July 2013. A total of 22 SNPs were selected and genotyped using the commercially available KASP™ assay. A tandem-repeat polymorphism, located in the ALOX-5 gene, was genotyped by multi-titre plate sequencing. Haplotypes were inferred using PHASE 2.1.
  
  
  RESULTS
  During a median follow-up of 17.0 years we identified 3,089 cases of incident MI. In FLAP, two SNPs were negatively associated with incident MI (rs9551963 & rs17222842) while one SNP (rs2247570) located in LTA4-H, was associated with higher risk of MI when comparing subjects with two copies of the variant allele to homozygotes for the wild type. However, only rs17222842 remained significantly associated with MI after correcting for multiple testing. Furthermore, the promoter polymorphism rs59439148 was associated with risk of MI in men. For male carriers of two variant alleles we found a hazard ratio of 1.63 (95% CI: 1.06;2.52) compared to homozygotes for the wild type. Previously described haplotypes (Hap-A -B, -E and -K) were not associated with MI in our population.
  
  
  CONCLUSIONS
  In conclusion, some common polymorphisms in the 5-lipoxygenase pathway were modestly associated with incident MI, suggesting a potential role for this pathway in the development of cardiovascular disease.
authors.affiliation: Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Gammelmark
authors.affiliation: Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nielsen
authors.affiliation: Unit for Clinical Biostatistics and Bioinformatics, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Lundbye-Christensen
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.affiliation: Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Schmidt
authors.affiliation: Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.|Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
mesh_terms: D000368:Aged; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D001094:Arachidonate 5-Lipoxygenase