5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia

doi:10.1016/j.atherosclerosis.2009.02.019

Atherosclerosis

Volume 206, Issue 1, September 2009, Pages 223-227

https://doi.org/10.1016/j.atherosclerosis.2009.02.019 Get rights and content

Abstract

Background

Tendon xanthomas are characteristic for familial hypercholesterolemia (FH), and are associated with a higher risk of coronary heart disease (CHD). They often present with local inflammation. Inflammation may therefore be involved in their pathogenesis, as it is in the pathogenesis of CHD. A key role in the inflammatory pathway is played by the 5-lipoxygenase activating protein (ALOX5AP), which is known to influence the risk of CHD in FH. To test our hypothesis that ALOX5AP contributes to the development of xanthomas, we studied whether variants in the ALOX5AP gene influence the risk of xanthomas.

Methods

We examined 945 patients with genetically confirmed heterozygous FH to determine whether they had tendon xanthomas. We genotyped seven polymorphisms in the ALOX5AP gene and constructed haplotypes of these polymorphisms.

Results

The A allele of the rs9551963 polymorphism was associated with an increased risk of xanthomas (OR 1.52, 95% CI 1.11–2.07, p = 0.01), while the A allele of rs17222842 was protective (OR 0.62, 95% CI 0.43–0.90, p = 0.01). These two polymorphisms fully explained the risk estimates of all haplotypes. Individual haplotypes, however, were not significantly associated with xanthomas.

Conclusion

Variants in the ALOX5AP gene are associated with the presence of xanthomas in FH patients. This result supports our hypothesis that inflammation is a pathogenetic factor of xanthomas.

Introduction

Familial hypercholesterolemia (FH) is an inherited disorder characterized by high plasma levels of low-density lipoprotein (LDL) cholesterol levels, tendon xanthomas, and premature coronary heart disease (CHD) [1]. Xanthomas are cholesterol deposits found at tendons and are pathognomonic for FH. The composition of xanthomas has many similarities to that of an atherosclerotic plaque, as they consist of connective tissue matrix and macrophages transformed into foam cells [2]. An association of xanthomas with a higher risk of CHD has been described and a number of drugs such as pravastatin can induce simultaneous regression of both xanthomas and atheromatous vascular lesions [3], [4], [5], [6], [7]. Therefore, xanthomas and atherosclerosis may share pathophysiological pathways.

The ‘response-to-injury’ theory emphasizes that atherosclerosis is a chronic inflammatory fibro-proliferative disease of the arterial wall [8]. In FH patients, there is indeed a chronic inflammation of the arterial walls [9], [10]. In addition, on physical examination xanthomas often exhibit signs of inflammation and they are associated with higher levels of plasma inflammatory mediators [11]. Recently we have also demonstrated that variation in the 5-lipoxygenase activating protein (ALOX5AP) gene is involved in CHD in FH [12]. The product of this gene is involved in inflammation by mediating the activity of 5-lipoxygenase (5-LO). 5-LO is a regulator of the biosynthesis of leukotrienes, which are pro-inflammatory lipid mediators secreted by inflammatory cells [13], [14]. The genes of the 5-LO inflammatory pathway, including ALOX5AP, are highly expressed in the arterial walls of patients with CHD [8]. In addition to observations in our FH cohort, involvement of ALOX5AP in CHD was also demonstrated in other populations [14], [15].

In the present study, we investigated whether or not variation in the ALOX5AP gene is associated with the presence of xanthomas in a large cohort of Dutch FH patients.

Section snippets

Study population

Heterozygous FH patients were recruited from 27 lipid clinics in The Netherlands between 1989 and 2002. Detailed information of the study design and population was described previously [16], [17]. In brief, when FH is suspected in a patient, DNA is routinely submitted to a central laboratory for LDL-receptor mutation analysis. A mutation was identified in 1382 patients of a random selection of 2400 unrelated FH patients. Of these patients with genetically confirmed FH, DNA was available of 945

Results

The general characteristics of the study population are shown in Table 1. The patients with xanthomas were older, had a higher BMI, and had higher total cholesterol and LDL cholesterol levels compared to those without xanthomas (p < 0.01). The prevalence of CHD was higher among the patients with xanthomas (p < 0.01, Table 1).

All polymorphisms were in Hardy–Weinberg equilibrium in the whole group with the exception of rs17216473 (p = 0.04). This is most probably a by chance finding, because this

Discussion

We have demonstrated that variation in the ALOX5AP gene influences the risk of xanthomas in FH patients. The A allele of the rs9551963 polymorphism of the ALOX5AP gene was associated with an increased risk of xanthomas in FH patients, while the A allele of the rs17222842 polymorphism was associated with a reduced risk of xanthomas.

Acknowledgement

This work was funded by the Dutch Heart Foundation (2006B190).

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Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Over the last decade, advances in data analysis, screening, diagnosis and cardiovascular risk stratification has significantly improved our ability to deliver precision medicine for these patients. Furthermore, recent updates on guideline recommendations and new therapeutic approaches have also proven to be highly beneficial. It is anticipated that both ongoing and upcoming clinical trials will offer further insights for the care and treatment of FH patients.
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These authors proposed that tendon xanthomas formation was associated with higher intracellular lipid content and higher inflammatory response of macrophages. In addition, Oosterveer et al [33] indicated that variants in the ALOX5AP (5-lipoxygenase activating protein) gene were associated with the presence of tendon xanthomas in FH patients. ALOX5AP is involved in the biosynthesis of leukotrienes by mediating the activity of 5-lipoxygenase.
Tendon pathology is a general term used to describe a group of musculoskeletal conditions related to tendons and surrounding structures. There is only limited evidence available regarding the exact aetiology and natural history of tendon pathology. In hypercholesterolaemia environments, lipids could accumulate within the extracellular matrix of the tendon and thus affect the mechanical properties of the tendon. Current evidence suggested that hypercholesterolaemia was an important risk factor in the development and progression of tendon pathology. The severity of hypercholesterolaemia was correlated with the severity of tendon pathology.
The translational potential of this article: Hypercholesterolaemia lead to the structural, inflammatory and mechanical changes in tendons, which predispose hypercholesterolaemia patients to a greater risk of tendon pathology. Measurements of serum cholesterol are suggested to be performed in patients presenting with tendon pathology. The strict control of hypercholesterolaemia would mitigate the development and progression of tendon pathology.
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It has been estimated that the presence of xanthomatas is associated with a three-fold higher risk of CHD in patients with FH suggesting that xanthomatas and CHD may share common pathophysiological mechanisms [28]. Recent studies have demonstrated that genetic variations in inflammation, reverse cholesterol transport and LDL oxidation pathways contribute to the risk of xanthomatas in FH [29,30]. The prevalence of TX in heFH patients in this study was comparable to that in heFH in Spain [19] and in Taiwan (29%) [21] but was much lower than that in Japanese (88%) although Japanese FH patients had lower average LDL-C levels (6.4 mmol/L in both males and females) than that in Hong Kong [20].
Earlier studies reported that Chinese subjects with heterozygous familial hypercholesterolemia (heFH) living in Mainland China or in Western countries had lower plasma low-density lipoprotein cholesterol (LDL-C) levels and lower prevalence of xanthomata or coronary heart disease (CHD) than Caucasians with heFH and a greater proportion went unrecognized. We characterized the features of Hong Kong Chinese with heFH identified by cascade screening.
Potential probands with primary hypercholesterolemia manifesting total cholesterol (TC) greater than 7.5 mmol/L or LDL-C greater than 4.9 mmol/L were selected from a lipid clinic in a public hospital in Hong Kong. After screening of 132 unrelated potential probands and their relatives, 252 subjects from 87 pedigrees were clinically diagnosed as heFH.
In 252 heFH patients (mean age 37 ± 17 years, 100 males), the plasma TC and LDL-C were 9.1 ± 1.5 mmol/L and 7.2 ± 1.5 mmol/L, respectively. In subjects aged ≥ 18 years, the prevalence of xanthomata and corneal arcus was 40.6% and 81.2% in males, and 54.8% and 66.9% in females respectively. The overall incidence of CHD was 9.9% in males and 8.5% in females in patients aged over 18 years with CHD history available. Multiple logistic regression analysis showed that advanced age and presence of xanthelasmata were significantly associated with increased risk of CHD.
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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.
Tendon xanthomas are characteristic of familial hypercholesterolemia (FH). It is not clear whether FH patients with xanthomas have higher risk of cardiovascular disease (CVD) than those without xanthomas. The clinical diagnosis of FH in patients without xanthomas, namely requires the presence of CVD in the patient or in a first-degree relative. This may have masked the association between xanthomas and CVD in a number of studies. A diagnosis of FH based on the presence of a mutation in the low-density lipoprotein receptor (LDLR) gene is free from this selection on CVD. In this systematic review and meta-analysis, we therefore compared the risk of CVD between patients heterozygous for LDLR mutation with and without xanthomas.
We conducted a literature search with PubMed and the Web of Science up to January 14, 2009. We selected all articles examining more than 25 human heterozygous FH patients, that provided information about xanthomas. Articles had to be written in a Western European language. A total of 22 articles suited for analyses. A genetic confirmation of FH was compulsory to correctly assess the risk of CVD with presence of xanthomas. Age, male gender, LDL-cholesterol and triglyceride level were associated with the presence of xanthomas (p < 0.05 for all). In patients with genetically confirmed FH, xanthomas were associated with a 3.20-fold higher risk of CVD (95% CI 2.12–4.82, p < 0.01).
Xanthomas are associated with a 3 times higher risk of CVD among FH patients, suggesting that xanthomas and CVD may share etiology.

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5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Results

Discussion

Acknowledgement

Free Radic Biol Med

J Lipid Res

FEBS Lett

Atherosclerosis

J Clin Epidemiol

Am J Hum Genet

Am J Hum Genet

Atherosclerosis

Mechanisms of disease: genetic causes of familial hypercholesterolemia

Nat Clin Pract

Interaction of collagen with the lipids of tendon xanthomata

J Clin Invest

l-Arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice

Circulation

Preventive effect of pravastatin sodium, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on coronary atherosclerosis and xanthoma in WHHL rabbits

Biochim Biophys Acta

Effect of probucol on macrophages, leading to regression of xanthomas and atheromatous vascular lesions

Am J Cardiol

Diagnosing familial hypercholesterolaemia: the relevance of genetic testing

Eur Heart J

Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation

Arterioscler Thromb Vasc Biol