ALOX5AP gene variants and risk of coronary artery disease: an angiography-based study

Abstract

The aim of this study was to explore the role of variants of the gene encoding arachidonate 5-lipoxygenase-activating protein (ALOX5AP) as possible susceptibility factors for coronary artery disease (CAD) and myocardial infarction (MI) in patients with or without angiographically proven CAD. A total of 1431 patients with or without angiographically documented CAD were examined simultaneously for seven ALOX5AP single-nucleotide polymorphisms, allowing reconstruction of the at-risk haplotypes (HapA and HapB) previously identified in the Icelandic and British populations. Using a haplotype-based approach, HapA was not associated with either CAD or MI. On the other hand, HapB and another haplotype within the same region (that we named HapC) were significantly more represented in CAD versus CAD-free patients, and these associations remained significant after adjustment for traditional cardiovascular risk factors by logistic regression (HapB: odds ratio (OR) 1.67, 95% confidence interval (CI) 1.04 -2.67; P ¼ 0.032; HapC: OR 2.41, 95% CI 1.09-5.32; P ¼ 0.030). No difference in haplotype distributions was observed between CAD subjects with or without a previously documented MI. Our angiography-based study suggests a possible modest role of ALOX5AP in the development of the atheroma rather than in its late thrombotic complications such as MI.

Targeted deep resequencing of ALOX5 and ALOX5AP in patients with diabetes and association of rare variants with leukotriene pathways

“…In previous epidemiological correlation studies, common genetic variations, predominantly in the untranslated regions, in ALOX genes have been associated with an increased risk of colorectal cancer, stroke, bronchial asthma and atherosclerosis (2,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). To the best of our knowledge, the present study is the first to conduct a complete resequencing of the two LT pathway genes ALOX5 and ALOX5AP in patients with diabetes and receiving ASA therapy, and its association with LT metabolite production.…”

“…Another previous study reported that potentially damaging variants are present in pedigrees with inherited platelet function disorders and may contribute to complex laboratory phenotypes (46). The genetic variants involved in the function of ALOX5 and ALOX5AP were described previously with mixed results regarding their involvement in the regulation of LT metabolism or vascularity, including platelet functions (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, the majority of previous studies have investigated the common polymorphic variants in the ALOX5 and ALOX5AP genes, as neither gene exhibits any significant common variants in their coding sequences.…”

“…in patients with diabetes and association of rare variants with leukotriene pathways in Caucasian populations) and the other variants are either rare or even private (7)(8)(9)11,12,(14)(15)(16)(17)(18). This situation has lead to the use of a number of common polymorphisms in the untranslated sequences of these genes as the potential proxies for the coding parts (14)(15)(16)(17).…”

“…This situation has lead to the use of a number of common polymorphisms in the untranslated sequences of these genes as the potential proxies for the coding parts (14)(15)(16)(17). The majority of these studies (including one from our laboratory) have produced no significant evidence of an association between investigated polymorphisms in the ALOX5 and ALOX5AP genes and the 5-LOX pathway, when investigated using measurement of different LT products, including LTB 4 and LTE 4 (7)(8)(9)11,12,(14)(15)(16)(17)(18). Therefore, the aim of the present study was to determine whether there is association between the accumulation of rare coding variants in ALOX5 and ALOX5AP and LT and the production of its associated metabolites.…”

“…In leukocytes, ALOX5 and ALOX5-activating protein (ALOX5AP), initialize the biosynthesis of LTs from AA (2)(3)(4)(5)(6). Previous studies indicate that a number of genetic variants in LT pathway genes may modulate LT production, metabolism and response (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). In addition, genetic linkage and association studies, in addition to gene expression studies, have indicated an association between the ALOX5/ALOX5AP pathway and cardiovascular disease (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”