The LPA gene C93T polymorphism influences plasma lipoprotein(a) levels and is independently associated with susceptibility to peripheral arterial disease

Abstract

Background

Plasma lipoprotein(a) [Lp(a)] levels are mainly genetically determined. The C93T polymorphism is a naturally occurring variant of the LPA gene that may influence Lp(a) concentration. The role of Lp(a) in the pathogenesis of peripheral arterial disease (PAD) has not been firmly established.

Methods

A total of 299 patients with PAD and 312 PAD-free control subjects were investigated. Genotyping of the LPA C93T polymorphism was performed by means of PCR-RFLPs. Plasma Lp(a) levels were determined by ELISA.

Results

Subjects carrying at least one LPA 93T allele had lower Lp(a) levels. The prevalence rate of the 93T allele was significantly higher in control subjects (19.5%) than in PAD patients (13.0%, P = 0.012). In multivariate logistic regression analysis with covariates including traditional risk factors, the 93T allele was independently associated with a reduced risk of PAD (OR = 0.75, 95% CI = 0.51-0.95, P = 0.031).

Conclusion

The 93T allele of the LPA gene is associated with a reduced risk of PAD and low Lp(a) levels.

Introduction

Peripheral arterial disease (PAD) of the lower extremities, due to atherosclerosis occurring at the aortic bifurcation, femoral and popliteal arteries, affects approximately 27 million people in Europe and North America [1]. Despite advances in its treatment, the pathophysiology of PAD is not entirely elucidated. Several traditional risk factors such as diabetes mellitus, hypertension, smoking and hypercholesterolemia might contribute to the development of PAD [2]. Moreover, the possible role of lipoprotein alterations in the pathophysiology of PAD has attracted considerable interest [3], [4]. As a recent approach, numerous genetic factors in lipoprotein metabolism have been investigated, which alone or in combination with environmental factors, may have a role in the development of PAD [5], [6], [7], [8].

Lipoprotein(a) [Lp(a)] is a complex lipoprotein consisting of a low-density lipoprotein particle which is linked to apolipoprotein(a) [apo(a)] through a single disulfide bond [9]. Lp(a) shares a high degree of sequence identity with plasminogen and may exert atherogenic and thrombogenic effects [10]. Accordingly, Lp(a) may contribute to lipid deposition in the arterial walls and can delay clot lysis [11]. Plasma Lp(a) concentrations exhibit a high degree of heritability and are highly skewed in the general population [12]. Circulating concentrations of Lp(a) may be influenced by the size of the apo(a) isoform [13] and by genetic polymorphisms in the LPA gene on chromosome 6q27 [14], [15]. Ichinose and Kuriyama [16] have initially identified a functional C93T poymorphism (rs1853021) in the 5′ flanking region of the LPA gene that may affect Lp(a) synthesis. Accordingly, the carriage of the homozygous TT genotype may reduce LPA protein translation by 60%, thereby resulting in lower plasma Lp(a) levels [17].

Numerous studies have suggested that elevated Lp(a) levels could play a role in the development of PAD [18], [19], [20], [21]. In contrast, very limited data are available on the C93T polymorphism in the LPA gene as a potential genetic risk marker for PAD. Under these circumstances, we sought to investigate the possible pathogenic role of the C93T variant in the development of PAD in a retrospective case-control study.