Polymorphisms of genes involved in the hypoxia signaling pathway and the development of abdominal aortic aneurysms or large-artery atherosclerosis

Abstract

Background: The pathogenesis of aortic diseases, both aneurysmal and occlusive, is associated with the occurrence of local ischemic/hypoxic conditions, but the genetic factors that differentiate the predisposition to specific types of aortic diseases are largely unknown. In this study, the functional variants in genes involved in the hypoxia signaling pathway, hypoxia-inducible factor-1α (HIF1A) 1772C>T, 1790G>A, and vascular endothelial growth factor (VEGFA) -634G>C, were analyzed in search of the associations specific to abdominal aortic aneurysm (AAA) development.

Methods: The study encompassed a series of 518 patients with AAA, 354 patients with aortoiliac occlusive disease, and 541 controls. In AAA patients, the occurrence of peripheral arterial disease (PAD) was examined with duplex arterial scanning. Genotypes were determined by the polymerase chain reaction/restriction fragment length polymorphism method or with TaqMan probes.

Results: In univariate analysis, a significantly increased risk for development of AAA without coexisting PAD was found in VEGFA -634C allele carriers (effect of allele dose: odds ratio [OR], 1.38; P = .012). In VEGFA -634CC homozygotes, the risk was enhanced by the interaction with HIF1A 1772CC-1790GG genotype (OR, 2.41; P = .008). This joint effect of homozygous genotypes also influenced the AAA risk independently of PAD coexistence (OR, 1.87; P = .036). In contrast, the minor allele of the HIF1A 1772C>T polymorphism (1772T and 1772T-1790G haplotype) was significantly associated with the occurrence of AAA with concomitant PAD (OR, 2.02; P = .009 for the dominant model). This effect was enhanced in the VEGF -634GG homozygotes (OR, 2.86; P = .005) and among smokers (OR, 3.10; P = .001). The individual effects of the HIF1A 1772 and VEGFA -634 polymorphisms on AAA risk remained significant in multivariable analysis after adjustment for the traditional vascular risk factors and analyzed polymorphisms. None of the studied variants influenced the risk of aortoiliac occlusive disease.

Conclusions: This study identifies polymorphisms in the HIF1A and VEGF genes as potential genetic markers that indicate the predisposition to either AAA coexisting with peripheral atherosclerosis or AAA without such lesions, suggesting the genetic heterogeneity of this disease. The HIF1A 1772T allele also seems to be a genetic risk factor that determines sensitivity to cigarette smoke exposure. Further work is needed to confirm the findings in an independent samples set and to study the functional role of studied variants in AAA.