Elsevier

Atherosclerosis

Volume 203, Issue 2, April 2009, Pages 472-478
Atherosclerosis

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia

https://doi.org/10.1016/j.atherosclerosis.2008.07.025Get rights and content

Abstract

Objectives

To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH).

Background

The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH.

Methods

In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking.

Results

HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17–1.89, p = 0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20–2.76, p = 0.005). HapA was not associated with CHD.

Conclusion

We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.

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)

  • E.S. van Aalst-Cohen et al.

    Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia

    Semin Vasc Med

    (2004)
  • E.J. Sijbrands et al.

    Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study

    BMJ

    (2001)
  • M.A. Umans-Eckenhausen et al.

    Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population

    Circulation

    (2002)
  • A.C. Jansen et al.

    Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia

    Arterioscler Thromb Vasc Biol

    (2005)
  • R.A. Dixon et al.

    Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis

    Nature

    (1990)
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