title: Genetic contribution of the leukotriene pathway to coronary artery disease.
abstract: We evaluated the genetic contribution of the leukotriene (LT) pathway to risk of coronary artery disease (CAD) in 4,512 Caucasian and African American subjects ascertained through elective cardiac evaluation. Of the three previously associated variants, the shorter "3" and "4" alleles of a promoter repeat polymorphism in ALOX5 increased risk of CAD in African Americans (OR = 1.4, 95% CI 1.0-1.9; p = 0.04), whereas a haplotype of LTA4H (HapK) was associated with CAD in Caucasians (OR = 1.2, 95% CI 1.01-1.4; p = 0.03). In Caucasians, first-stage analysis of 254 haplotype-tagging SNPs in 15 LT pathway genes with follow-up of 19 variants in stage 2 revealed an LTA4H SNP (rs2540477) that increased risk of CAD (OR = 1.2, 95% CI 1.1-1.5; p = 0.003) and a PLA2G4A SNP (rs12746200) that decreased risk of CAD (OR = 0.7, 95% CI 0.6-0.9; p = 0.0007). The PLA2G4A rs12746200 variant also decreased risk of experiencing a major adverse cardiac event (MACE = myocardial infarction, stroke, or death) over 3 years of follow-up (HR = 0.7, 95% CI 0.5-0.9; p = 0.01), consistent with its cardioprotective effect. Functional experiments demonstrated that stimulated monocytes from carriers of LTA4H variants HapK or rs2540477 had 50% (p = 0.002) and 33% (p = 0.03) higher LTB(4) production, respectively, compared to non-carriers. These ex vivo results are consistent with LTB(4) being the direct product of the reaction catalyzed by LTA4H and its role in promoting monocyte chemotaxis to sites of inflammation, including the artery wall of atherosclerotic lesions. Taken together, this study provides additional evidence that functional genetic variation of the LT pathway can mediate atherogenic processes and the risk of CAD in humans.
authors.affiliation: Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Dalin
authors.initials: D
authors.lastname: Li
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.forename: Susanna
authors.initials: S
authors.lastname: Vikman
authors.forename: Yesha
authors.initials: Y
authors.lastname: Patel
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Brennan
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.forename: Charles B
authors.initials: CB
authors.lastname: Stephensen
authors.forename: Patrice
authors.initials: P
authors.lastname: Armstrong
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
mesh_terms: D000368:Aged; D044383:Black People; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People; D001741:Black or African American
chemical_list: D015289:Leukotrienes