Leukotrienes are potent inflammatory and lipid mediators that participate in atherosclerosis. We analyzed the association of Leukotriene gene (ALOX5, ALOX5AP, LTA4H, and LTC4S) polymorphisms and plasma Leukotriene B4 (LTB4) levels with coronary artery disease (CAD) in a representative cohort of Asian Indians. In all, 136 functional single nucleotide polymorphisms (SNPs) were selected using in silico tools. Forty-five polymorphic SNPs were ranked for predicted functional effect using FastSNP. Finally, 14 functional SNPs along with 10 SNPs identified from the literature were genotyped in 340 CAD patients and 340 controls. Plasma LTB4 levels were measured in 150 cases and 150 controls. None of the 24 SNPs showed significant association with CAD. Plasma LTB4 levels were higher in cases than in controls ( ？pg/mL versus ？pg/mL) ( ), with greater risk being associated with the top quartile as compared to the bottom quartile after adjusting for potential confounders (OR 8.94, 95% CI 2.56–31.95; ). Four SNPs in the LTA4H gene showed significant association with LTB4 levels ( ) of which rs1978331 ( ) remained significant after correction for multiple testing. LTB4 showed strong correlation with lipids ( –34) only in cases. Our pilot study suggests that the association between Leukotrienes gene polymorphisms and CAD risk may be modulated through plasma LTB4 levels. 1. Introduction Both genetics and environmental factors combined with unhealthy lifestyle play an important role in the development of coronary artery disease (CAD) [1]. Hypercholesterolemia and inflammation are two key players in CAD [2]. Leukotrienes act as mediators in the lipid and inflammatory pathway and are synthesized from Arachidonic acid through a cascade process in immune-competent cells. During this process, 5-lipoxygenase (ALOX5) in association with 5-LO activating protein (ALOX5AP), metabolizes Arachidonic acid to Leukotriene A4 (LTA4). LTA4 is unstable and is further converted to Leukotriene B4 (LTB4) and Cysteinyl Leukotrienes (LTC4, LTD4, and LTE4) by LTA4 Hydrolase (LTA4H) and LTC4 Synthase (LTC4S) enzymes, respectively [3]. These Leukotrienes then modulate immune response by triggering the synthesis and release of cytokines and interacting with their cognate receptors [4]. Leukotrienes are known to play a significant role in CAD development, based on biochemical, genetic, and pharmacological studies [5–7]. Immunohistochemical studies demonstrate abundant expression of Leukotrienes on the arterial walls [8, 9], which correlate with symptoms of plaque instability [10]. Population
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