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Jing Cao Michael Y. Tsai University of Minnesota

This study investigates the association between LOX/FLAP genes and markers of inflammation and subclinical cardiovascular disease. It explores the role of LOX genes in atherosclerosis susceptibility and hypertension, as well as the impact of FLAP gene on CAD. Additionally, the study examines the effects of LOX polymorphisms on subclinical markers of CAD and inflammation in the MESA Family cohort.

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Jing Cao Michael Y. Tsai University of Minnesota

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  1. MESA Family Candidate Gene Study : LOX/FLAP Genes & their Association with Markers of Inflammation and Subclinical CVD Jing Cao Michael Y. Tsai University of Minnesota

  2. Lipoxygenases (LOX) • LOXs are involved in biosynthesis of lipid “hormones” such as leukotrienes, lipoxins, hepoxilins, and other hydroxylated fatty acid derivatives • Classified as 5-, 8-, 12-, 15- LOX based on their ability to insert molecular oxygen at the corresponding carbon position of arachidonic acid

  3. Lipids in Cell Signaling

  4. 5-LOX • 5-LOX has been identified as a major gene contributing to atheroscleorosis susceptibility in mice • Patients with a history of MI has been shown to have increased production of LTB4 in neutrophils compared to healthy controls. • LTB4 is a potent leukocyte chemoattractant, while cysteinyl leukotrienes increase vascular permeability. Mehrabian M. Circulation2002:91:120-6 Lotzer K. Biochim Biophys Acta 2005;1736:30-7

  5. 5-LOX Genotype and IMT • A cohort of 470 healthy, middle-aged womenand men were genotyped for the commonallele and two variant alleles • Mean carotid IMT were significantly higher in carriers of two variant allele than in carriers of common alleles Dwyer JH. N Engl J Med2004;350:29-37

  6. Omega-3 Fatty Acid Intake and 5-LOX Genotype on IMT Dwyer JH. N Engl J Med2004;350:29-37

  7. 12-LOX and Atherosclerosis • Treatment of human aortic endothelial cells with 12S-HETE increased monocyte binding to endothelial cells - key step in development of atherosclerosis Yoshimoto T. Prostaglandins & other Lipid Mediators 2002; 68-69:245-62 Natarajan R. Arterioscler Thromb Vasc Biol 2004; 24:1524-1548

  8. 12-LOX Polymorphism and Hypertension • Patients with essential hypertension have increased levels of 12S-HETE and 12-LOX protein • R261Q in the coding region is associated with essential hypertension Quintana LF. Kidney Int 2006;69:526-30

  9. 15-LOX • 15-LOX is implicated in the development of atheroscleorosis • 15-HETE is often elevated in inflammation • A promoter variant -292C>T increases transcription by two fold Kuhn H. Prostaglandins & other Lipid Mediators 2002;68-69:263-290

  10. FLAP- 5-Lipoxygenase Activating Protein-a key enzyme in the Lipoxygenase Pathway

  11. Lipids in Cell Signaling FLAP

  12. 5-Lipoxygenase Activating Protein (FLAP)and CAD • FLAP is a membrane-associated protein which modulates the activities of 5-lipoxygenase- an enzyme which produces leukotrienes such as LTA4, LTB4, LTC4, LTD4, and LTE4. • Association of FLAP with CAD was first reported by -Helgadottir, A et al, in an Icelandic cohort. Nature Genetics 2004.

  13. 5-lipoxygenase activating protein (FLAP) • Helgadottir et al: a haplotype known as Hap A – (defined by four SNPs) confers increased activities to FLAP resulting in increased production of leukotrienes • Individuals with the Hap A of the FLAP gene has an increased risk for MI and Stroke (1.8 for MI and 2.0 for stroke). • (Nature Genetics: 36:233-39, 2004)

  14. DG031 – an Inhibitors of FLAP • DG031 was administered to individuals with Hap A genotype and CAD .(JAMA 293:2245-56, 2005) • In a randomized placebo-controlled cross-over trial, it was demonstrated that DG-031 is anti-inflammatory in individuals with CAD and the Hap A genotype : • Reduced leukotriene B4 by 26% • reduced CRP by 25%, • myeloperoxidase in plasma by 11%

  15. LOX Polymorphisms and Subclinical Markers of CAD---MESA Family • Subclinical parameters --CAC: calcium presence --AGA: : agatston calcium score --IMT_Maxcom: common carotid intimal-medial thickness --IMT_Maxint: internal carotid intimal-medial thickness

  16. LOX Polymorphisms and Markers of Inflammation--MESA Inflammatory markers --HS: heat shock protein (log transformed) --CRP: C-reactive protein (log transformed) --Fib: fibrinogen --IL-2sr: interleukin-2 soluble receptor (log transformed) --IL-6: interleukin-6 (log transformed) --TNF-α: tumor necrosis factor-α

  17. Additive Marginal Test --significant associations are shown as either (+): positive or (-): negative --CAC (absent vs present) OR are shown when significant for heterozygotes vs. wildtype and homozygotes vs. wildtype

  18. LOX5 * P <0.05 for additive marginal test in the entire cohort

  19. LOX5

  20. LOX5P (FLAP)

  21. LOX5AP (FLAP)

  22. LOX12 * P <0.01 for additive marginal test in overall population

  23. LOX12

  24. LOX15

  25. LOX15

  26. Summary • In LOX5, rs2288619 is positively associated with common carotid IMT in African Americans, and with internalcarotid IMT in European Americans and Hispanics • Rs892691 in LOX5 is negatively associated with fibrinogen and IL-6 in African Americans and with IL-6 in European Americans • In LOX5AP, rs12019512 is positively associated with internal carotid IMT, HS, IL-6 and TNF-α in African Americans, and with fibrinogen in European Americans

  27. Summary • In LOX12, rs11571342 is negatively associated with AGA in African Americans (P=0.052) and in Hispanics (P<0.05) • In LOX15, rs916055 is positively associated with CRP, IL-2sr and IL-6 in African Americans, and borderline significantly associated with CAC and CRP in European Americans

  28. Summary and Conclusion • These data are preliminary • Phenotypes include those available on the entire cohort and those on the MESA1000 • Different types of markers of inflammation were used in the analysis.

  29. Summary and Conclusion • A number of SNPS showed significant association with either subclinical markers and/or inflammation markers • Associations are for the most part ethnic-specific • Haplotype analysis may yield insight • Adding SNPS/Haplotypes reported in the literature may be helpful

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