ARS | Publication request: Genetic contribution of the leukotriene pathway to coronary artery disease

Submitted to: Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 27, 2011
Publication Date: June 1, 2011
Citation: Hartiala, J., Li, D., Conti, D.V., Vikman, S., Patel, Y., Tang, W., Brennan, M., Newman, J.W., Stephensen, C.B., Armstrong, P., Hazen, S.L., Allayee, H. 2011. Genetic contribution of the leukotriene pathway to coronary artery disease. Human Genetics. 129(6):617-627.

Interpretive Summary: Risk of heart disease is influenced by a variety of factors, including both diet and genetics. This paper shows that normally occurring, common variants in genes of the leukotriene synthesis pathway are associated with risk of heart disease. This pathway produces mediators of inflammation that influence the formation of arterial plaque, thus modulating the risk of a heart attack. These mediators are produced from fatty acids found in the diet, thus dietary interventions can reduce the risk of heart disease and this reduced risk is mediated via effects on the same leukotriene synthesis pathway. The implication of this study is that certain common gene variants increase the risk of heart disease but these findings also suggest that improvements in diet quality may help reduce this risk for subjects with high-risk gene variants.

Technical 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.