Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia
Introduction
Familial hypercholesterolemia (FH) is an autosomal dominant disorder commonly caused by mutations in the low-density lipoprotein (LDL) receptor gene [1]. Coronary heart disease (CHD) is the major burden of FH [2], but there is considerable variation in the onset of CHD and all-cause mortality among FH patients [3], [4]. In addition to classical risk factors, modifier genes may be of importance in determining the risk of CHD in FH [5], [6].
The 5-lipoxygenase-activating protein (FLAP), encoded by the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene, is an important mediator of the activity of 5-lipoxygenase, a key enzyme in the biosynthesis of leukotrienes [7]. Leukotrienes are proinflammatory eicosanoid signaling molecules that are produced by inflammatory cells from omega-3 and omega-6 fatty acid precursors [8]. Because it has been suggested that the arterial wall of hypercholesterolemic patients is continuously subjected to an inflammatory challenge [9], [10], the ALOX5AP gene could be an important candidate gene for CHD in FH patients. The accumulating evidence that atherosclerosis, the main cause of CHD, is a chronic inflammatory disorder supports this notion [11].
Previous studies have indicated that genetic variation in the ALOX5AP gene is associated with myocardial infarction (MI), the main complication of CHD [12], [13]. Haplotype HapA, which is defined by four single nucleotide polymorphisms and spans the ALOX5AP gene, was associated with MI and stroke in an Icelandic population, and another haplotype HapB (also based on four polymorphisms), was associated with MI in British cohorts [12]. In subsequent studies, HapB has been replicated in other Caucasian populations: a significant association was found with CHD in an Italian cohort [14] and with MI in a German case-control study [15].
Because of the high prevalence of CHD and the proposed chronic inflammatory state of the arterial wall in individuals with FH, the ALOX5AP gene may influence the clinical consequences of FH. The aim of the present study was to investigate the association between CHD and genetic variation in this potential modifier gene of CHD risk in a large FH population.
Section snippets
Study design, population and data collection
We performed a multicenter cohort study of heterozygous FH patients who were recruited from 27 lipid clinics in the Netherlands between 1989 and 2002. More detailed information on the study design and the study population was published previously [16], [17]. In brief, the DNA of suspected FH individuals from Dutch lipid clinics is routinely submitted to a central laboratory for LDL-receptor-mutation analysis. We randomly selected 2400 unrelated FH individuals who fulfilled the internationally
Patient characteristics
Haplotyping was successful for 1817 FH patients, due to missing genotype data in the remaining patients. These remaining patients did not differ from the group in the analysis with regard to CHD or cardiovascular risk factors (data not shown). The clinical characteristics of the patients are presented in Table 1 together with the cumulative risk of CHD at the age of 40, 50, and 60 years. During a total of 90,473 person years, 514 patients had at least one CHD event (mean incidence rate: 5.7 new
Discussion
In the present study, we have shown that genetic variation within the ALOX5AP gene is associated with CHD in FH patients. Both HapB and Hap6 were associated with an increased risk of CHD in our FH population, and the patients with more severely raised LDL cholesterol levels contributed mainly to these associations.
With these findings we have validated HapB as a CHD risk factor. This haplotype was found to be associated with MI in a British cohort study with a haplotype frequency of 4.0% in the
Funding
This work was supported by grants from the Dutch Heart Foundation (2006B190 and 2007R017), the Foundation ‘Vereniging Trustfonds Erasmus Universiteit Rotterdam’ in the Netherlands (J.B.N.), the American Heart Association (0655195Y to C.R.P.), the Hellman Family Award (C.R.P.), the Leducq Foundation (C.R.P., M.J.M. and J.P.K.), and the NCRR (KL2RR024130 to B.E.A.), a component of the NIH. These funding sources were not involved in study design; in the collection, analysis, or interpretation of
References (30)
- et al.
Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia
Atherosclerosis
(2000) - et al.
Lipoxygenase pathways in atherogenesis
Trends Cardiovasc Med
(2004) - et al.
Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide
Free Radic Biol Med
(2002) - et al.
Guidelines were developed for data collection from medical records for use in retrospective analyses
J Clin Epidemiol
(2005) - et al.
A new statistical method for haplotype reconstruction from population data
Am J Hum Genet
(2001) - et al.
No association of polymorphisms in the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a large central European population
Genet Med
(2007) - et al.
Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe
Atherosclerosis
(2003) - et al.
Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects
J Lipid Res
(2007) - et al.
Oxidized low density lipoprotein increases U937 cell 5-lipoxygenase activity: induction of 5-lipoxygenase activating protein
Biochem Biophys Res Commun
(1994) - et al.
Familial hypercholesterolemia
Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia
Semin Vasc Med
Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study
BMJ
Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population
Circulation
Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia
Arterioscler Thromb Vasc Biol
Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis
Nature
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2010, Archives of Medical ResearchCitation Excerpt :One article studied the association with in-stent restenosis after percutaneous coronary intervention (30). There were 12 articles that met the inclusion criteria (5–16). Helgadottir et al. (5) reported two cohorts.
Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: A systematic review and meta-analysis
2009, AtherosclerosisCitation Excerpt :This is supported by a number of findings: xanthomas and atherosclerotic plaques both consist of collagen and foam cells [18]; a number of drugs like probucol and statins, induce simultaneous regression and prevention of both xanthomas and atheromatous vascular lesions [19–21]; and macrophages of FH patients with xanthomas have a higher predisposition to form foam cells in response to oxidized LDL-C than macrophages from FH patients without xanthomas [22]. Recently, we have demonstrated that variation in the 5-lipoxygenase activating protein (ALOX5AP) gene, involved in inflammation, is associated with both xanthomas and CHD [40,41]. This accumulation of circumstantial evidence suggests that in addition to diagnostic value, the presence of xanthomas may indicate severe risk of CVD and point at a pleiotrophic expression of risk factors of CVD in patients with FH.
5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia
2009, AtherosclerosisCitation Excerpt :Furthermore, haplotype HapB8, in which the A allele of rs17222842 of HapB9 is replaced by the G allele of this polymorphism, results in an increased risk. This higher risk of CVD in carriers of HapB8 also has been confirmed in our FH cohort and in the general population [12,15,21,26,29]. We had limited power to perform haplotype analysis in the present study.