Association of Leukotriene Gene Variants and Plasma LTB4 Levels with Coronary Artery Disease in Asian Indians

Abstract

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 (76.42 ± 4.46 pg/mL versus 60.89 ± 2.61 pg/mL) ( = 0.003), 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; = 0.001). Four SNPs in the LTA4H gene showed significant association with LTB4 levels ( < 0.05) of which rs1978331 ( = 0.035) remained significant after correction for multiple testing. LTB4 showed strong correlation with lipids ( = 0.24-34) only in cases. Our pilot study suggests that the association between Leukotrienes gene polymorphisms and CAD risk may be modulated through plasma LTB4 levels.

Expression Analysis of Leukotriene-Inflammatory Gene Interaction Network in Patients with Coronary Artery Disease

“…The analysis of human atherosclerotic plaque has demonstrated an abundant expression of 5-LO, ALOX5AP, LTA4H and LTC4S genes on the arterial walls in patients with cardiovascular disease [13][14][15] . Our previous study 16) and other epidemiological reports have shown that genetic variants in the LTA4H gene are associated with a higher LTB4 level 17) . Taken together, these data suggest that leukotrienes elicit an immune response by augmenting the inflammatory gene expression.…”

“…Our pilot genetic association study showed that the plasma LTB4 level may modulate the risk of CAD 16) . Other functional studies have demonstrated increased LTB4 production in stimulated monocytes obtained from subjects carrying Haplotype K (HapK) of the LTA4H gene 50) .…”

“…We first selected all 16) were genotyped using Tm shift method on a 7900 HT Fast Real-time PCR instrument (Applied Biosystems, Foster City, USA).…”

Systemic Sclerosis: Elevated Levels of Leukotrienes in Saliva and Plasma Are Associated with Vascular Manifestations and Nailfold Capillaroscopic Abnormalities

“…In addition, it is postulated that intermittent hypoxia stimulates LTs synthesis and pro-inflammatory molecules derived from the 5-LO pathway and then lead to atherosclerosis, cardiac ischemia and reperfusion injury [45][46][47][48][49]. Some clinical studies have found higher urinary levels of LTE4 in patients with acute myocardial ischemia [50] and higher levels of plasmatic LTB4 in patients with coronary artery disease compared with healthy controls [51]. Nobili and colleagues [52] suggested that the vasoconstrictor and pro-inflammatory effects of chronic and acute CysLT signaling could aggravate myocardial hypoxia and inflammation during bouts of hypoxia in chronic ischemic heart disease.…”

Genetic and Epigenetic Regulation of Lipoxygenase Pathways and Reverse Cholesterol Transport in Atherogenesis

“…Another member of the leukotriene pathway, the LTA4H gene encoding leukotriene A4 hydrolase, confers a moderate risk of myocardial infarction [ 73 ]. Four single nucleotide polymorphisms (SNPs) in the LTA4H gene showed a significant association with levels of LTB4, which acts as a link to the risk of CHD [ 74 ]. In addition, the rs2540489 polymorphism in the LTA4H gene appears to be associated with ischemic stroke of the large arteries [ 75 ].…”