title: Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia.
abstract: OBJECTIVE
  To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH).
  
  
  BACKGROUND
  The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH.
  
  
  METHODS
  In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking.
  
  
  RESULTS
  HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17-1.89, p=0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20-2.76, p=0.005). HapA was not associated with CHD.
  
  
  CONCLUSIONS
  We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.
authors.affiliation: Department of Internal Medicine, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeroen B
authors.initials: JB
authors.lastname: van der Net
authors.forename: Jorie
authors.initials: J
authors.lastname: Versmissen
authors.forename: Daniëlla M
authors.initials: DM
authors.lastname: Oosterveer
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: Mojgan
authors.initials: M
authors.lastname: Yazdanpanah
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000235:genetics*; D007249:Inflammation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012306:Risk
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008078:Cholesterol, LDL; D008565:Membrane Proteins