ALOX5AP Gene Variants and Risk of Coronary Artery Disease in Italy. An Angiography-Based Study.

The gene encoding Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP; GeneID: 241; chromosome: 13q12) represents the paradigm of a new class of promising genes identified by powerful genome-wide investigations (Helgadottir A, Nature Genetics 2004), that are currently object of intense studies to confirm their role as possible susceptibility factors for atherothrombosis. Indeed, ALOX5AP encodes the 5-Lipoxygenase-Activating Protein (FLAP; Miller DK, Nature 1990), an essential regulator of the 5-LO/leukotriene pathway, that has been recently implicated in the pathogenesis of atherothrombosis (Funk CD, Nature Review Drug Discovery 2005). We studied a total of 1,431 subjects with or without angiographically documented coronary artery disease (CAD). Seven ALOX5AP single-nucleotide polymorphisms (SG13S25, SG13S377, SG13S114, SG13S89, SG13S32, SG13S41, SG13S35) were examined simultaneously, allowing reconstruction of the at-risk haplotypes “HapA” and “HapB” previously identified in the Icelandic and in the British populations, respectively (Helgadottir A, Nature Genetics 2004). Using a haplotype-based approach, HapA was not associated with either CAD or myocardial infarction (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 subjects, and these associations remained significant after adjustment for traditional cardiovascular risk factors by logistic regression (HapB: OR 1.67, 95% CI 1.04 to 2.67; P=0.032; HapC: OR 2.41, 95% CI 1.09 to 5.32; P=0.030). No difference in haplotype distributions was observed between CAD patients with or without a previous documented MI. Adding our data to current knowledge, some evidence on ALOX5AP as a genetic susceptibility factor for CAD has now emerged in several independent populations (Icelandic, British, Japanese, and Italian). Our study, the first angiography-based to our knowledge, points out a possible role of ALOX5AP in the development of the atheroma rather than in its late complications such as MI.