caa a22 4500 445861452 CHVBK 20180317145444.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00439-011-0963-3 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0963-3 Genetic contribution of the leukotriene pathway to coronary artery disease [Elektronische Daten] [Jaana Hartiala, Dalin Li, David Conti, Susanna Vikman, Yesha Patel, W. Wilson Tang, Marie-Louise Brennan, John Newman, Charles Stephensen, Patrice Armstrong, Stanley Hazen, Hooman Allayee] 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 3years 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 LTB4 production, respectively, compared to non-carriers. These ex vivo results are consistent with LTB4 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. The Author(s), 2011 Hartiala Jaana Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut Li Dalin Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut Conti David Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut Vikman Susanna Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut Patel Yesha Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut Wilson Tang W. Department of Cardiovascular Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA aut Brennan Marie-Louise Department of Cardiovascular Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA aut Newman John USDA Western Human Nutrition Research Center, University of California Davis, 95616, Davis, CA, USA aut Stephensen Charles USDA Western Human Nutrition Research Center, University of California Davis, 95616, Davis, CA, USA aut Armstrong Patrice USDA Western Human Nutrition Research Center, University of California Davis, 95616, Davis, CA, USA aut Hazen Stanley Department of Cardiovascular Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA aut Allayee Hooman Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut Human Genetics Springer-Verlag 129/6(2011-06-01), 617-627 0340-6717 129:6<617 2011 129 439 https://doi.org/10.1007/s00439-011-0963-3 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0963-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hartiala Jaana Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Li Dalin Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Conti David Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Vikman Susanna Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Patel Yesha Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Wilson Tang W. Department of Cardiovascular Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA aut NATIONALLICENCE 700 1- Brennan Marie-Louise Department of Cardiovascular Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA aut NATIONALLICENCE 700 1- Newman John USDA Western Human Nutrition Research Center, University of California Davis, 95616, Davis, CA, USA aut NATIONALLICENCE 700 1- Stephensen Charles USDA Western Human Nutrition Research Center, University of California Davis, 95616, Davis, CA, USA aut NATIONALLICENCE 700 1- Armstrong Patrice USDA Western Human Nutrition Research Center, University of California Davis, 95616, Davis, CA, USA aut NATIONALLICENCE 700 1- Hazen Stanley Department of Cardiovascular Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA aut NATIONALLICENCE 700 1- Allayee Hooman Department of Preventive Medicine, USC Keck School of Medicine, 90033, Los Angeles, CA, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/6(2011-06-01), 617-627 0340-6717 129:6<617 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer