The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

Abstract

NATURE GENETICS VOLUME 36 | NUMBER 3 | MARCH 2004 233Cardiovascular diseases (CVD) are the leading causes of death and disability in the developed world 1 , with an increasing prevalence due to the aging of the population and the obesity epidemic. More than 1 million deaths in the US alone were caused by myocardial infarction and stroke in 2003 (ref. 2). Some of the processes underlying myocardial infarction are now understood: it is generally attributed to atherosclerosis with arterial wall inflammation that ultimately leads to plaque rupture, fissure or erosion 3,4 . This process is known to involve diapedesis of monocytes across the endothelial barrier; activation of neutrophils, macrophage cells and platelets; and release of a variety of cytokines and chemokines 5,6 , but the genetic basis of the process has not yet been deciphered. Two different approaches have been used to search for genes associated with myocardial infarction. SNPs in candidate genes have been tested for association and have, in general, not been replicated or confer only a modest risk of myocardial infarction. Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect 7-9 . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 . This is an interesting cause of myocardial infarction, but the prevalence of this or other mutations in MEF2A outside this family remains to be determined.Here we report a genome-wide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction. Through suggestive linkage to a locus on chromosome 13q12-13, we identified the gene (ALOX5AP) encoding FLAP and found that a four-SNP haplotype in the gene confers a nearly two times greater risk of myocardial infarction and stroke. FLAP is a regulator 15 of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model 16 and in human studies 17,18 . Males had the strongest association to the at-risk haplotype, and male carriers of the at-risk haplotype also had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction. We confirmed the association of ALOX5AP with myocardial infarction in an independent cohort of British individuals with another haplotype. These results indicate that ALOX5AP is the first specific gene isolated that confers substantial population-attributable risk (PAR) of the complex traits of both myocardial infarction and stroke. We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13....

ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance

“…The CVD-associated haplotypes are observed with similar frequencies in the present and previous investigated populations. 16 This support that the haplotype structure is similar in studied populations. Furthermore, investigated obese subjects displayed a high frequency of insulin resistance as measured by HOMA IR .…”

“…16 We demonstrate that both the ALOX5AP protein FLAP and 5LO are present in fat cells. However, the quantitative comparison of gene expression suggests that ALOX5AP levels are lower in adipocytes than in stroma vascular cells of adipose tissue, such as macrophages and endothelial cells.…”

“…For this purpose, we genotyped 231 nonobese and 350 obese men for seven common SNPs defining two haplotypes previously shown to contribute to CVD. 16 Only men were studied since the association with CVD was much stronger in men than in women. As expected the obese men displayed more extensive insulin resistance syndrome phenotypes including high HOMA IR (7.476.6), low Pl-HDL cholesterol (1.170.3 mmol/l), and high Pl-triglycerides (2.171.2 mmol/l) as compared to nonobese men.…”

“…16 In the study by Helgadottir et al 16 ALOX5AP was shown to have a much stronger impact on CVD among men than women. Previously, FLAP has been reported to be primarily expressed in bone marrow-derived cells, and has been implicated in asthma and allergic disease (reviewed by Peters-Golden and Brock 17 ).…”

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

“…For example, we demonstrated that deficiency of the gene encoding 5-lipoxygenase (Alox5) in mice protects against the development of aortic lesions [3,4], and that promoter variants of the human ALOX5 gene are associated with increased carotid intima-media thickness [5]. Other groups have also reported findings that support the involvement of the 5-LO/LT pathway in CVD traits [6][7][8][9][10][11][12][13].…”