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

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% Cl 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. (C) 2009 Elsevier Ireland Ltd. All rights reserved.